Purpose: Large-scale sequencing efforts have established that cancer-associated genetic alteratio... more Purpose: Large-scale sequencing efforts have established that cancer-associated genetic alterations are highly diverse, posing a challenge to the identification of variants that regulate complex phenotypes like radiation sensitivity. The impact of the vast majority of rare or common genetic variants on the sensitivity of cancers to radiotherapy remains largely unknown. Experimental Design: We developed a scalable gene editing and irradiation platform to assess the role of categories of variants in cells. Variants were prioritized on the basis of genotype–phenotype associations from a previously completed large-scale cancer cell line radiation profiling study. Altogether, 488 alleles (396 unique single-nucleotide variants) from 92 genes were generated and profiled in an immortalized lung cell line, BEAS-2B. We validated our results in other cell lines (TRT-HU1 and NCI-H520), in vivo via the use of both cell line and patient-derived murine xenografts, and in clinical cohorts. Results:...
Chemokine (C-C motif) receptor 7 (CCR7), a class A subtype G-Protein Coupled Receptor (GPCR), is ... more Chemokine (C-C motif) receptor 7 (CCR7), a class A subtype G-Protein Coupled Receptor (GPCR), is involved in the migration, activation and survival of multiple cell types includ-ing dendritic cells, T cells, eosinophils, B cells, endothelial cells and different cancer cells. Together, CCR7 signaling system has been implicated in diverse biological processes such as lymph node homeostasis, T cell activation, immune tolerance, inflammatory re-sponse and cancer metastasis. CCL19 and CCL21, the two well-characterized CCR7 lig-ands, have been established to be differential in their signaling through CCR7 in multiple cell types. Although the differential ligand signaling through single receptor have been suggested for many receptors including GPCRs, there exists no resource or platform to analyse them globally. Here, first of its kind, we present the cell-type-specific differential signaling network of CCL19/CCL21-CCR7 system for effective visualization and differen-tial analysis of chemo...
International Journal of Radiation Oncology*Biology*Physics, 2020
observed in both groups, but there was no difference in the extent of this decrease between two g... more observed in both groups, but there was no difference in the extent of this decrease between two groups. Conclusion: Compared with the concurrent combination, RT with sequential anti-PD-1 mAb is more effective in promoting the inflammatory tumor microenvironment in out-field tumors and inducing the abscopal effect, which provides a new perspective for further exploring the mechanism of optimal timing of combination. Funding:
e20587 Background: Small cell lung carcinoma (SCLC) is an aggressive, tobacco-associated tumor wi... more e20587 Background: Small cell lung carcinoma (SCLC) is an aggressive, tobacco-associated tumor with neuroendocrine features characterized by rapid growth, metastatic progression, and initial response followed by almost invariable resistance to therapy. Studies to date have not resolved the extent that diverse transcriptional programs drive SCLC and contribute to its lethality. Methods: We combined one of the largest and most diverse inventories of patient-derived xenograft models of SCLC with an ex vivo culture system that maintains transcriptional fidelity with matched primary SCLC tumor to identify transcriptional state heterogeneity. Using the expression of the Ascl1, NeuroD1, and Yap1 as markers of well-conserved SCLC states, we developed a state-of-the-art fluorescent platform that can directly measure single-cell state transitions in a multi-layered ecosystem using tandemly integrated reporters. We modeled population dynamics using a discrete time Markov chain and directly mea...
3129Background: The impact of common or rare gene mutations on the sensitivity of cancers to ioni... more 3129Background: The impact of common or rare gene mutations on the sensitivity of cancers to ionizing radiation remains largely unknown. We conducted a systematic, arrayed (single variant per well)...
TET2 is frequently mutated in myeloid neoplasms. Genetic TET2 deficiency leads to skewed myeloid ... more TET2 is frequently mutated in myeloid neoplasms. Genetic TET2 deficiency leads to skewed myeloid differentiation and clonal expansion, but minimal residual TET activity is critical for survival of neoplastic progenitor and stem cells. Consistent with mutual exclusivity of TET2 and neomorphic IDH1/2 mutations, here we report that IDH1/2 mutant–derived 2-hydroxyglutarate is synthetically lethal to TET dioxygenase–deficient cells. In addition, a TET-selective small-molecule inhibitor decreases cytosine hydroxymethylation and restricted clonal outgrowth of TET2 mutant but not normal hematopoietic precursor cells in vitro and in vivo. Although TET inhibitor phenocopied somatic TET2 mutations, its pharmacologic effects on normal stem cells are, unlike mutations, reversible. Treatment with TET inhibitor suppresses the clonal evolution of TET2-mutant cells in murine models and TET2-mutated human leukemia xenografts. These results suggest that TET inhibitors may constitute a new class of tar...
