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Selective mTORC2 Inhibitor Therapeutically Blocks Breast Cancer Cell Growth and Survival.
Werfel TA, Wang S, Jackson MA, Kavanaugh TE, Joly MM, Lee LH, Hicks DJ, Sanchez V, Ericsson PG, Kilchrist KV, Dimobi SC, Sarett SM, Brantley-Sieders DM, Cook RS, Duvall CL
(2018) Cancer Res 78: 1845-1858
MeSH Terms: Animals, Antineoplastic Agents, Cell Proliferation, Cell Survival, Disease Models, Animal, Female, Humans, Lapatinib, Mechanistic Target of Rapamycin Complex 2, Mice, Mice, Inbred BALB C, Mice, Nude, Nanoparticles, Protein Kinase Inhibitors, RNA, Small Interfering, Rapamycin-Insensitive Companion of mTOR Protein, Receptor, ErbB-2, Triple Negative Breast Neoplasms, Xenograft Model Antitumor Assays
Show Abstract · Added March 14, 2018
Small-molecule inhibitors of the mTORC2 kinase (torkinibs) have shown efficacy in early clinical trials. However, the torkinibs under study also inhibit the other mTOR-containing complex mTORC1. While mTORC1/mTORC2 combined inhibition may be beneficial in cancer cells, recent reports describe compensatory cell survival upon mTORC1 inhibition due to loss of negative feedback on PI3K, increased autophagy, and increased macropinocytosis. Genetic models suggest that selective mTORC2 inhibition would be effective in breast cancers, but the lack of selective small-molecule inhibitors of mTORC2 have precluded testing of this hypothesis to date. Here we report the engineering of a nanoparticle-based RNAi therapeutic that can effectively silence the mTORC2 obligate cofactor Rictor. Nanoparticle-based Rictor ablation in HER2-amplified breast tumors was achieved following intratumoral and intravenous delivery, decreasing Akt phosphorylation and increasing tumor cell killing. Selective mTORC2 inhibition , combined with the HER2 inhibitor lapatinib, decreased the growth of HER2-amplified breast cancers to a greater extent than either agent alone, suggesting that mTORC2 promotes lapatinib resistance, but is overcome by mTORC2 inhibition. Importantly, selective mTORC2 inhibition was effective in a triple-negative breast cancer (TNBC) model, decreasing Akt phosphorylation and tumor growth, consistent with our findings that RICTOR mRNA correlates with worse outcome in patients with basal-like TNBC. Together, our results offer preclinical validation of a novel RNAi delivery platform for therapeutic gene ablation in breast cancer, and they show that mTORC2-selective targeting is feasible and efficacious in this disease setting. This study describes a nanomedicine to effectively inhibit the growth regulatory kinase mTORC2 in a preclinical model of breast cancer, targeting an important pathogenic enzyme in that setting that has been undruggable to date. .
©2018 American Association for Cancer Research.
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19 MeSH Terms
Genomic profiling of ER breast cancers after short-term estrogen suppression reveals alterations associated with endocrine resistance.
