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Article ; Online: Mechanisms of immune-related adverse events associated with immune checkpoint blockade: using germline genetics to develop a personalized approach.

Khan, Zia / Hammer, Christian / Guardino, Ellie / Chandler, G Scott / Albert, Matthew L

2019 Volume 11, Issue 1, Page(s) 39

Abstract: Personalized care of cancer patients undergoing treatment with immune checkpoint inhibitors will require approaches that can predict their susceptibility to immune-related adverse events. Understanding the role of germline genetic factors in determining ... ...

Abstract	Personalized care of cancer patients undergoing treatment with immune checkpoint inhibitors will require approaches that can predict their susceptibility to immune-related adverse events. Understanding the role of germline genetic factors in determining individual responses to immunotherapy will deepen our understanding of immune toxicity and, importantly, it may lead to tools for identifying patients who are at risk.
MeSH term(s)	Animals ; Antineoplastic Agents, Immunological/adverse effects ; Antineoplastic Agents, Immunological/therapeutic use ; Genetic Testing/methods ; Genome-Wide Association Study/methods ; Humans ; Neoplasms/drug therapy ; Neoplasms/genetics ; Neoplasms/immunology ; Precision Medicine/methods ; Receptors, Immunologic/antagonists & inhibitors ; Receptors, Immunologic/genetics
Chemical Substances	Antineoplastic Agents, Immunological ; Receptors, Immunologic
Language	English
Publishing date	2019-06-20
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2484394-5
ISSN	1756-994X ; 1756-994X
ISSN (online)	1756-994X
ISSN	1756-994X
DOI	10.1186/s13073-019-0652-8
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Article ; Online: Phase I Trial of Everolimus and Capecitabine in Metastatic HER2

Vidal, Gregory A / Chen, Mary / Sheth, Shruti / Svahn, Tiffany / Guardino, Ellie

Clinical breast cancer

2017 Volume 17, Issue 6, Page(s) 418–426

Abstract: Background: The mammalian target of rapamycin (mTOR) pathway is a driver of breast tumorigenesis. The mTOR inhibitor everolimus reverses antihormonal therapy resistance and is an approved therapy for metastatic breast cancer. A synergistic effect with ... ...

Abstract	Background: The mammalian target of rapamycin (mTOR) pathway is a driver of breast tumorigenesis. The mTOR inhibitor everolimus reverses antihormonal therapy resistance and is an approved therapy for metastatic breast cancer. A synergistic effect with fluoropyrimidine has been suggested. The present study evaluated the safety and tolerability of an all-oral combination of everolimus and capecitabine for metastatic breast cancer (MBC). Patients and methods: MBC patients naive to capecitabine and mTOR inhibitors who had received ≤ 3 previous chemotherapy regimens in the metastatic setting were eligible for the present study. The patients were scheduled to receive capecitabine 825 mg/m Results: A total of 18 patients were enrolled in the present trial. The median age was 58 years. Most had received previous anthracycline (83%) and taxane (94%) therapy. The maximum tolerated dose was everolimus 7.5 mg daily and capecitabine 825 mg/m Conclusion: The all-oral regimen of everolimus with capecitabine is active and well tolerated, with encouraging results for progression-free survival, overall survival, and clinical benefit rate in patients with MBC.
MeSH term(s)	Administration, Oral ; Adult ; Aged ; Antineoplastic Combined Chemotherapy Protocols/administration & dosage ; Antineoplastic Combined Chemotherapy Protocols/adverse effects ; Breast Neoplasms/drug therapy ; Breast Neoplasms/mortality ; Capecitabine/administration & dosage ; Capecitabine/adverse effects ; Disease-Free Survival ; Dose-Response Relationship, Drug ; Everolimus/administration & dosage ; Everolimus/adverse effects ; Female ; Humans ; Maximum Tolerated Dose ; Middle Aged ; Treatment Outcome
Chemical Substances	Capecitabine (6804DJ8Z9U) ; Everolimus (9HW64Q8G6G)
Language	English
Publishing date	2017
Publishing country	United States
Document type	Clinical Trial, Phase I ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2106734-X
ISSN	1938-0666 ; 1526-8209
ISSN (online)	1938-0666
ISSN	1526-8209
DOI	10.1016/j.clbc.2017.03.003
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Zs.A 5800: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 498: Show issues

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Article ; Online: Author's Response to "A Letter in Support of Real-World RECIST".