International Journal of Radiation Oncology*Biology*Physics, 2021
PURPOSE/OBJECTIVE(S) The impact of common or rare gene mutations on the sensitivity of cancers to... more PURPOSE/OBJECTIVE(S) The impact of common or rare gene mutations on the sensitivity of cancers to ionizing radiation remains largely unknown. We conducted a systematic, arrayed (single variant per well) profiling effort to identify gene mutations that alter cellular sensitivity to radiation and validated some of our findings using a clinical cohort of patients who received thoracic radiotherapy alone. MATERIALS/METHODS Candidate mutations were prioritized on the basis of genotype-phenotype associations from our previously completed large-scale cancer cell line irradiation profiling study (doi: 10.1038/ncomms11428), location within conserved protein domains, and functional impact. We used site-directed mutagenesis to generate mutant clones (2 clones per variant) and transferred the ORFs into lentiviral vectors in SV40 lung primary immortalized cells (BEAS2B). For clinical validation, an IRB-approved study was used to identify patients treated with lung radiotherapy alone. 197 patients with primary (stage I-IV) or recurrent lung cancer and patients with other cancer types and solitary metastases or oligometastases to the lung were included. Death without evidence of local failure was treated as a competing event, and Fine and Gray regression modeling was used to examine potential predictors of local failure. RESULTS Over 600 cancer variants were tested in ∼1200 experimental replicates, comprising 91 genes. We identified known and new radioresistant and radiosensitive variants involved in several cellular functional categories including cellular signaling, cytoskeleton, cell cycle, apoptosis, DNA methylation, and DNA repair. Variants that conferred resistance in BEAS2B cells were significantly more likely to confer resistance in TERT-HU1 and NCI-H520 cells, suggesting that most functional variants are cellular context indifferent. Variants under somatic oncogenic selection (hotspot mutants) were significantly more likely to confer resistance to radiation. Several infrequent cancer variants (< 1% prevalence in cancer), including those in ERBB3, SMAD4, TGFBR1, VHL, CTNNB1, and MAP2K1, conferred radiation resistance. Some genes (e.g., KEAP1) demonstrated significant intragenic allelic variation in the magnitude of conferred resistance and other genes (e.g., CTNNB1) displayed both resistance and sensitivity in a protein domain-dependent manner. KRAS (resistant; HR 2.23; P = 0.02) and CTNNB1 exon 3 (sensitive; HR 0.3; P = 0.04) mutants conferred resistance and sensitivity, respectively, to radiotherapy in our clinical cohort. CONCLUSION We report on a large-scale profiling effort to identify mutant alleles that govern radiation survival. Our results reveal new insights into potentially actionable determinants of tumor sensitivity to radiotherapy and accelerate clinical validation of common and rare gene mutations that impact radiation sensitivity.
Molecular determinants governing the evolution of tumor subclones toward phylogenetic branches or... more Molecular determinants governing the evolution of tumor subclones toward phylogenetic branches or fixation remain unknown. Using sequencing data, we model the propagation and selection of clones expressing distinct categories of BRAF mutations to estimate their evolutionary trajectories. We show that strongly activating BRAF mutations demonstrate hard sweep dynamics, whereas mutations with less pronounced activation of the BRAF signaling pathway confer soft sweeps or are subclonal. We use clonal reconstructions to estimate the strength of “driver” selection in individual tumors. Using tumors cells and human-derived murine xenografts, we show that tumor sweep dynamics can significantly affect responses to targeted inhibitors of BRAF/MEK or DNA damaging agents. Our study uncovers patterns of distinct BRAF clonal evolutionary dynamics and nominates therapeutic strategies based on the identity of the BRAF mutation and its clonal composition.