Giltnane JM, Hutchinson KE, Stricker TP, Formisano L, Young CD, Estrada MV, Nixon MJ, Du L, Sanchez V, Ericsson PG, Kuba MG, Sanders ME, Mu XJ, Van Allen EM, Wagle N, Mayer IA, Abramson V, Gόmez H, Rizzo M, Toy W, Chandarlapaty S, Mayer EL, Christiansen J, Murphy D, Fitzgerald K, Wang K, Ross JS, Miller VA, Stephens PJ, Yelensky R, Garraway L, Shyr Y, Meszoely I, Balko JM, Arteaga CL
(2017) Sci Transl Med 9:
MeSH Terms: Breast Neoplasms, Cell Line, Tumor, Cyclin D1, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, Female, Humans, In Vitro Techniques, Receptor, ErbB-2, Receptor, Fibroblast Growth Factor, Type 1, Receptors, Estrogen
Show Abstract · Added March 14, 2018
Inhibition of proliferation in estrogen receptor-positive (ER) breast cancers after short-term antiestrogen therapy correlates with long-term patient outcome. We profiled 155 ER/human epidermal growth factor receptor 2-negative (HER2) early breast cancers from 143 patients treated with the aromatase inhibitor letrozole for 10 to 21 days before surgery. Twenty-one percent of tumors remained highly proliferative, suggesting that these tumors harbor alterations associated with intrinsic endocrine therapy resistance. Whole-exome sequencing revealed a correlation between 8p11-12 and 11q13 gene amplifications, including and , respectively, and high Ki67. We corroborated these findings in a separate cohort of serial pretreatment, postneoadjuvant chemotherapy, and recurrent ER tumors. Combined inhibition of FGFR1 and CDK4/6 reversed antiestrogen resistance in ER/ coamplified CAMA1 breast cancer cells. RNA sequencing of letrozole-treated tumors revealed the existence of intrachromosomal fusion transcripts and increased expression of gene signatures indicative of enhanced E2F-mediated transcription and cell cycle processes in cancers with high Ki67. These data suggest that short-term preoperative estrogen deprivation followed by genomic profiling can be used to identify druggable alterations that may cause intrinsic endocrine therapy resistance.
Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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11 MeSH Terms
Two distinct mTORC2-dependent pathways converge on Rac1 to drive breast cancer metastasis.
Morrison Joly M, Williams MM, Hicks DJ, Jones B, Sanchez V, Young CD, Sarbassov DD, Muller WJ, Brantley-Sieders D, Cook RS
(2017) Breast Cancer Res 19: 74
MeSH Terms: Animals, Breast Neoplasms, Cell Line, Tumor, Cell Movement, Disease Models, Animal, Female, Gene Amplification, Heterografts, Humans, Mechanistic Target of Rapamycin Complex 2, Mice, Mice, Transgenic, Neoplasm Metastasis, Neoplasm Staging, Prognosis, Proto-Oncogene Proteins c-akt, Rapamycin-Insensitive Companion of mTOR Protein, Receptor, ErbB-2, Signal Transduction, rac1 GTP-Binding Protein, rho Guanine Nucleotide Dissociation Inhibitor beta
Show Abstract · Added April 15, 2019
BACKGROUND - The importance of the mTOR complex 2 (mTORC2) signaling complex in tumor progression is becoming increasingly recognized. HER2-amplified breast cancers use Rictor/mTORC2 signaling to drive tumor formation, tumor cell survival and resistance to human epidermal growth factor receptor 2 (HER2)-targeted therapy. Cell motility, a key step in the metastatic process, can be activated by mTORC2 in luminal and triple negative breast cancer cell lines, but its role in promoting metastases from HER2-amplified breast cancers is not yet clear.
METHODS - Because Rictor is an obligate cofactor of mTORC2, we genetically engineered Rictor ablation or overexpression in mouse and human HER2-amplified breast cancer models for modulation of mTORC2 activity. Signaling through mTORC2-dependent pathways was also manipulated using pharmacological inhibitors of mTOR, Akt, and Rac. Signaling was assessed by western analysis and biochemical pull-down assays specific for Rac-GTP and for active Rac guanine nucleotide exchange factors (GEFs). Metastases were assessed from spontaneous tumors and from intravenously delivered tumor cells. Motility and invasion of cells was assessed using Matrigel-coated transwell assays.
RESULTS - We found that Rictor ablation potently impaired, while Rictor overexpression increased, metastasis in spontaneous and intravenously seeded models of HER2-overexpressing breast cancers. Additionally, migration and invasion of HER2-amplified human breast cancer cells was diminished in the absence of Rictor, or upon pharmacological mTOR kinase inhibition. Active Rac1 was required for Rictor-dependent invasion and motility, which rescued invasion/motility in Rictor depleted cells. Rictor/mTORC2-dependent dampening of the endogenous Rac1 inhibitor RhoGDI2, a factor that correlated directly with increased overall survival in HER2-amplified breast cancer patients, promoted Rac1 activity and tumor cell invasion/migration. The mTORC2 substrate Akt did not affect RhoGDI2 dampening, but partially increased Rac1 activity through the Rac-GEF Tiam1, thus partially rescuing cell invasion/motility. The mTORC2 effector protein kinase C (PKC)α did rescue Rictor-mediated RhoGDI2 downregulation, partially rescuing Rac-guanosine triphosphate (GTP) and migration/motility.