Griffith, Sandra D / Tucker, Melisa / Bowser, Bryan / Calkins, Geoffrey / Chang, Che-Hsu Joe / Guardino, Ellie / Khozin, Sean / Kraut, Josh / You, Paul / Schrag, Deb / Miksad, Rebecca A

Advances in therapy

2020 Volume 37, Issue 4, Page(s) 1691–1693

MeSH term(s)	Abstracting and Indexing ; Carcinoma, Non-Small-Cell Lung ; Electronic Health Records ; Humans ; Lung Neoplasms ; Response Evaluation Criteria in Solid Tumors ; Tumor Burden
Language	English
Publishing date	2020-02-13
Publishing country	United States
Document type	Letter ; Comment
ZDB-ID	632651-1
ISSN	1865-8652 ; 0741-238X
ISSN (online)	1865-8652
ISSN	0741-238X
DOI	10.1007/s12325-020-01246-9
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Zs.A 2101: Show issues

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Article ; Online: Generating Real-World Tumor Burden Endpoints from Electronic Health Record Data: Comparison of RECIST, Radiology-Anchored, and Clinician-Anchored Approaches for Abstracting Real-World Progression in Non-Small Cell Lung Cancer.

Griffith, Sandra D / Tucker, Melisa / Bowser, Bryan / Calkins, Geoffrey / Chang, Che-Hsu Joe / Guardino, Ellie / Khozin, Sean / Kraut, Josh / You, Paul / Schrag, Deb / Miksad, Rebecca A

Advances in therapy

2019 Volume 36, Issue 8, Page(s) 2122–2136

Abstract: Introduction: Real-world evidence derived from electronic health records (EHRs) is increasingly recognized as a supplement to evidence generated from traditional clinical trials. In oncology, tumor-based Response Evaluation Criteria in Solid Tumors ( ... ...

Abstract	Introduction: Real-world evidence derived from electronic health records (EHRs) is increasingly recognized as a supplement to evidence generated from traditional clinical trials. In oncology, tumor-based Response Evaluation Criteria in Solid Tumors (RECIST) endpoints are standard clinical trial metrics. The best approach for collecting similar endpoints from EHRs remains unknown. We evaluated the feasibility of a RECIST-based methodology to assess EHR-derived real-world progression (rwP) and explored non-RECIST-based approaches. Methods: In this retrospective study, cohorts were randomly selected from Flatiron Health's database of de-identified patient-level EHR data in advanced non-small cell lung cancer. A RECIST-based approach tested for feasibility (N = 26). Three non-RECIST approaches were tested for feasibility, reliability, and validity (N = 200): (1) radiology-anchored, (2) clinician-anchored, and (3) combined. Qualitative and quantitative methods were used. Results: A RECIST-based approach was not feasible: cancer progression could be ascertained for 23% (6/26 patients). Radiology- and clinician-anchored approaches identified at least one rwP event for 87% (173/200 patients). rwP dates matched 90% of the time. In 72% of patients (124/173), the first clinician-anchored rwP event was accompanied by a downstream event (e.g., treatment change); the association was slightly lower for the radiology-anchored approach (67%; 121/180). Median overall survival (OS) was 17 months [95% confidence interval (CI) 14, 19]. Median real-world progression-free survival (rwPFS) was 5.5 months (95% CI 4.6, 6.3) and 4.9 months (95% CI 4.2, 5.6) for clinician-anchored and radiology-anchored approaches, respectively. Correlations between rwPFS and OS were similar across approaches (Spearman's rho 0.65-0.66). Abstractors preferred the clinician-anchored approach as it provided more comprehensive context. Conclusions: RECIST cannot adequately assess cancer progression in EHR-derived data because of missing data and lack of clarity in radiology reports. We found a clinician-anchored approach supported by radiology report data to be the optimal, and most practical, method for characterizing tumor-based endpoints from EHR-sourced data. Funding: Flatiron Health Inc., which is an independent subsidiary of the Roche group.
MeSH term(s)	Aged ; Aged, 80 and over ; Carcinoma, Non-Small-Cell Lung/epidemiology ; Carcinoma, Non-Small-Cell Lung/physiopathology ; Electronic Health Records/statistics & numerical data ; Female ; Humans ; Lung Neoplasms/epidemiology ; Male ; Middle Aged ; Progression-Free Survival ; Reproducibility of Results ; Response Evaluation Criteria in Solid Tumors ; Retrospective Studies ; Tumor Burden
Language	English
Publishing date	2019-05-28
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	632651-1
ISSN	1865-8652 ; 0741-238X
ISSN (online)	1865-8652
ISSN	0741-238X
DOI	10.1007/s12325-019-00970-1
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Zs.A 2101: Show issues

