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BMC Cancer Oct 2019Although the dual anti-HER2 therapy, namely, pertuzumab plus trastuzumab and docetaxel, has shown promising results in HER2+ breast cancer patients, whether the dose,... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Although the dual anti-HER2 therapy, namely, pertuzumab plus trastuzumab and docetaxel, has shown promising results in HER2+ breast cancer patients, whether the dose, efficacy and safety of this treatment differs from those of other pertuzumab-based dual anti-HER2 therapies remain controversial. This systematic review evaluates the efficacy and safety of H (trastuzumab or trastuzumab emtansine ± chemotherapy) + P (pertuzumab) compared with those of H in HER2+ breast cancer patients.
METHODS
A comprehensive search was performed to identify eligible studies comparing the efficacy and safety of H + P versus H. The pathologic complete response (pCR), median progression-free survival (PFS) and overall survival (OS) were the primary outcomes, and safety was the secondary outcome. A subgroup analysis of pCR according to hormone receptor (HR) status was performed. All analyses were conducted using STATA 11.0.
RESULTS
Twenty-six studies (9872 patients) were identified. In the neoadjuvant setting, H + P significantly improved the pCR [odds ratio (OR) = 1.33; 95% confidence interval (CI), 1.08-1.63; p = 0.006]. In the metastatic setting, H + P significantly improved PFS [hazard ratios (HRs) = 0.75; 95% CI, 0.68-0.84; p < 0.001]. There was a trend towards better OS but that it did not reach statistical significance (HRs = 0.81; 95% CI, 0.64-1.03; p = 0.082). A subgroup analysis revealed that the HER2+/HR- patients who received H + P showed the highest increase in the pCR. Rash, diarrhea, epistaxis, mucosal inflammation, and anemia were significantly more frequently observed with H + P than with H, whereas myalgia was less frequent (OR = 0.91; 95% CI, 0.82-1.01; p = 0.072), and no significant difference in cardiac toxicity was observed between these therapies (OR = 1.26; 95% CI, 0.81-1.95; P = 0.309).
CONCLUSIONS
Our study confirms that H + P is superior to H in the (neo)adjuvant treatment of HER2+ breast cancer, and increase the risk of acceptable and tolerable toxicity (rash, diarrhea, epistaxis, mucosal inflammation, and anemia).
TRIAL REGISTRATION
A systematic review protocol was registered with PROSPERO (identification number: CRD42018110415 ).
Topics: Ado-Trastuzumab Emtansine; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Diarrhea; Docetaxel; Epistaxis; Exanthema; Female; Humans; Molecular Targeted Therapy; Neoadjuvant Therapy; Progression-Free Survival; Receptor, ErbB-2; Trastuzumab
PubMed: 31638935
DOI: 10.1186/s12885-019-6132-0 -
Medicine Sep 2019This study will systematically investigate the efficacy and safety of the combination of pertuzumab, trastuzumab, and docetaxel (PTD) for treatment of patients with...
BACKGROUND
This study will systematically investigate the efficacy and safety of the combination of pertuzumab, trastuzumab, and docetaxel (PTD) for treatment of patients with HER2-positive breast cancer (HER2-PBC).
METHODS
A comprehensive literature search for this study will consist of 2 parts: electronic database records and gray literature. The electronic database literatures are searched from PubMed, EMBASE, Cochrane Library, Web of Science, Google Scholar, Allied and Complementary Medicine Database, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure. All databases will be searched from inception up to the present. In addition, gray literatures, such as dissertations, ongoing trials, and so on, will also be searched. Two authors will independently read the records, extract data collection, and evaluate the risk of bias. RevMan V.5.3 software will be applied for statistical analysis.
RESULTS
This study will summarize up-to-date evidence of PTD for patients with HER2-PBC via overall survival, complete response, cancer-specific survival, recurrence-free survival, disease-free survival, quality of life, and toxicities.
CONCLUSION
This study will provide efficacy and safety of PTD for HER2-PBC.
Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Docetaxel; Female; Genes, erbB-2; Humans; Receptor, ErbB-2; Trastuzumab; Treatment Outcome
PubMed: 31568001
DOI: 10.1097/MD.0000000000017262 -
JAMA Cardiology Oct 2019Echocardiographic left ventricular global longitudinal strain (GLS) detects early subclinical ventricular dysfunction and can be used in patients receiving potentially... (Meta-Analysis)
Meta-Analysis
Assessment of Prognostic Value of Left Ventricular Global Longitudinal Strain for Early Prediction of Chemotherapy-Induced Cardiotoxicity: A Systematic Review and Meta-analysis.
IMPORTANCE
Echocardiographic left ventricular global longitudinal strain (GLS) detects early subclinical ventricular dysfunction and can be used in patients receiving potentially cardiotoxic chemotherapy. A meta-analysis of the prognostic value of GLS for cancer therapy-related cardiac dysfunction (CTRCD) has not been performed, to our knowledge.
OBJECTIVE
To explore the prognostic value of GLS for the prediction of CTRCD.
DATA SOURCES
Systematic search of the MEDLINE, Embase, Scopus, and the Cochrane Library databases from database inception to June 1, 2018.
STUDY SELECTION
Cohort studies assessing the prognostic or discriminatory performance of GLS before or during chemotherapy for subsequent CTRCD.
DATA EXTRACTION AND SYNTHESIS
Random-effects meta-analysis and hierarchical summary receiver operating characteristic curves (HSROCs) were used to summarize the prognostic and discriminatory performance of different GLS indices. Publication bias was assessed using the Egger test, and meta-regression was performed to assess sources of heterogeneity.
MAIN OUTCOMES AND MEASURES
The primary outcome was CTRCD, defined as a clinically significant change in left ventricular ejection fraction with or without new-onset heart failure symptoms.
RESULTS
Analysis included 21 studies comprising 1782 patients with cancer, including breast cancer, hematologic malignancies, or sarcomas, treated with anthracyclines with or without trastuzumab. The incidence of CTRCD ranged from 9.3% to 43.8% over a mean follow-up of 4.2 to 23.0 months (pooled incidence, 21.0%). For active treatment absolute GLS (9 studies), the high-risk cutoff values ranged from -21.0% to -13.8%, with worse GLS associated with a higher CTRCD risk (odds ratio, 12.27; 95% CI, 7.73-19.47; area under the HSROC, 0.86; 95% CI, 0.83-0.89). For relative changes vs a baseline value (9 studies), cutoff values ranged from 2.3% to 15.9%, with a greater decrease linked to a 16-fold higher risk of CTRCD (odds ratio, 15.82; 95% CI, 5.84-42.85; area under the HSROC, 0.86; 95% CI, 0.83-0.89). Both indices showed significant publication bias. Meta-regression identified differences in sample size and CTRCD definition but not GLS cutoff value as significant sources of interstudy heterogeneity.
CONCLUSIONS AND RELEVANCE
In this meta-analysis, measurement of GLS after initiation of potentially cardiotoxic chemotherapy with anthracyclines with or without trastuzumab had good prognostic performance for subsequent CTRCD. However, risk of bias in the original studies, publication bias, and limited data on the incremental value of GLS and its optimal cutoff values highlight the need for larger prospective multicenter studies.
Topics: Antineoplastic Agents; Cardiotoxicity; Early Diagnosis; Echocardiography; Heart Ventricles; Humans; Neoplasms; Stroke Volume; Ventricular Dysfunction, Left; Ventricular Function, Left
PubMed: 31433450
DOI: 10.1001/jamacardio.2019.2952 -
Expert Review of Clinical Pharmacology Aug 2019: Breast cancer remains to be the globally leading female cancer. About 15% to 20% of breast cancers have human epidermal growth factor receptor 2 (HER2)-positive tumors... (Meta-Analysis)
Meta-Analysis
: Breast cancer remains to be the globally leading female cancer. About 15% to 20% of breast cancers have human epidermal growth factor receptor 2 (HER2)-positive tumors - a more aggressive breast cancer subtype with shortened survival. In the light of new and updated trial data on trastuzumab therapy for HER2-positive early-stage breast cancer (EBC), we conducted a systematic review and meta-analysis to update the pooling of its relative treatment effects. : Systematic search was performed through Pubmed and Scopus to identify studies comparing survival outcomes and risks of heart toxicity effects of adjuvant trastuzumab with chemotherapy versus chemotherapy alone for HER2-positive EBC patients. : Based on the eight included studies in the review, combining trastuzumab with chemotherapy continues to show lowered death and relapse risks by one-third. The decision to initiate trastuzumab, however, needs to be prudently deliberated as two to three times more cardiotoxicity risk was shown to be associated with its use. : Administering adjuvant trastuzumab in a weekly cycle concurrently with anthracycline-taxane chemotherapy regimen appears to be a preferable option to optimize its favorable effect in improving DFS and to prevent significantly higher risk for cardiotoxic effects.