CONCLUSION - These findings suggest that mTORC2 uses two coordinated pathways to activate cell invasion/motility, both of which converge on Rac1. Akt signaling activates Rac1 through the Rac-GEF Tiam1, while PKC signaling dampens expression of the endogenous Rac1 inhibitor, RhoGDI2.
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MeSH Terms
Comparison of Breast Cancer Molecular Features and Survival by African and European Ancestry in The Cancer Genome Atlas.
Huo D, Hu H, Rhie SK, Gamazon ER, Cherniack AD, Liu J, Yoshimatsu TF, Pitt JJ, Hoadley KA, Troester M, Ru Y, Lichtenberg T, Sturtz LA, Shelley CS, Benz CC, Mills GB, Laird PW, Shriver CD, Perou CM, Olopade OI
(2017) JAMA Oncol 3: 1654-1662
MeSH Terms: African Americans, Aged, Breast Neoplasms, Breast Neoplasms, Male, Class I Phosphatidylinositol 3-Kinases, Databases, Factual, European Continental Ancestry Group, Female, Gene Expression Regulation, Neoplastic, Humans, Male, Middle Aged, Mutation, Precision Medicine, Receptor, ErbB-2, Survival Analysis, Tumor Suppressor Protein p53, United States
Show Abstract · Added May 10, 2017
Importance - African Americans have the highest breast cancer mortality rate. Although racial difference in the distribution of intrinsic subtypes of breast cancer is known, it is unclear if there are other inherent genomic differences that contribute to the survival disparities.
Objectives - To investigate racial differences in breast cancer molecular features and survival and to estimate the heritability of breast cancer subtypes.
Design, Setting, and Participants - Among a convenience cohort of patients with invasive breast cancer, breast tumor and matched normal tissue sample data (as of September 18, 2015) were obtained from The Cancer Genome Atlas.
Main Outcomes and Measures - Breast cancer–free interval, tumor molecular features, and genetic variants.
Results - Participants were 930 patients with breast cancer, including 154 black patients of African ancestry (mean [SD] age at diagnosis, 55.66 [13.01] years; 98.1% [n = 151] female) and 776 white patients of European ancestry (mean [SD] age at diagnosis, 59.51 [13.11] years; 99.0% [n = 768] female). Compared with white patients, black patients had a worse breast cancer-free interval (hazard ratio, HR=1.67; 95% CI, 1.02-2.74; P = .043). They had a higher likelihood of basal-like (odds ratio, 3.80; 95% CI, 2.46-5.87; P < .001) and human epidermal growth factor receptor 2 (ERBB2 [formerly HER2])–enriched (odds ratio, 2.22; 95% CI, 1.10-4.47; P = .027) breast cancer subtypes, with the Luminal A subtype as the reference. Blacks had more TP53 mutations and fewer PIK3CA mutations than whites. While most molecular differences were eliminated after adjusting for intrinsic subtype, the study found 16 DNA methylation probes, 4 DNA copy number segments, 1 protein, and 142 genes that were differentially expressed, with the gene-based signature having an excellent capacity for distinguishing breast tumors from black vs white patients (cross-validation C index, 0.878). Using germline genotypes, the heritability of breast cancer subtypes (basal vs nonbasal) was estimated to be 0.436 (P = 1.5 × 10−14). The estrogen receptor–positive polygenic risk score built from 89 known susceptibility variants was higher in blacks than in whites (difference, 0.24; P = 2.3 × 10−5), while the estrogen receptor–negative polygenic risk score was much higher in blacks than in whites (difference, 0.48; P = 2.8 × 10−11).
Conclusions and Relevance - On the molecular level, after adjusting for intrinsic subtype frequency differences, this study found a modest number of genomic differences but a significant clinical survival outcome difference between blacks and whites in The Cancer Genome Atlas data set. Moreover, more than 40% of breast cancer subtype frequency differences could be explained by genetic variants. These data could form the basis for the development of molecular targeted therapies to improve clinical outcomes for the specific subtypes of breast cancers that disproportionately affect black women. Findings also indicate that personalized risk assessment and optimal treatment could reduce deaths from aggressive breast cancers for black women.
