Observational GHEA Study: Adjuvant-Trastuzumab-Treatment of HER2-Positive Breast Carcinoma.

We previously identified an extracellular matrix (ECM) gene expression pattern in breast cancer (BC), called ECM3, characterized by a high expression of genes encoding structural ECM proteins. Since ECM is reportedly implicated in response to therapy of BCs, the aim of this work is to investigate the prognostic and predictive value of ECM3 molecular classification in HER2-positive BCs. ECM3 resulted in a robust cluster that identified a subset of 25–37% of HER2-positive tumors with molecular aggressive features. ECM3 was significantly associated with worse prognosis in two datasets of HER2-positive BCs untreated with adjuvant therapy. Analyses carried out on two of our cohorts of patients treated or not with adjuvant trastuzumab showed association of ECM3 with worse prognosis only in patients not treated with trastuzumab. Moreover, investigating a dataset that includes gene profile data of tumors treated with neoadjuvant trastuzumab plus chemotherapy or chemotherapy alone, ECM3 was associated with increased pathological complete response if treated with trastuzumab. In the in vivo experiments, increased diffusion and trastuzumab activity were found in tumors derived from injection of HER2-positive cells with Matrigel that creates an ECM-rich tumor environment. Taken together, these results indicate that HER2-positive BCs classified as ECM3 have an aggressive phenotype but they are sensitive to trastuzumab treatment.

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De-escalating adjuvant trastuzumab in human epidermal growth factor receptor 2 (HER2)-positive early-stage breast cancer: A systemic review and meta-analysis.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.524 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 524-524

Author(s):

Hadar Goldvaser ◽

Korzets Ceder Yasmin ◽

Daniel Shepshelovich ◽

Rinat Yerushalmi ◽

Michal Sarfaty ◽

...

Keyword(s):

Breast Cancer ◽

Cardiac Dysfunction ◽

Early Stage ◽

Nodal Involvement ◽

Her2 Positive ◽

Adjuvant Trastuzumab ◽

Trastuzumab Treatment ◽

Her2 Positive Breast Cancer ◽

One Year ◽

Positive Breast Cancer

524 Background: One year of adjuvant trastuzumab in combination with chemotherapy is the standard of care in early-stage HER2 positive breast cancer. Existing data on shortening trastuzumab treatment show conflicting results. Methods: A search of PubMed and conferences identified randomized trials that compared abbreviated trastuzumab therapy to one year of treatment in early-stage HER2 positive breast cancer. Hazard ratios (HRs) and 95% confidence intervals (CI) were extracted for disease free survival (DFS) and overall survival (OS). Data on the number of DFS and distant relapse events were also collected as were the number of patients at risk in each group. Subgroup analyses evaluated the effect of nodal involvement, estrogen receptor (ER) expression and the duration of abbreviated trastuzumab (9-12 weeks versus 6 months). Odds ratios (ORs) and 95% CI were computed for pre-specified cardiotoxicity events including cardiac dysfunction and congestive heart failure (CHF). Results: Analysis included 6 trials comprising 11603 patients. In most studies adjuvant chemotherapy included anthracyclines and taxanes. Shorter trastuzumab treatment was associated with worse DFS (HR = 1.14, 95% CI 1.05-1.25, p = 0.002) and OS (HR = 1.15, 95% CI 1.02-1.29. p = 0.02). The effect on DFS was not influenced by ER status (p for the subgroup difference = 0.23), nodal involvement (p = 0.44) or the different duration of trastuzumab in the experimental arm (p = 0.08). In absolute terms, after an estimated median follow-up of 71 months, shorter treatment with trastuzumab was associated with an absolute increase in DFS events of 2.3%. Shorter trastuzumab treatment was associated with lower odds of cardiac dysfunction (OR = 0.67, 95% CI 0.55-0.81, p < 0.001) and CHF (OR = 0.66, 95% CI 0.50-0.86, p = 0.003). Conclusions: Compared to one year, shorter duration of adjuvant trastuzumab is associated with significantly worse DFS and OS, despite favorable cardiotoxicity profile. One year of trastuzumab should remain the standard adjuvant treatment in early-stage HER2 positive breast cancer with appropriate cardiac monitoring.

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Stability of HER2-positive status in breast carcinoma: a comparison between primary and paired metastatic tumors with regard to the possible impact of intervening trastuzumab treatment

Annals of Oncology ◽

10.1093/annonc/mdq623 ◽

2011 ◽

Vol 22 (7) ◽

pp. 1547-1553 ◽

Cited By ~ 33

Author(s):

C. Xiao ◽

Y. Gong ◽

E.Y. Han ◽

A.M. Gonzalez-Angulo ◽

N. Sneige

Keyword(s):

Breast Carcinoma ◽

Her2 Positive ◽

Metastatic Tumors ◽

Trastuzumab Treatment

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Deescalating Adjuvant Trastuzumab in HER2-Positive Early-Stage Breast Cancer: A Systemic Review and Meta-Analysis

JNCI Cancer Spectrum ◽

10.1093/jncics/pkz033 ◽

2019 ◽

Vol 3 (2) ◽

Cited By ~ 10

Author(s):

Hadar Goldvaser ◽

Yasmin Korzets ◽

Daniel Shepshelovich ◽

Rinat Yerushalmi ◽

Michal Sarfaty ◽

...