Topics: Antineoplastic Agents, Immunological; Breast Neoplasms; Cardiotoxicity; Chemotherapy, Adjuvant; Disease-Free Survival; Female; Humans; Neoplasm Staging; Receptor, ErbB-2; Trastuzumab
PubMed: 31287333
DOI: 10.1080/17512433.2019.1637252 -
Value in Health Regional Issues May 2019To systematically review and assess the quality of the economic evidence of adjuvant trastuzumab usage in early breast cancer in Asian countries.
OBJECTIVES
To systematically review and assess the quality of the economic evidence of adjuvant trastuzumab usage in early breast cancer in Asian countries.
METHODS
Literature search was performed using 6 electronic databases (PubMed, Scopus, Ovid MEDLINE, EconLit, National Health Service Economic Evaluation Database, and ISI Web of Knowledge). The final search was performed in October 2018. All potential economic studies were then checked for eligibility. The reporting and methodological qualities of each study were independently assessed by 2 authors of this review, using the Consolidated Health Economic Evaluation Reporting Standards, Drummond, and Philips checklists. To compare the different currencies used in these studies, all costs were converted into US dollars (2016).
RESULTS
A total of 6 studies were included; most of them were performed from the healthcare provider perspective. The incremental cost-effectiveness ratio for evaluation performed for a lifetime horizon were reported at $8573 and $20 816 per quality-adjusted life-year in 2 studies. The model outcome was generally sensitive to the changes in trastuzumab drug acquisition cost and discount rate, as well as its clinical effectiveness. For the quality assessment, all studies fulfilled more than 50% of the requirements in the Consolidated Health Economic Evaluation Reporting Standards, Drummond, and Philips checklists.
CONCLUSIONS
Adjuvant trastuzumab therapy is considered a cost-effective option for early breast cancer in Asian countries including China, Iran, Japan, Singapore, and Taiwan. All studies were generally well conducted. Economic evaluations from the societal perspective, with inclusion of indirect and informal care costs, are warranted to facilitate informed decision making among policy makers.
Topics: Breast Neoplasms; Cost-Benefit Analysis; Female; Humans; Secondary Prevention; Trastuzumab
PubMed: 31082795
DOI: 10.1016/j.vhri.2019.02.003 -
The Lancet. Oncology Mar 2019Although frequently used as a primary endpoint, disease-free survival has not been validated as a surrogate for overall survival in early breast cancer. We investigated... (Meta-Analysis)
Meta-Analysis
Disease-free survival as a surrogate for overall survival in patients with HER2-positive, early breast cancer in trials of adjuvant trastuzumab for up to 1 year: a systematic review and meta-analysis.
BACKGROUND
Although frequently used as a primary endpoint, disease-free survival has not been validated as a surrogate for overall survival in early breast cancer. We investigated this surrogacy in the adjuvant setting of treatment with anti-HER2 antibodies.