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18 MeSH Terms
An Acquired Gatekeeper Mutation Induces Resistance to Neratinib in a Patient with HER2 Mutant-Driven Breast Cancer.
Hanker AB, Brewer MR, Sheehan JH, Koch JP, Sliwoski GR, Nagy R, Lanman R, Berger MF, Hyman DM, Solit DB, He J, Miller V, Cutler RE, Lalani AS, Cross D, Lovly CM, Meiler J, Arteaga CL
(2017) Cancer Discov 7: 575-585
MeSH Terms: Afatinib, Antineoplastic Agents, Breast Neoplasms, Cell Line, Tumor, Drug Resistance, Neoplasm, Female, Humans, Middle Aged, Mutation, Phenotype, Protein Kinase Inhibitors, Quinazolines, Quinolines, Receptor, ErbB-2
Show Abstract · Added April 8, 2017
We report a gatekeeper mutation in a patient with -mutant breast cancer with acquired resistance to neratinib. Laboratory studies suggested that is a neratinib-sensitive, gain-of-function mutation that upon dimerization with mutant HER3, also present in the breast cancer, amplifies HER2 signaling. The patient was treated with neratinib and exhibited a sustained partial response. Upon clinical progression, was detected in plasma tumor cell-free DNA. Structural modeling of this acquired mutation suggested that the increased bulk of isoleucine in HER2 reduces neratinib binding. Neratinib blocked HER2-mediated signaling and growth in cells expressing HER2 but not HER2 In contrast, afatinib and the osimertinib metabolite AZ5104 strongly suppressed HER2-induced signaling and cell growth. Acquisition of HER2 upon development of resistance to neratinib in a breast cancer with an initial activating mutation suggests is a driver mutation. HER2-mediated neratinib resistance may be overcome by other irreversible HER2 inhibitors like afatinib. We found an acquired gatekeeper mutation in a patient with -mutant breast cancer upon clinical progression on neratinib. We speculate that may arise as a secondary mutation following response to effective HER2 tyrosine kinase inhibitors (TKI) in other cancers with -activating mutations. This resistance may be overcome by other irreversible HER2 TKIs, such as afatinib. .
©2017 American Association for Cancer Research.
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14 MeSH Terms
HER2 Testing and Clinical Decision Making in Gastroesophageal Adenocarcinoma: Guideline From the College of American Pathologists, American Society for Clinical Pathology, and the American Society of Clinical Oncology.
Bartley AN, Washington MK, Colasacco C, Ventura CB, Ismaila N, Benson AB, Carrato A, Gulley ML, Jain D, Kakar S, Mackay HJ, Streutker C, Tang L, Troxell M, Ajani JA
(2017) J Clin Oncol 35: 446-464
MeSH Terms: Adenocarcinoma, Algorithms, Biomarkers, Tumor, Esophageal Neoplasms, Esophagogastric Junction, Humans, Receptor, ErbB-2, Stomach Neoplasms
Show Abstract · Added March 14, 2018
Context ERBB2 (erb-b2 receptor tyrosine kinase 2 or HER2) is currently the only biomarker established for selection of a specific therapy for patients with advanced gastroesophageal adenocarcinoma (GEA). However, there are no comprehensive guidelines for the assessment of HER2 in patients with GEA. Objectives To establish an evidence-based guideline for HER2 testing in patients with GEA, formalize the algorithms for methods to improve the accuracy of HER2 testing while addressing which patients and tumor specimens are appropriate, and to provide guidance on clinical decision making. Design The College of American Pathologists (CAP), American Society for Clinical Pathology (ASCP), and the American Society of Clinical Oncology (ASCO) convened an Expert Panel to conduct a systematic review of the literature to develop an evidence-based guideline with recommendations for optimal HER2 testing in patients with GEA. Results The Panel is proposing 11 recommendations with strong agreement from the open comment participants. Recommendations The Panel recommends that tumor specimen(s) from all patients with advanced GEA, who are candidates for HER2-targeted therapy, should be assessed for HER2 status before the initiation of HER2-targeted therapy. Clinicians should offer combination chemotherapy and an HER2-targeted agent as initial therapy for all patients with HER2-positive advanced GEA. For pathologists, guidance is provided for morphologic selection of neoplastic tissue, testing algorithms, scoring methods, interpretation and reporting of results, and laboratory quality assurance. Conclusion This guideline provides specific recommendations for assessment of HER2 in patients with advanced GEA while addressing pertinent technical issues and clinical implications of the results.