Targeted α-particle–emitting radionuclides have great potential for the treatment of a broad rang... more Targeted α-particle–emitting radionuclides have great potential for the treatment of a broad range of cancers at different stages of progression. A platform that accurately measures cancer cellular sensitivity to α-particle irradiation could guide and accelerate clinical translation. Here, we performed high-content profiling of cellular survival following exposure to α-particles emitted from radium-223 (223Ra) using 28 genetically diverse human tumor cell lines. Significant variation in cellular sensitivity across tumor cells was observed. 223Ra was significantly more potent than sparsely ionizing irradiation, with a median relative biological effectiveness of 10.4 (IQR: 8.4–14.3). Cells that are the most resistant to γ radiation, such as Nrf2 gain-of-function mutant cells, were sensitive to α-particles. Combining these profiling results with genetic features, we identified several somatic copy-number alterations, gene mutations, and the basal expression of gene sets that correlated...
Tumors have genetically distinct subclones that compete for space and resources and differentiall... more Tumors have genetically distinct subclones that compete for space and resources and differentially resist efforts to make them extinct. We studied the intratumoral heterogeneity of BRAF mutations across several cancer types. We identified BRAF driver mutations as predominately clonal in some cancer types (e.g. melanoma) and subclonal in others (e.g. lung adenocarcinoma). Clonality corresponded to the amplification of BRAF and prevalence of V600 mutations in each cancer type. We mathematically and experimentally modeled the propagation and selection of tumors containing BRAF mutations and determined that the speed of clonal sweeps were associated with the extent of activation of MAPK signaling pathway and BRAF copy number. Consistent with these findings, tumors with "hard" sweeps were more likely to respond to BRAF and/or MEK inhibitors. Furthermore, some PDX models treated with cytotoxic therapy underwent BRAF mutant subclone expansion over time and this effect is mitigate...
The identification of malignant cells in pleural fluid has critical prognostic and therapeutic im... more The identification of malignant cells in pleural fluid has critical prognostic and therapeutic implications but is frequently a diagnostic challenge. The first step in determining the cause of a suspected malignant pleural effusion, thoracentesis, has an unsatisfying low sensitivity (~60-70%). Patient-derived xenografts (PDX) retain the principal characteristics of the tumor of origin. However, there has been little progress in the application of these models to guide diagnostic and staging strategies. We assessed the feasibility, cellular yield and comparative diagnostic accuracy of pleural-derived xenografts in patients with effusions. An institutional review board-approved single-institution prospective registry of patients was used to identify patients undergoing diagnostic and/or therapeutic thoracentesis. Cells isolated from the pleural fluid of these patients were injected into NSG mice. A diagnosis of the cancer in the xenograft was confirmed by a staff pathologist with expe...
It is increasingly apparent that tumors represent dynamic structures in which cell populations, d... more It is increasingly apparent that tumors represent dynamic structures in which cell populations, defined by genetic, epigenetic and non-genetic variation, compete for space and resources, while attempting to evade host defenses, resist therapeutic interventions and colonize new environments. Yet, the extent of this intratumoral genetic heterogeneity and the rules governing this ecosystem remain largely unknown. Using a large inventory of patient-derived xenograft models and an ex vivo culture system that maintains the transcriptional fidelity of the primary tumors, we have interrogated small cell lung cancer (SCLC) as a tractable model system for studying tumor evolution. In the process, we have identified at least three morphologically distinct intratumoral subpopulations across several samples: (i) suspended aggregates of small cells (neuroendocrine or NE), (ii) larger, pleomorphic cells with visible cytoplasm and spindle-like membrane extensions growing as a monolayer (mesenchymal...
There has been little progress in the use of patient-derived xenografts (PDX) to guide individual... more There has been little progress in the use of patient-derived xenografts (PDX) to guide individual therapeutic strategies. In part, this can be attributed to the operational challenges of effecting successful engraftment and testing multiple candidate drugs in a clinically workable timeframe. It also remains unclear whether the ancestral tumor will evolve along similar evolutionary trajectories in its human and rodent hosts in response to similar selective pressures (i.e., drugs). Herein, we combine a metastatic clear cell adenocarcinoma PDX with a timely 3 mouse 1 drug experimental design, followed by a co-clinical trial to longitudinally guide a patient's care. Using this approach, we accurately predict response to first- and second-line therapies in so far as tumor response in mice correlated with the patient's clinical response to first-line therapy (gemcitabine/nivolumab), development of resistance and response to second-line therapy (paclitaxel/neratinib) before these e...