METHODS
In a systematic review and meta-analysis, we identified published and non-published randomised controlled trials with completed accrual and available disease-free survival and overall survival results for the intention-to-treat population as of September 2016. Bibliographic databases (MEDLINE, Embase, and Cochrane Central Register of Controlled Trials), clinical trial registries (Clinicaltrials.gov, EU Clinical Trials Register, WHO International Clinical Trials Registry Platform, and PharmNet.Bund), and trial registries from relevant pharmaceutical companies were searched. Eligibility for treatment of HER2-positive early breast cancer required at least one group to have an anti-HER antibody treatment (ie, trastuzumab, pertuzumab, or trastuzumab emtansine) planned for 12 months, and at least one control arm with chemotherapy without the antibody, a lower total dose or duration of the antibody, or observation alone. Units of analysis were contrasts: two-group trials gave rise to one contrast, whereas trials with more than two groups gave rise to more than one contrast. We excluded trials enrolling patients with recurrent, metastatic, or non-invasive disease, and those testing neoadjuvant therapy exclusively. Our primary objective was to estimate patient-level and trial-level correlations between disease-free survival and overall survival. We measured the association between disease-free survival and overall survival using Spearman's correlation coefficient (r), and the association between hazard ratios (HRs) for disease-free survival and overall survival using R. We computed the surrogate threshold effect, the maximum HR for disease-free survival that statistically predicts an HR for overall survival less than 1·00 in a future trial.
FINDINGS
Eight trials (n=21 480 patients) gave rise to a full set (12 contrasts). Patient-level associations between disease-free and overall survival were strong (r=0·90 [95% CI 0·89-0·90]). Trial-level associations gave rise to values of R of 0·75 (95% CI 0·50-1·00) for the full set. Subgroups defined by nodal status and hormone receptor status yielded qualitatively similar results. Depending on the expected number of deaths in a future trial, the surrogate threshold effects ranged from 0·56 to 0·81, based on the full set.
INTERPRETATION
These findings suggest that it is appropriate to continue to use disease-free survival as a surrogate for overall survival in trials in HER-2-positive, early breast cancer. The key limitation of this study is the dependence of its results on the trials included and on the existence of an outlying trial.
FUNDING
Roche Pharma AG.
Topics: Ado-Trastuzumab Emtansine; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Chemotherapy, Adjuvant; Disease-Free Survival; Drug Administration Schedule; Female; Humans; Neoplasm Staging; Proportional Hazards Models; Receptor, ErbB-2; Treatment Outcome
PubMed: 30709633
DOI: 10.1016/S1470-2045(18)30750-2 -
Journal of Managed Care & Specialty... Feb 2019Pharmacogenetic testing can provide predictive insights about the efficacy and safety of drugs used in cancer treatment. Although many drug-gene associations have been...
BACKGROUND
Pharmacogenetic testing can provide predictive insights about the efficacy and safety of drugs used in cancer treatment. Although many drug-gene associations have been reported in the literature, the strength of evidence supporting each association can vary significantly. Even among the subgroup of drugs classified by the PharmGKB database to have a high or moderate level of evidence, there is limited information regarding the economic value of pharmacogenetic testing.
OBJECTIVES
To: (a) summarize the available pharmacoeconomic evidence assessing the value of pharmacogenetic testing for cancer drugs with clinically relevant drug-gene associations; (b) determine the quality of the studies that contain this evidence; and (c) discuss the quality of this evidence with respect to the level of evidence of the drug-gene associations.
METHODS
The PharmGKB database was used to identify cancer drugs with clinically relevant drug-gene associations graded high (1A, 1B) or moderate (2A, 2B). A systematic literature review was conducted using these drugs. Ovid MEDLINE and Embase databases were searched to identify cost-effectiveness, cost-utility, or cost-minimization studies comparing pharmacogenetic testing to an alternative. Cost and effect values from every relevant comparison within the studies were extracted, and the incremental cost-effectiveness ratio (ICER) was either extracted or calculated for each comparison. Quality assessment was conducted for each study using the Quality of Health Economic Studies (QHES) instrument. Qualitative synthesis was used to summarize the data.
RESULTS
The search yielded 2,191 citations, of which 35 studies met the inclusion criteria. Pharmacoeconomic studies were available for the following drugs from the PharmGKB database: fluoropyrimidine, 6-mercaptopurine, irinotecan, carboplatin, cisplatin, erlotinib, gefitinib, cetuximab, panitumumab, and trastuzumab. The studies were conducted in Asia, Europe, Canada, the United States, and Mexico and reported cost-utility, cost-effectiveness, and cost-minimization outcomes. The mean QHES score was 80 (SD = 22) for the studies of drug-gene pairs with high (1A, 1B) and moderate (2A, 2B) levels of evidence (1A = 82, 1B = 93, 2A = 71, and 2B = 74). There was variation across studies in terms of reporting. 109 relevant comparisons were identified within the studies. Of those that reported cost per life-year or cost per quality-adjusted life-year (n = 58 comparisons), pharmacogenetic testing was dominant in 21% overall and 42%, 21%, 17%, and 5% of the comparisons in Asia, Europe, Canada, and the United States, respectively. Variability was observed in the ICER values regardless of geographic region or drug. Pharmacogenetic testing was cost saving in 17 of 19 cost-minimization comparisons and was favored most frequently when compared with genetically indiscriminate strategies containing the drug of interest.