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8 MeSH Terms
HER2 Testing and Clinical Decision Making in Gastroesophageal Adenocarcinoma: Guideline From the College of American Pathologists, American Society for Clinical Pathology, and American Society of Clinical Oncology.
Bartley AN, Washington MK, Ventura CB, Ismaila N, Colasacco C, Benson AB, Carrato A, Gulley ML, Jain D, Kakar S, Mackay HJ, Streutker C, Tang L, Troxell M, Ajani JA
(2016) Am J Clin Pathol 146: 647-669
MeSH Terms: Adenocarcinoma, Antineoplastic Agents, Clinical Decision-Making, Esophageal Neoplasms, Esophagogastric Junction, Genetic Testing, Humans, Medical Oncology, Receptor, ErbB-2, Stomach Neoplasms, United States
Show Abstract · Added March 14, 2018
CONTEXT - ERBB2 (erb-b2 receptor tyrosine kinase 2 or HER2) is currently the only biomarker established for selection of a specific therapy for patients with advanced gastroesophageal adenocarcinoma (GEA). However, there are no comprehensive guidelines for the assessment of HER2 in patients with GEA.
OBJECTIVES - To establish an evidence-based guideline for HER2 testing in patients with GEA, to formalize the algorithms for methods to improve the accuracy of HER2 testing while addressing which patients and tumor specimens are appropriate, and to provide guidance on clinical decision making.
DESIGN - The College of American Pathologists, American Society for Clinical Pathology, and American Society of Clinical Oncology convened an expert panel to conduct a systematic review of the literature to develop an evidence-based guideline with recommendations for optimal HER2 testing in patients with GEA.
RESULTS - The panel is proposing 11 recommendations with strong agreement from the open-comment participants.
RECOMMENDATIONS - The panel recommends that tumor specimen(s) from all patients with advanced GEA, who are candidates for HER2-targeted therapy, should be assessed for HER2 status before the initiation of HER2-targeted therapy. Clinicians should offer combination chemotherapy and a HER2-targeted agent as initial therapy for all patients with HER2-positive advanced GEA. For pathologists, guidance is provided for morphologic selection of neoplastic tissue, testing algorithms, scoring methods, interpretation and reporting of results, and laboratory quality assurance.
CONCLUSIONS - This guideline provides specific recommendations for assessment of HER2 in patients with advanced GEA while addressing pertinent technical issues and clinical implications of the results.
© 2016 College of American Pathologists, American Society for Clinical Pathology, and the American Society of Clinical Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
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11 MeSH Terms
HER2 Testing and Clinical Decision Making in Gastroesophageal Adenocarcinoma: Guideline Summary From the College of American Pathologists, American Society for Clinical Pathology, and American Society of Clinical Oncology.
Bartley AN, Washington MK, Ismaila N, Ajani JA
(2017) J Oncol Pract 13: 53-57
MeSH Terms: Adenocarcinoma, Clinical Decision-Making, Female, Guidelines as Topic, Humans, Male, Medical Oncology, Pathology, Clinical, Receptor, ErbB-2, Stomach Neoplasms, United States
Added March 14, 2018
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1 Members
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11 MeSH Terms
HER2 Testing and Clinical Decision Making in Gastroesophageal Adenocarcinoma: Guideline From the College of American Pathologists, American Society for Clinical Pathology, and American Society of Clinical Oncology.