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Article ; Online: Polygenic risk for skin autoimmunity impacts immune checkpoint blockade in bladder cancer.

Khan, Zia / Di Nucci, Flavia / Kwan, Antonia / Hammer, Christian / Mariathasan, Sanjeev / Rouilly, Vincent / Carroll, Jonathan / Fontes, Magnus / Ley Acosta, Sergio / Guardino, Ellie / Chen-Harris, Haiyin / Bhangale, Tushar / Mellman, Ira / Rosenberg, Jonathan / Powles, Thomas / Hunkapiller, Julie / Chandler, G Scott / Albert, Matthew L

Proceedings of the National Academy of Sciences of the United States of America

2020 Volume 117, Issue 22, Page(s) 12288–12294

Abstract: PD-1 and PD-L1 act to restrict T cell responses in cancer and contribute to self-tolerance. Consistent with this role, PD-1 checkpoint inhibitors have been associated with immune-related adverse events (irAEs), immune toxicities thought to be autoimmune ... ...

Abstract	PD-1 and PD-L1 act to restrict T cell responses in cancer and contribute to self-tolerance. Consistent with this role, PD-1 checkpoint inhibitors have been associated with immune-related adverse events (irAEs), immune toxicities thought to be autoimmune in origin. Analyses of dermatological irAEs have identified an association with improved overall survival (OS) following anti-PD-(L)1 therapy, but the factors that contribute to this relationship are poorly understood. We collected germline whole-genome sequencing data from IMvigor211, a recent phase 3 randomized controlled trial comparing atezolizumab (anti-PD-L1) monotherapy to chemotherapy in bladder cancer. We found that high vitiligo, high psoriasis, and low atopic dermatitis polygenic risk scores (PRSs) were associated with longer OS under anti-PD-L1 monotherapy as compared to chemotherapy, reflecting the Th17 polarization of these diseases. PRSs were not correlated with tumor mutation burden, PD-L1 immunohistochemistry, nor T-effector gene signatures. Shared genetic factors impact risk for dermatological autoimmunity and anti-PD-L1 monotherapy in bladder cancer.
MeSH term(s)	Antibodies, Monoclonal, Humanized/administration & dosage ; Autoimmunity ; B7-H1 Antigen/genetics ; B7-H1 Antigen/immunology ; Cohort Studies ; Humans ; Multifactorial Inheritance ; Programmed Cell Death 1 Receptor/genetics ; Programmed Cell Death 1 Receptor/immunology ; Skin/drug effects ; Skin/immunology ; Th17 Cells/immunology ; Urinary Bladder Neoplasms/drug therapy ; Urinary Bladder Neoplasms/genetics ; Urinary Bladder Neoplasms/immunology
Chemical Substances	Antibodies, Monoclonal, Humanized ; B7-H1 Antigen ; CD274 protein, human ; PDCD1 protein, human ; Programmed Cell Death 1 Receptor ; atezolizumab (52CMI0WC3Y)
Language	English
Publishing date	2020-05-19
Publishing country	United States
Document type	Journal Article ; Randomized Controlled Trial
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1922867117
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Zs.A 1148: Show issues

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Article ; Online: Phase 1b/2a study of trastuzumab emtansine (T-DM1), paclitaxel, and pertuzumab in HER2-positive metastatic breast cancer.