CONCLUSIONS
There was mixed evidence regarding the value of pharmacogenetic testing to guide cancer treatment. For future pharmacogenomic-related economic studies, we recommend prioritizing clinically relevant drug-gene associations and greater adherence to available best practice guidelines for conducting and reporting economic evaluation studies.
DISCLOSURES
No outside funding supported this review. Part of Hussain's research time was supported by a Merit Review Award (I01 BX000545), Medical Research Service, U.S. Department of Veterans Affairs. Hussain also reports personal fees from Bristol-Myers Squibb, AstraZeneca, Novartis, Bayer HealthCare Pharmaceuticals, and France Foundation, outside the submitted work. Onukwugha reports grants from Pfizer and Bayer HealthCare Pharmaceuticals, along with advisory board fees from Novo Nordisk, outside the submitted work. Faruque, Neuberger, and Noh have nothing to disclose.
Topics: Antineoplastic Agents; Cost-Benefit Analysis; Economics, Pharmaceutical; Humans; Neoplasms; Pharmacogenomic Testing; Quality-Adjusted Life Years
PubMed: 30698084
DOI: 10.18553/jmcp.2019.25.2.260 -
OncoTargets and Therapy 2019To evaluate efficacy and safety of lapatinib or trastuzumab alone or both plus chemotherapy for the treatment of breast cancer patients with positive HER-2 expression.
AIM
To evaluate efficacy and safety of lapatinib or trastuzumab alone or both plus chemotherapy for the treatment of breast cancer patients with positive HER-2 expression.
METHODS
Cochrane Central Register of Controlled Trials, PubMed, MEDLINE, OVID, Embase, Chinese Biomedical Literature Database, and China Academic Journals Database were searched from 1994 through December 2017 using the keywords "breast cancer", "preoperative", "neo-adjuvant", "lapatinib", "pertuzumab", "Herceptin", and "trastuzumab".
RESULTS
Meta-analysis found that pathological complete response (PCR; risk ratio [RR]=0.82, 95% CI: 0.72-0.93) and tall PCR (tPCR; RR=0.77, 95% CI: 0.67-0.88) of chemotherapy plus lapatinib were significantly less effective or safe compared to that of chemotherapy plus trastuzumab (<0.05). PCR (RR=1.30, 95% CI: 1.15-1.47) and tPCR (RR=1.32, 95% CI: 1.16-1.50) of chemotherapy plus both lapatinib and trastuzumab were significantly superior to that of chemotherapy plus trastuzumab alone (<0.05). However, there was no significant difference in breast reservation rate between chemotherapy plus lapatinib vs chemotherapy plus trastuzumab (RR=0.91, 95% CI: 0.72-1.16) or chemotherapy plus both lapatinib and trastuzumab (RR=1.11, 95% CI: 0.73-1.68, >0.05). Incidence of diarrhea, hepatic toxicity, and skin rash in the groups of chemotherapy plus lapatinib or chemotherapy plus both lapatinib and trastuzumab was significantly higher than that in chemotherapy plus trastuzumab (<0.05).
CONCLUSION
Efficacy of lapatinib was less than that of trastuzumab, but incidence of adverse effect of lapatinib was higher than that of trastuzumab. Combination of chemotherapy plus both lapatinib and trastuzumab could significantly increase PCR and tPCR in breast cancer patients, but rate of breast conservation, event-free survival, and overall survival was not significantly improved. Incidence of diarrhea, hepatic toxicity, and skin rash was significantly increased in the groups using lapatinib.