Bartley AN, Washington MK, Ventura CB, Ismaila N, Colasacco C, Benson AB, Carrato A, Gulley ML, Jain D, Kakar S, Mackay HJ, Streutker C, Tang L, Troxell M, Ajani JA
(2016) Arch Pathol Lab Med 140: 1345-1363
MeSH Terms: Adenocarcinoma, Biomarkers, Tumor, Clinical Decision-Making, Combined Modality Therapy, Decision Trees, Diagnosis, Differential, Esophageal Neoplasms, Evidence-Based Medicine, Humans, Medical Oncology, Molecular Diagnostic Techniques, Molecular Targeted Therapy, Mutation, Neoplasm Grading, Neoplasm Staging, Pathology, Clinical, Receptor, ErbB-2, Societies, Medical, Stomach Neoplasms, United States
Show Abstract · Added March 14, 2018
CONTEXT - - ERBB2 (erb-b2 receptor tyrosine kinase 2 or HER2) is currently the only biomarker established for selection of a specific therapy for patients with advanced gastroesophageal adenocarcinoma (GEA). However, there are no comprehensive guidelines for the assessment of HER2 in patients with GEA.
OBJECTIVES - - To establish an evidence-based guideline for HER2 testing in patients with GEA, to formalize the algorithms for methods to improve the accuracy of HER2 testing while addressing which patients and tumor specimens are appropriate, and to provide guidance on clinical decision making.
DESIGN - - The College of American Pathologists, American Society for Clinical Pathology, and American Society of Clinical Oncology convened an expert panel to conduct a systematic review of the literature to develop an evidence-based guideline with recommendations for optimal HER2 testing in patients with GEA.
RESULTS - - The panel is proposing 11 recommendations with strong agreement from the open-comment participants.
RECOMMENDATIONS - - The panel recommends that tumor specimen(s) from all patients with advanced GEA, who are candidates for HER2-targeted therapy, should be assessed for HER2 status before the initiation of HER2-targeted therapy. Clinicians should offer combination chemotherapy and a HER2-targeted agent as initial therapy for all patients with HER2-positive advanced GEA. For pathologists, guidance is provided for morphologic selection of neoplastic tissue, testing algorithms, scoring methods, interpretation and reporting of results, and laboratory quality assurance.
CONCLUSIONS - - This guideline provides specific recommendations for assessment of HER2 in patients with advanced GEA while addressing pertinent technical issues and clinical implications of the results.
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20 MeSH Terms
Quantitative [F]FMISO PET Imaging Shows Reduction of Hypoxia Following Trastuzumab in a Murine Model of HER2+ Breast Cancer.
Sorace AG, Syed AK, Barnes SL, Quarles CC, Sanchez V, Kang H, Yankeelov TE
(2017) Mol Imaging Biol 19: 130-137
MeSH Terms: Animals, Biomarkers, Tumor, Cell Line, Tumor, Disease Models, Animal, Female, Fluorescent Antibody Technique, Mammary Neoplasms, Animal, Misonidazole, Nitroimidazoles, Positron-Emission Tomography, Receptor, ErbB-2, Trastuzumab, Tumor Burden, Tumor Hypoxia
Show Abstract · Added April 6, 2017
PURPOSE - Evaluation of [F]fluoromisonidazole ([F]FMISO)-positron emission tomography (PET) imaging as a metric for evaluating early response to trastuzumab therapy with histological validation in a murine model of HER2+ breast cancer.
PROCEDURES - Mice with BT474, HER2+ tumors, were imaged with [F]FMISO-PET during trastuzumab therapy. Pimonidazole staining was used to confirm hypoxia from imaging.
RESULTS - [F]FMISO-PET indicated significant decreases in hypoxia beginning on day 3 (P < 0.01) prior to changes in tumor size. These results were confirmed with pimonidazole staining on day 7 (P < 0.01); additionally, there was a significant positive linear correlation between histology and PET imaging (r  = 0.85).
CONCLUSIONS - [F]FMISO-PET is a clinically relevant modality which provides the opportunity to (1) predict response to HER2+ therapy before changes in tumor size and (2) identify decreases in hypoxia which has the potential to guide subsequent therapy.
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14 MeSH Terms