Purpose: Large-scale sequencing efforts have established that cancer-associated genetic alteratio... more Purpose: Large-scale sequencing efforts have established that cancer-associated genetic alterations are highly diverse, posing a challenge to the identification of variants that regulate complex phenotypes like radiation sensitivity. The impact of the vast majority of rare or common genetic variants on the sensitivity of cancers to radiotherapy remains largely unknown. Experimental Design: We developed a scalable gene editing and irradiation platform to assess the role of categories of variants in cells. Variants were prioritized on the basis of genotype–phenotype associations from a previously completed large-scale cancer cell line radiation profiling study. Altogether, 488 alleles (396 unique single-nucleotide variants) from 92 genes were generated and profiled in an immortalized lung cell line, BEAS-2B. We validated our results in other cell lines (TRT-HU1 and NCI-H520), in vivo via the use of both cell line and patient-derived murine xenografts, and in clinical cohorts. Results:...
Chemokine (C-C motif) receptor 7 (CCR7), a class A subtype G-Protein Coupled Receptor (GPCR), is ... more Chemokine (C-C motif) receptor 7 (CCR7), a class A subtype G-Protein Coupled Receptor (GPCR), is involved in the migration, activation and survival of multiple cell types includ-ing dendritic cells, T cells, eosinophils, B cells, endothelial cells and different cancer cells. Together, CCR7 signaling system has been implicated in diverse biological processes such as lymph node homeostasis, T cell activation, immune tolerance, inflammatory re-sponse and cancer metastasis. CCL19 and CCL21, the two well-characterized CCR7 lig-ands, have been established to be differential in their signaling through CCR7 in multiple cell types. Although the differential ligand signaling through single receptor have been suggested for many receptors including GPCRs, there exists no resource or platform to analyse them globally. Here, first of its kind, we present the cell-type-specific differential signaling network of CCL19/CCL21-CCR7 system for effective visualization and differen-tial analysis of chemo...
International Journal of Radiation Oncology*Biology*Physics, 2020
observed in both groups, but there was no difference in the extent of this decrease between two g... more observed in both groups, but there was no difference in the extent of this decrease between two groups. Conclusion: Compared with the concurrent combination, RT with sequential anti-PD-1 mAb is more effective in promoting the inflammatory tumor microenvironment in out-field tumors and inducing the abscopal effect, which provides a new perspective for further exploring the mechanism of optimal timing of combination. Funding:
e20587 Background: Small cell lung carcinoma (SCLC) is an aggressive, tobacco-associated tumor wi... more e20587 Background: Small cell lung carcinoma (SCLC) is an aggressive, tobacco-associated tumor with neuroendocrine features characterized by rapid growth, metastatic progression, and initial response followed by almost invariable resistance to therapy. Studies to date have not resolved the extent that diverse transcriptional programs drive SCLC and contribute to its lethality. Methods: We combined one of the largest and most diverse inventories of patient-derived xenograft models of SCLC with an ex vivo culture system that maintains transcriptional fidelity with matched primary SCLC tumor to identify transcriptional state heterogeneity. Using the expression of the Ascl1, NeuroD1, and Yap1 as markers of well-conserved SCLC states, we developed a state-of-the-art fluorescent platform that can directly measure single-cell state transitions in a multi-layered ecosystem using tandemly integrated reporters. We modeled population dynamics using a discrete time Markov chain and directly mea...
3129Background: The impact of common or rare gene mutations on the sensitivity of cancers to ioni... more 3129Background: The impact of common or rare gene mutations on the sensitivity of cancers to ionizing radiation remains largely unknown. We conducted a systematic, arrayed (single variant per well)...
TET2 is frequently mutated in myeloid neoplasms. Genetic TET2 deficiency leads to skewed myeloid ... more TET2 is frequently mutated in myeloid neoplasms. Genetic TET2 deficiency leads to skewed myeloid differentiation and clonal expansion, but minimal residual TET activity is critical for survival of neoplastic progenitor and stem cells. Consistent with mutual exclusivity of TET2 and neomorphic IDH1/2 mutations, here we report that IDH1/2 mutant–derived 2-hydroxyglutarate is synthetically lethal to TET dioxygenase–deficient cells. In addition, a TET-selective small-molecule inhibitor decreases cytosine hydroxymethylation and restricted clonal outgrowth of TET2 mutant but not normal hematopoietic precursor cells in vitro and in vivo. Although TET inhibitor phenocopied somatic TET2 mutations, its pharmacologic effects on normal stem cells are, unlike mutations, reversible. Treatment with TET inhibitor suppresses the clonal evolution of TET2-mutant cells in murine models and TET2-mutated human leukemia xenografts. These results suggest that TET inhibitors may constitute a new class of tar...