Krop, Ian E / Modi, Shanu / LoRusso, Patricia M / Pegram, Mark / Guardino, Ellie / Althaus, Betsy / Lu, Dan / Strasak, Alexander / Elias, Anthony

Breast cancer research : BCR

2016 Volume 18, Issue 1, Page(s) 34

Abstract: Background: In pre-clinical studies, the anti-tumor activity of T-DM1 was enhanced when combined with taxanes or pertuzumab. This phase 1b/2a study evaluated the safety/tolerability of T-DM1 + paclitaxel ± pertuzumab in HER2-positive advanced breast ... ...

Abstract	Background: In pre-clinical studies, the anti-tumor activity of T-DM1 was enhanced when combined with taxanes or pertuzumab. This phase 1b/2a study evaluated the safety/tolerability of T-DM1 + paclitaxel ± pertuzumab in HER2-positive advanced breast cancer. Methods: In phase 1b (n = 60), a 3 + 3 dose-escalation approach was used to determine the maximum tolerated dose (MTD) of T-DM1 + paclitaxel ± pertuzumab. The primary objective of phase 2a was feasibility, with 44 patients randomized to T-DM1 + paclitaxel ± pertuzumab at the MTD identified in phase 1b. Results: The MTD was T-DM1 3.6 mg/kg every three weeks (q3w) or 2.4 mg/kg weekly + paclitaxel 80 mg/m(2) weekly ± pertuzumab 840 mg loading dose followed by 420 mg q3w. Phase 2a patients had received a median of 5.0 (range: 0-10) prior therapies for advanced cancer. In phase 2a, 51.2 % received ≥12 paclitaxel doses within 15 weeks, and 14.0 % received 12 paclitaxel doses by week 12. Common all-grade adverse events (AEs) were peripheral neuropathy (90.9 %) and fatigue (79.5 %). A total of 77.3 % experienced grade ≥3 AEs, most commonly neutropenia (25.0 %) and peripheral neuropathy (18.2 %). Among the 42 phase 2a patients with measurable disease, the objective response rate (ORR) was 50.0 % (95 % confidence interval (CI) 34.6-65.4); the clinical benefit rate (CBR) was 56.8 % (95 % CI 41.6-71.0). No pharmacokinetic interactions were observed between T-DM1 and paclitaxel. Conclusions: This regimen showed clinical activity. Although there is potential for paclitaxel to be added to T-DM1 ± pertuzumab, peripheral neuropathy was common in this heavily pretreated population. Trial registration: ClinicalTrials.gov NCT00951665 . Registered August 3, 2009.
MeSH term(s)	Adult ; Aged ; Antibodies, Monoclonal, Humanized/administration & dosage ; Antibodies, Monoclonal, Humanized/adverse effects ; Antineoplastic Combined Chemotherapy Protocols/administration & dosage ; Antineoplastic Combined Chemotherapy Protocols/adverse effects ; Breast Neoplasms/drug therapy ; Breast Neoplasms/pathology ; Female ; Humans ; Maximum Tolerated Dose ; Maytansine/administration & dosage ; Maytansine/adverse effects ; Maytansine/analogs & derivatives ; Middle Aged ; Paclitaxel/administration & dosage ; Paclitaxel/adverse effects ; Trastuzumab
Chemical Substances	Antibodies, Monoclonal, Humanized ; Maytansine (14083FR882) ; pertuzumab (K16AIQ8CTM) ; Trastuzumab (P188ANX8CK) ; Paclitaxel (P88XT4IS4D) ; ado-trastuzumab emtansine (SE2KH7T06F)
Language	English
Publishing date	2016-03-15
Publishing country	England
Document type	Clinical Trial, Phase I ; Clinical Trial, Phase II ; Journal Article ; Randomized Controlled Trial
ZDB-ID	2015059-3
ISSN	1465-542X ; 1465-5411
ISSN (online)	1465-542X
ISSN	1465-5411
DOI	10.1186/s13058-016-0691-7
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Zs.A 5494: Show issues