PubMed: 30655674
DOI: 10.2147/OTT.S183304 -
Systematic Reviews Nov 2018Originator trastuzumab (Herceptin®; H) is an antibody-targeted therapy to treat patients with human epidermal growth factor receptor 2-positive (HER2+) early breast... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Originator trastuzumab (Herceptin®; H) is an antibody-targeted therapy to treat patients with human epidermal growth factor receptor 2-positive (HER2+) early breast cancer (EBC). We investigated the overall survival (OS) advantage conferred by the addition of H to chemotherapy for HER2+ EBC patients and how the OS advantage changed over time.
METHODS
A systematic literature review (SLR) identified randomized controlled trials (RCTs) and non-randomized studies (NRSs) published from January 1, 1990 to January 19, 2017, comparing systemic therapies used in the neoadjuvant/adjuvant settings to treat HER2+ EBC patients. Bayesian cumulative network meta-analyses (cNMAs) of OS were conducted to assess the published literature over time. Heterogeneity was assessed through sensitivity and subgroup analyses.
RESULTS
The SLR identified 31 unique studies (28 RCTs, 3 NRSs) included in the OS analyses from 2008 to 2016. In the reference case cNMA (RCTs alone), initial evidence demonstrated an OS advantage for H/chemotherapy compared with chemotherapy alone in HER2+ EBC patients. As additional OS data were published, the precision around this survival benefit strengthened over time. Both H/anthracycline-containing chemotherapy and H/non-anthracycline-containing chemotherapy regimens provided similar OS advantages for HER2+ EBC patients.
CONCLUSION
This analysis represents the most comprehensive SLR/cNMA to date of published OS data in HER2+ EBC studies. These findings demonstrate why H/chemotherapy is now the established standard of care in HER2+ EBC. In the case of H, the benefits of early patient access far outweighed the risk of waiting for more precise information.
SYSTEMATIC REVIEW REGISTRATION
PROSPERO CRD42017055763.
Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Humans; Network Meta-Analysis; Receptor, ErbB-2; Survival Rate; Trastuzumab
PubMed: 30428932
DOI: 10.1186/s13643-018-0854-y -
Cardiovascular Therapeutics Dec 2018Cases of cardiotoxicity related to trastuzumab have been reported. This systematic review and meta-analysis evaluated the risk of atrial fibrillation (AF) in patients of... (Meta-Analysis)
Meta-Analysis
AIM
Cases of cardiotoxicity related to trastuzumab have been reported. This systematic review and meta-analysis evaluated the risk of atrial fibrillation (AF) in patients of breast cancer treated with trastuzumab.
METHODS
PubMed and EMBASE were searched until September 2017 for articles that investigated AF incidence in patients receiving trastuzumab for breast cancer.
RESULTS
A total of 15 studies involving 8124 patients treated with trastuzumab were included. Of the total cohort, 37 patients suffered from AF, giving rise to an incidence of 1.22% (95% confidence interval [CI]: 0.56%-2.68%). No significant difference in the incidence of AF was found between ado-trastuzumab emtansine (0.95%, 95% CI: 0.36%-2.52%) and trastuzumab groups (1.32%, 95% CI: 0.52%-3.34%), trastuzumab combined with other antineoplastic agents (2.09%, 95% CI: 1.16%-3.73%) and trastuzumab alone (0.36%, 95% CI: 0.04%-3.08%), prior exposure to anthracyclines (1.72%, 95% CI: 0.75%-3.88%) and no prior exposure (1.03%, 95% CI: 0.30%-3.51%), and radiotherapy (1.26%, 95% CI: 0.68%-2.33%) vs. no radiotherapy (1.21%, 95% CI: 0.35%-4.14%).
CONCLUSIONS
Atrial fibrillation incidence in breast cancer patients receiving trastuzumab was around 1.2%. It was not influenced by the formulation of trastuzumab, the additional use of neoplastic agents, anthracycline exposure status, or concurrent radiotherapy.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Immunological; Atrial Fibrillation; Breast Neoplasms; Breast Neoplasms, Male; Cardiotoxicity; Female; Humans; Incidence; Male; Middle Aged; Risk Assessment; Risk Factors; Trastuzumab; Young Adult
PubMed: 30372591
DOI: 10.1111/1755-5922.12475