Keyword(s):

Breast Cancer ◽

Heart Failure ◽

Cardiac Dysfunction ◽

Early Stage ◽

Nodal Involvement ◽

Her2 Positive ◽

Adjuvant Trastuzumab ◽

Trastuzumab Treatment ◽

One Year ◽

Positive Breast Cancer

AbstractBackgroundOne year of adjuvant trastuzumab in combination with chemotherapy is the standard of care in early-stage human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Existing data on shortening trastuzumab treatment show conflicting results.MethodsA search of PubMed and abstracts from key conferences identified randomized trials that compared abbreviated trastuzumab therapy to 1 year of treatment in early-stage HER2-positive breast cancer. Hazard ratios (HRs) and 95% confidence intervals (CIs) were extracted for disease-free survival (DFS) and overall survival (OS). Subgroup analyses evaluated the effect of nodal involvement, estrogen receptor expression, and the duration of abbreviated trastuzumab (9–12 weeks vs 6 months). Odds ratios (ORs) and 95% confidence intervals were computed for prespecified cardiotoxicity events including cardiac dysfunction and congestive heart failure. P values were two-sided.ResultsAnalysis included six trials comprising 11 603 patients. Shorter trastuzumab treatment was associated with worse DFS (HR = 1.14, 95% CI = 1.05 to 1.25, P = .002) and OS (HR = 1.15, 95% CI = 1.02 to 1.29. P = .02). The effect on DFS was not influenced by estrogen receptor status (P for the subgroup difference = .23), nodal involvement (P = .44), or the different duration of trastuzumab in the experimental arm (P = .09). Shorter trastuzumab treatment was associated with lower odds of cardiac dysfunction (OR = 0.67, 95% CI = 0.55 to 0.81, P < .001) and congestive heart failure (OR = 0.66, 95% CI = 0.50 to 0.86, P = .003).ConclusionsCompared with 1 year, shorter duration of adjuvant trastuzumab is associated with statistically significantly worse DFS and OS despite favorable cardiotoxicity profile. One year of targeted HER2 treatment should remain the standard adjuvant treatment in early-stage HER2-positive disease with appropriate cardiac monitoring.

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Abstract P4-12-06: Small HER2-positive breast carcinomas: Prognostic factors to consider in deciding on adjuvant trastuzumab treatment

10.1158/0008-5472.sabcs13-p4-12-06 ◽

2013 ◽

Author(s):

M Campiglio ◽

M Sandri ◽

M Sasso ◽

F Bianchi ◽

F Turdo ◽

...

Keyword(s):

Prognostic Factors ◽

Breast Carcinomas ◽

Her2 Positive ◽

Adjuvant Trastuzumab ◽

Trastuzumab Treatment

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Cardiotoxicity and cardiac monitoring during adjuvant trastuzumab in daily Dutch practice.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e11558 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e11558-e11558

Author(s):

Vivianne C. Tjan-Heijnen ◽

Shanly C. Seferina ◽

Maaike De Boer ◽

Franchette W.P.J. van den Berkmortel ◽

Roel JW Van Kampen ◽

...

Keyword(s):

The Netherlands ◽

Daily Practice ◽

Left Ventricular ◽

Cardiac Monitoring ◽

Left Ventricular Ejection ◽

Her2 Positive ◽

Adjuvant Trastuzumab ◽

Ventricular Ejection Fraction ◽

Trastuzumab Treatment ◽

Guidelines Adherence

e11558 Background: In this study we assessed the cardiotoxic effects of adjuvant trastuzumab in daily practice after its introduction in the Netherlands in 2005. Methods: We included all patients with stage I-III breast cancer diagnosed in the years 2005 to 2007 in 5 hospitals in the South of the Netherlands. We studied guidelines adherence on left ventricular ejection fraction (LVEF) monitoring and the incidence of cardiotoxicity in patients with HER2 positive disease treated with adjuvant trastuzumab, using similar cardiac-endpoints as in prior randomized trials. In addition, we determined predictors of onset of cardiotoxicity. Results: Of 2685 patients included, 494 (18.4%) had a HER2 positive tumor. From these 494, 266 (53.8%) were treated with adjuvant chemotherapy and 228 (85.7%) received trastuzumab. Anthracycline based chemotherapy was given to 218 (96%) patients prior to trastuzumab treatment. LVEF measurements were done in 222 patients (97.4%). Fifty eight patients (25.4%) had ‘symptomatic cardiotoxicity’ during trastuzumab treatment, of whom 43 (18.9%) patients had a drop in LVEF of ≥ 10 percentage points. In 36 (15.8%) patients, cardiotoxicity led to permanent discontinuation of trastuzumab although in 50% LVEF recovered to levels permitting continuation, and in 22 (9.6%) patients treatment was temporary discontinued. No cardiac deaths were seen. The largest drops in LVEF occurred between baseline and the first 3-month assessment. Only 3.1% permanently discontinued treatment ≥ 6 months measurement. Patients with trastuzumab related cardiotoxicity did not show more cardiac comorbidities at baseline (14% vs. 24% p=0.12) and did not receive a higher cumulative dose of anthracyclines (mean 549mg vs. 546mg, p=0.48) than those without trastuzumab related cardiotoxicity. Conclusions: Regarding cardiotoxicity,trastuzumab was cautiously implemented in the Netherlands. In the first years, physicians based their decision to discontinue treatment frequently on patient ‘symptoms’ apart from LVEF outcome. Treatment discontinuation occurred mainly in the first three months after start of trastuzumab. Funding:Netherlands Organization for Health Research and Development and Roche Netherlands.

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