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Article ; Online: Investigation of adverse-event-related costs for patients with metastatic breast cancer in a real-world setting.

Hurvitz, Sara / Guerin, Annie / Brammer, Melissa / Guardino, Ellie / Zhou, Zheng-Yi / Latremouille Viau, Dominick / Wu, Eric Q / Lalla, Deepa

The oncologist

2014 Volume 19, Issue 9, Page(s) 901–908

Abstract: Background: Existing treatments for metastatic breast cancer (mBC) are often effective but can cause adverse events (AEs). This study aimed to identify AEs associated with chemotherapies commonly used in mBC treatment (phase 1) and to quantify the ... ...

Abstract	Background: Existing treatments for metastatic breast cancer (mBC) are often effective but can cause adverse events (AEs). This study aimed to identify AEs associated with chemotherapies commonly used in mBC treatment (phase 1) and to quantify the economic impact of these AEs (phase 2). Materials and methods: Patients in phase 1 had at least one claim for therapy for mBC, with at least one episode with single or multiple agents. The most common chemotherapy-related complications were identified using medical and pharmacy claims data. In phase 2, patients meeting study criteria were divided into four treatment cohorts by the line of treatment and chemotherapy received: first-line taxane-treated patients, second-line taxane-treated patients, first-line capecitabine-treated patients, and second-line capecitabine-treated patients. Average monthly AE-related health care costs per cohort were stratified by cost component. Total monthly costs per number of AEs were also calculated. Results: On average, patients in phase 1 (n = 1,551) had 2 episodes of treatment, with a mean duration of 131 days. The most frequently noted complications were anemia (50.7% of mBC treatment episodes), bilirubin elevation (26.4%), and leukopenia (24.8%). In phase 2, costs related to AEs were primarily driven by incremental inpatient, outpatient, and pharmacy costs. Increases in average monthly costs ranged from $854 (9.0%) to $5,320 (69.5%), according to cohort. Overall costs increased with increasing numbers of AEs. Conclusion: Chemotherapy-related AEs in patients with mBC are associated with a substantial economic burden that increases with the number of AEs reported.
MeSH term(s)	Aged ; Breast Neoplasms/drug therapy ; Breast Neoplasms/economics ; Breast Neoplasms/epidemiology ; Bridged-Ring Compounds/economics ; Bridged-Ring Compounds/therapeutic use ; Capecitabine ; Costs and Cost Analysis/economics ; Deoxycytidine/analogs & derivatives ; Deoxycytidine/economics ; Deoxycytidine/therapeutic use ; Drug-Related Side Effects and Adverse Reactions/economics ; Drug-Related Side Effects and Adverse Reactions/epidemiology ; Female ; Fluorouracil/analogs & derivatives ; Fluorouracil/economics ; Fluorouracil/therapeutic use ; Health Care Costs ; Humans ; Middle Aged ; Neoplasm Metastasis ; Taxoids/economics ; Taxoids/therapeutic use
Chemical Substances	Bridged-Ring Compounds ; Taxoids ; Deoxycytidine (0W860991D6) ; taxane (1605-68-1) ; Capecitabine (6804DJ8Z9U) ; Fluorouracil (U3P01618RT)
Language	English
Publishing date	2014-08-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1409038-7
ISSN	1549-490X ; 1083-7159
ISSN (online)	1549-490X
ISSN	1083-7159
DOI	10.1634/theoncologist.2014-0059
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Zs.A 4845: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 494: Show issues

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Article: Trastuzumab emtansine: a unique antibody-drug conjugate in development for human epidermal growth factor receptor 2-positive cancer.