International Journal of Radiation Oncology*Biology*Physics, 2021
PURPOSE/OBJECTIVE(S) The impact of common or rare gene mutations on the sensitivity of cancers to... more PURPOSE/OBJECTIVE(S) The impact of common or rare gene mutations on the sensitivity of cancers to ionizing radiation remains largely unknown. We conducted a systematic, arrayed (single variant per well) profiling effort to identify gene mutations that alter cellular sensitivity to radiation and validated some of our findings using a clinical cohort of patients who received thoracic radiotherapy alone. MATERIALS/METHODS Candidate mutations were prioritized on the basis of genotype-phenotype associations from our previously completed large-scale cancer cell line irradiation profiling study (doi: 10.1038/ncomms11428), location within conserved protein domains, and functional impact. We used site-directed mutagenesis to generate mutant clones (2 clones per variant) and transferred the ORFs into lentiviral vectors in SV40 lung primary immortalized cells (BEAS2B). For clinical validation, an IRB-approved study was used to identify patients treated with lung radiotherapy alone. 197 patients with primary (stage I-IV) or recurrent lung cancer and patients with other cancer types and solitary metastases or oligometastases to the lung were included. Death without evidence of local failure was treated as a competing event, and Fine and Gray regression modeling was used to examine potential predictors of local failure. RESULTS Over 600 cancer variants were tested in ∼1200 experimental replicates, comprising 91 genes. We identified known and new radioresistant and radiosensitive variants involved in several cellular functional categories including cellular signaling, cytoskeleton, cell cycle, apoptosis, DNA methylation, and DNA repair. Variants that conferred resistance in BEAS2B cells were significantly more likely to confer resistance in TERT-HU1 and NCI-H520 cells, suggesting that most functional variants are cellular context indifferent. Variants under somatic oncogenic selection (hotspot mutants) were significantly more likely to confer resistance to radiation. Several infrequent cancer variants (< 1% prevalence in cancer), including those in ERBB3, SMAD4, TGFBR1, VHL, CTNNB1, and MAP2K1, conferred radiation resistance. Some genes (e.g., KEAP1) demonstrated significant intragenic allelic variation in the magnitude of conferred resistance and other genes (e.g., CTNNB1) displayed both resistance and sensitivity in a protein domain-dependent manner. KRAS (resistant; HR 2.23; P = 0.02) and CTNNB1 exon 3 (sensitive; HR 0.3; P = 0.04) mutants conferred resistance and sensitivity, respectively, to radiotherapy in our clinical cohort. CONCLUSION We report on a large-scale profiling effort to identify mutant alleles that govern radiation survival. Our results reveal new insights into potentially actionable determinants of tumor sensitivity to radiotherapy and accelerate clinical validation of common and rare gene mutations that impact radiation sensitivity.
Molecular determinants governing the evolution of tumor subclones toward phylogenetic branches or... more Molecular determinants governing the evolution of tumor subclones toward phylogenetic branches or fixation remain unknown. Using sequencing data, we model the propagation and selection of clones expressing distinct categories of BRAF mutations to estimate their evolutionary trajectories. We show that strongly activating BRAF mutations demonstrate hard sweep dynamics, whereas mutations with less pronounced activation of the BRAF signaling pathway confer soft sweeps or are subclonal. We use clonal reconstructions to estimate the strength of “driver” selection in individual tumors. Using tumors cells and human-derived murine xenografts, we show that tumor sweep dynamics can significantly affect responses to targeted inhibitors of BRAF/MEK or DNA damaging agents. Our study uncovers patterns of distinct BRAF clonal evolutionary dynamics and nominates therapeutic strategies based on the identity of the BRAF mutation and its clonal composition.