LoRusso, Patricia M / Weiss, Denise / Guardino, Ellie / Girish, Sandhya / Sliwkowski, Mark X

Clinical cancer research : an official journal of the American Association for Cancer Research

2011 Volume 17, Issue 20, Page(s) 6437–6447

Abstract: Trastuzumab emtansine (T-DM1) is a human epidermal growth factor receptor (HER2)-targeted antibody-drug conjugate, composed of trastuzumab, a stable thioether linker, and the potent cytotoxic agent DM1 (derivative of maytansine), in phase III development ...

Abstract	Trastuzumab emtansine (T-DM1) is a human epidermal growth factor receptor (HER2)-targeted antibody-drug conjugate, composed of trastuzumab, a stable thioether linker, and the potent cytotoxic agent DM1 (derivative of maytansine), in phase III development for HER2-positive cancer. Extensive analysis of T-DM1 in preclinical studies has shown that T-DM1 combines the distinct mechanisms of action of both DM1 and trastuzumab, and has antitumor activity in trastuzumab- and lapatinib-refractory experimental models. Clinically, T-DM1 has a consistent pharmacokinetics profile and minimal systemic exposure to free DM1, with no evidence of DM1 accumulation following repeated T-DM1 doses. Although a few covariates were shown to affect interindividual variability in T-DM1 exposure and clearance in population-pharmacokinetics analyses, the magnitude of their effect on T-DM1 exposure was not clinically relevant. Phase I and phase II clinical trials of T-DM1 as a single agent and in combination with paclitaxel, docetaxel, and pertuzumab have shown clinical activity and a favorable safety profile in patients with HER2-positive metastatic breast cancer. Two randomized phase III trials of T-DM1 are recruiting patients: EMILIA (NCT00829166) is evaluating T-DM1 compared with lapatinib plus capecitabine, and MARIANNE (NCT01120184) is evaluating T-DM1 plus placebo versus T-DM1 plus pertuzumab versus trastuzumab plus a taxane. Additional combinations of T-DM1 (for example, with GDC-0941) and additional disease settings (early-stage HER2-positive breast cancer) are also under investigation. Data from the phase III trials and other studies of T-DM1-containing agents are eagerly awaited.
MeSH term(s)	Antibodies, Monoclonal, Humanized/pharmacokinetics ; Antibodies, Monoclonal, Humanized/therapeutic use ; Clinical Trials as Topic ; Drug Therapy, Combination ; Humans ; Immunoconjugates/therapeutic use ; Maytansine/analogs & derivatives ; Maytansine/pharmacokinetics ; Maytansine/therapeutic use ; Neoplasms/drug therapy ; Neoplasms/metabolism ; Receptor, ErbB-2/immunology ; Trastuzumab
Chemical Substances	Antibodies, Monoclonal, Humanized ; Immunoconjugates ; Maytansine (14083FR882) ; Receptor, ErbB-2 (EC 2.7.10.1) ; Trastuzumab (P188ANX8CK) ; ado-trastuzumab emtansine (SE2KH7T06F)
Language	English
Publishing date	2011-10-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-11-0762
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Zs.A 4223: Show issues

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Article ; Online: Patient-reported outcomes from EMILIA, a randomized phase 3 study of trastuzumab emtansine (T-DM1) versus capecitabine and lapatinib in human epidermal growth factor receptor 2-positive locally advanced or metastatic breast cancer.

Welslau, Manfred / Diéras, Veronique / Sohn, Joo-Hyuk / Hurvitz, Sara A / Lalla, Deepa / Fang, Liang / Althaus, Betsy / Guardino, Ellie / Miles, David

Cancer

2014 Volume 120, Issue 5, Page(s) 642–651

Abstract: Background: This report describes the results of an analysis of patient-reported outcomes from EMILIA (TDM4370g/BO21977), a randomized phase 3 study of the antibody-drug conjugate trastuzumab emtansine (T-DM1) versus capecitabine and lapatinib in human ... ...