Targeted α-particle–emitting radionuclides have great potential for the treatment of a broad rang... more Targeted α-particle–emitting radionuclides have great potential for the treatment of a broad range of cancers at different stages of progression. A platform that accurately measures cancer cellular sensitivity to α-particle irradiation could guide and accelerate clinical translation. Here, we performed high-content profiling of cellular survival following exposure to α-particles emitted from radium-223 (223Ra) using 28 genetically diverse human tumor cell lines. Significant variation in cellular sensitivity across tumor cells was observed. 223Ra was significantly more potent than sparsely ionizing irradiation, with a median relative biological effectiveness of 10.4 (IQR: 8.4–14.3). Cells that are the most resistant to γ radiation, such as Nrf2 gain-of-function mutant cells, were sensitive to α-particles. Combining these profiling results with genetic features, we identified several somatic copy-number alterations, gene mutations, and the basal expression of gene sets that correlated...
Tumors have genetically distinct subclones that compete for space and resources and differentiall... more Tumors have genetically distinct subclones that compete for space and resources and differentially resist efforts to make them extinct. We studied the intratumoral heterogeneity of BRAF mutations across several cancer types. We identified BRAF driver mutations as predominately clonal in some cancer types (e.g. melanoma) and subclonal in others (e.g. lung adenocarcinoma). Clonality corresponded to the amplification of BRAF and prevalence of V600 mutations in each cancer type. We mathematically and experimentally modeled the propagation and selection of tumors containing BRAF mutations and determined that the speed of clonal sweeps were associated with the extent of activation of MAPK signaling pathway and BRAF copy number. Consistent with these findings, tumors with "hard" sweeps were more likely to respond to BRAF and/or MEK inhibitors. Furthermore, some PDX models treated with cytotoxic therapy underwent BRAF mutant subclone expansion over time and this effect is mitigate...
The identification of malignant cells in pleural fluid has critical prognostic and therapeutic im... more The identification of malignant cells in pleural fluid has critical prognostic and therapeutic implications but is frequently a diagnostic challenge. The first step in determining the cause of a suspected malignant pleural effusion, thoracentesis, has an unsatisfying low sensitivity (~60-70%). Patient-derived xenografts (PDX) retain the principal characteristics of the tumor of origin. However, there has been little progress in the application of these models to guide diagnostic and staging strategies. We assessed the feasibility, cellular yield and comparative diagnostic accuracy of pleural-derived xenografts in patients with effusions. An institutional review board-approved single-institution prospective registry of patients was used to identify patients undergoing diagnostic and/or therapeutic thoracentesis. Cells isolated from the pleural fluid of these patients were injected into NSG mice. A diagnosis of the cancer in the xenograft was confirmed by a staff pathologist with expe...
It is increasingly apparent that tumors represent dynamic structures in which cell populations, d... more It is increasingly apparent that tumors represent dynamic structures in which cell populations, defined by genetic, epigenetic and non-genetic variation, compete for space and resources, while attempting to evade host defenses, resist therapeutic interventions and colonize new environments. Yet, the extent of this intratumoral genetic heterogeneity and the rules governing this ecosystem remain largely unknown. Using a large inventory of patient-derived xenograft models and an ex vivo culture system that maintains the transcriptional fidelity of the primary tumors, we have interrogated small cell lung cancer (SCLC) as a tractable model system for studying tumor evolution. In the process, we have identified at least three morphologically distinct intratumoral subpopulations across several samples: (i) suspended aggregates of small cells (neuroendocrine or NE), (ii) larger, pleomorphic cells with visible cytoplasm and spindle-like membrane extensions growing as a monolayer (mesenchymal...
There has been little progress in the use of patient-derived xenografts (PDX) to guide individual... more There has been little progress in the use of patient-derived xenografts (PDX) to guide individual therapeutic strategies. In part, this can be attributed to the operational challenges of effecting successful engraftment and testing multiple candidate drugs in a clinically workable timeframe. It also remains unclear whether the ancestral tumor will evolve along similar evolutionary trajectories in its human and rodent hosts in response to similar selective pressures (i.e., drugs). Herein, we combine a metastatic clear cell adenocarcinoma PDX with a timely 3 mouse 1 drug experimental design, followed by a co-clinical trial to longitudinally guide a patient's care. Using this approach, we accurately predict response to first- and second-line therapies in so far as tumor response in mice correlated with the patient's clinical response to first-line therapy (gemcitabine/nivolumab), development of resistance and response to second-line therapy (paclitaxel/neratinib) before these e...
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Papers by Priyanka Gopal