Abstract	Background: This report describes the results of an analysis of patient-reported outcomes from EMILIA (TDM4370g/BO21977), a randomized phase 3 study of the antibody-drug conjugate trastuzumab emtansine (T-DM1) versus capecitabine and lapatinib in human epidermal growth factor receptor 2 (HER2)-positive locally advanced or metastatic breast cancer. Methods: A secondary endpoint of the EMILIA study was time to symptom worsening (time from randomization to the first documentation of a ≥ 5-point decrease from baseline) as measured by the Trial Outcome Index Physical/Functional/Breast (TOI-PFB) subset of the Functional Assessment of Cancer Therapy-Breast questionnaire. Predefined exploratory patient-reported outcome endpoints included proportion of patients with a clinically significant improvement in symptoms (per TOI-PFB) and proportion of patients with diarrhea symptoms (per Diarrhea Assessment Scale). Results: In the T-DM1 arm, 450 of 495 patients had a baseline and ≥ 1 postbaseline TOI-PFB score versus 445 of 496 patients in the capecitabine-plus-lapatinib arm. Time to symptom worsening was delayed in the T-DM1 arm versus the capecitabine-plus-lapatinib arm (7.1 months versus 4.6 months, respectively; hazard ratio = 0.796; P = .0121). In the T-DM1 arm, 55.3% of patients developed clinically significant improvement in symptoms from baseline versus 49.4% in the capecitabine-plus-lapatinib arm (P = .0842). Although similar at baseline, the number of patients reporting diarrhea symptoms increased 1.5- to 2-fold during treatment with capecitabine and lapatinib but remained near baseline levels in the T-DM1 arm. Conclusions: Together with the EMILIA primary data, these results support the concept that T-DM1 has greater efficacy and tolerability than capecitabine plus lapatinib, which may translate into improvements in health-related quality of life.
MeSH term(s)	Adult ; Aged ; Antibodies, Monoclonal, Humanized/administration & dosage ; Antineoplastic Combined Chemotherapy Protocols/adverse effects ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Biomarkers, Tumor/analysis ; Breast Neoplasms/chemistry ; Breast Neoplasms/drug therapy ; Breast Neoplasms/pathology ; Capecitabine ; Deoxycytidine/administration & dosage ; Deoxycytidine/analogs & derivatives ; Diarrhea/chemically induced ; Disease-Free Survival ; Drug Administration Schedule ; Female ; Fluorouracil/administration & dosage ; Fluorouracil/analogs & derivatives ; Health Status ; Humans ; Maytansine/administration & dosage ; Maytansine/analogs & derivatives ; Medication Adherence/statistics & numerical data ; Middle Aged ; Quality of Life ; Quinazolines/administration & dosage ; Receptor, ErbB-2/analysis ; Self Report ; Surveys and Questionnaires ; Time Factors ; Trastuzumab ; Treatment Outcome
Chemical Substances	Antibodies, Monoclonal, Humanized ; Biomarkers, Tumor ; Quinazolines ; lapatinib (0VUA21238F) ; Deoxycytidine (0W860991D6) ; Maytansine (14083FR882) ; Capecitabine (6804DJ8Z9U) ; ERBB2 protein, human (EC 2.7.10.1) ; Receptor, ErbB-2 (EC 2.7.10.1) ; Trastuzumab (P188ANX8CK) ; ado-trastuzumab emtansine (SE2KH7T06F) ; Fluorouracil (U3P01618RT)
Language	English
Publishing date	2014-03-01
Publishing country	United States
Document type	Clinical Trial, Phase III ; Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	1429-1
ISSN	1097-0142 ; 0008-543X ; 1934-662X
ISSN (online)	1097-0142
ISSN	0008-543X ; 1934-662X
DOI	10.1002/cncr.28465
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Article ; Online: Relationship between HER2 expression and efficacy with first-line trastuzumab emtansine compared with trastuzumab plus docetaxel in TDM4450g: a randomized phase II study of patients with previously untreated HER2-positive metastatic breast cancer.

Perez, Edith A / Hurvitz, Sara A / Amler, Lukas C / Mundt, Kirsten E / Ng, Vivian / Guardino, Ellie / Gianni, Luca

Breast cancer research : BCR

2014 Volume 16, Issue 3, Page(s) R50

Abstract: Introduction: The purpose of this study was to retrospectively explore the relationship between human epidermal growth factor receptor 2 (HER2) messenger RNA (mRNA) expression and efficacy in patients receiving trastuzumab plus docetaxel (HT) or ... ...

Abstract	Introduction: The purpose of this study was to retrospectively explore the relationship between human epidermal growth factor receptor 2 (HER2) messenger RNA (mRNA) expression and efficacy in patients receiving trastuzumab plus docetaxel (HT) or trastuzumab emtansine (T-DM1). Methods: Patients with HER2-positive, locally advanced or metastatic breast cancer (MBC) were randomly assigned to HT (n=70) or T-DM1 (n=67). HER2 status was assessed locally using immunohistochemistry or fluorescence in situ hybridization and confirmed retrospectively by central testing. HER2 mRNA expression was assessed using quantitative reverse transcriptase polymerase chain reaction. Results: HER2 mRNA levels were obtained for 116/137 patients (HT=61; T-DM1=55). Median pretreatment HER2 mRNA was 8.9. The risk of disease progression in the overall population was lower with T-DM1 than with HT (hazard ratio (HR)=0.59; 95% confidence interval (CI) 0.36 to 0.97). This effect was more pronounced in patients with HER2 mRNA≥median (HR=0.39; 95% CI 0.18 to 0.85) versus <median (HR=0.85; 95% CI 0.44 to 1.67). In the T-DM1 arm, median progression-free survival (PFS) was not reached in patients with HER2 mRNA≥median and was 10.6 months in patients with HER2 mRNA<median. In the HT arm, PFS was 8.8 versus 9.8 months in patients with HER2 mRNA≥median versus<median, respectively. The effect of HER2 mRNA expression on objective response rates was less pronounced.<br />Conclusions: This exploratory analysis suggests that while overall, patients with HER2-positive MBC show improved PFS with T-DM1 relative to HT, the effect is enhanced in patients with tumor HER2 mRNA ≥ median. Trial registration: ClinicalTrials.gov NCT00679341.
MeSH term(s)	Ado-Trastuzumab Emtansine ; Adult ; Aged ; Aged, 80 and over ; Antibodies, Monoclonal, Humanized/therapeutic use ; Antineoplastic Agents/therapeutic use ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Breast Neoplasms/drug therapy ; Disease-Free Survival ; Docetaxel ; Female ; Humans ; Maytansine/analogs & derivatives ; Maytansine/therapeutic use ; Middle Aged ; RNA, Messenger/biosynthesis ; Receptor, ErbB-2/biosynthesis ; Receptor, ErbB-2/genetics ; Receptor, ErbB-2/metabolism ; Retrospective Studies ; Taxoids/therapeutic use ; Trastuzumab ; Treatment Outcome
Chemical Substances	Antibodies, Monoclonal, Humanized ; Antineoplastic Agents ; RNA, Messenger ; Taxoids ; Maytansine (14083FR882) ; Docetaxel (15H5577CQD) ; ERBB2 protein, human (EC 2.7.10.1) ; Receptor, ErbB-2 (EC 2.7.10.1) ; Trastuzumab (P188ANX8CK) ; Ado-Trastuzumab Emtansine (SE2KH7T06F)
Language	English
Publishing date	2014-05-23
Publishing country	England
Document type	Clinical Trial, Phase II ; Journal Article ; Multicenter Study ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	2015059-3
ISSN	1465-542X ; 1465-5411
ISSN (online)	1465-542X
ISSN	1465-5411
DOI	10.1186/bcr3661
Database	MEDical Literature Analysis and Retrieval System OnLINE

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