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

2019 ◽  
Vol 3 (2) ◽  
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.

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

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.

scholarly journals Do all patients with HER2 positive breast cancer require one year of adjuvant trastuzumab? A systematic review and meta-analysis

The Breast ◽  
2020 ◽  
Vol 54 ◽  
pp. 203-210
Author(s):  
Paul Stewart ◽  
Phillip Blanchette ◽  
Prakesh S. Shah ◽  
Xiang Y. Ye ◽  
R. Gabriel Boldt ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Systematic Review ◽  
Meta Analysis ◽  
Her2 Positive ◽  
Adjuvant Trastuzumab ◽  
Her2 Positive Breast Cancer ◽  
One Year ◽  
Positive Breast Cancer

Do all patients with HER2-positive breast cancer require one year of adjuvant trastuzumab?: A systematic review and meta-analysis.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 522-522 ◽  
Author(s):  
Paul Stewart ◽  
Phillip S. Blanchette ◽  
Prakesh S Shah ◽  
Xiang Y Ye ◽  
R Gabriel Boldt ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Systematic Review ◽  
Randomized Trials ◽  
Meta Analysis ◽  
Her2 Positive ◽  
Adjuvant Trastuzumab ◽  
Her2 Positive Breast Cancer ◽  
Er Positive ◽  
One Year ◽  
Positive Breast Cancer

522 Background: One year of adjuvant trastuzumab (T) remains the standard treatment for patients with HER2 positive breast cancer. Results from randomized trials with diverse non-inferiority margins comparing one year to a shorter duration of adjuvant T were not consistent, particularly with the PERSEPHONE and the final PHARE and Short-HER trials’ results. Our objective was to conduct a systematic review and meta-analysis of randomized trials in patients with HER2 positive breast cancer to assess whether a shorter duration of adjuvant T was non-inferior to one year of treatment. Methods: PubMed, EMBASE and The Cochrane Library were searched for eligible randomized trials. Hazard ratios (HR) for disease free and overall survival (DFS, OS) were weighted using generic inverse variance and pooled in a meta-analysis using random-effects models. The median of non-inferiority margins derived from each trial was calculated to set a non-inferiority margin of 1.29 for the pooled analysis. Subgroup analyses compared survival outcomes by estrogen receptor (ER) status, nodal status, length and timing of trastuzumab treatment. Results: Data of 11,376 patients from 5 trials were analyzed. A shorter duration of T was non-inferior to one year of therapy for DFS (HR 1.13, 95%CI 1.03-1.24) but worse for OS (HR 1.16, 95%CI 1.01-1.32). In addition, the non-inferiority for DFS was met for patients with ER positive disease (HR 1.1, 95%CI 0.95-1.28) and patients treated with 6 months (HR 1.09, 95%CI 0.98-1.22) or sequential T (HR 0.97, 95%CI 0.75-1.27). Conversely, the non-inferiority for DFS was not met for patients with ER negative disease (HR 1.22, 95%CI 1.06-1.41), patients treated with 9 weeks (HR 1.26, 95%CI 1.02-1.55) or concomitant T (HR 1.25, 95%CI 1.07-1.45) and patients with node negative (HR 1.12, 95% 0.93-1.35) or positive (HR 1.16, 95%CI 0.99-1.36) disease. Conclusions: Within the limitations of the available data and the different non-inferiority margins used in randomized trials, a shorter duration of adjuvant T is non-inferior to one year of therapy for DFS in patients with HER2 positive breast cancer, particularly in patients with ER positive disease. Further trials with appropriately chosen non-inferiority margins are needed to confirm the optimal duration of T in patients with low-risk disease.

scholarly journals Impact of PTEN Protein Expression on Benefit From Adjuvant Trastuzumab in Early-Stage Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer in the North Central Cancer Treatment Group N9831 Trial

2013 ◽  
Vol 31 (17) ◽  
pp. 2115-2122 ◽  
Author(s):  
Edith A. Perez ◽  
Amylou C. Dueck ◽  
Ann E. McCullough ◽  
Beiyun Chen ◽  
Xochiquetzal J. Geiger ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Early Stage ◽  
Growth Factor Receptor ◽  
Her2 Positive ◽  
Adjuvant Trastuzumab ◽  
Pten Protein ◽  
North Central ◽  
Epidermal Growth ◽  
Positive Breast Cancer

Purpose It has been suggested that PTEN, a negative regulator of PI3K/AKT signaling, is involved in tumor sensitivity to trastuzumab. We investigated the association between tumor PTEN protein expression and disease-free survival (DFS) of patients randomly assigned to receive chemotherapy alone (arm A) or chemotherapy with sequential (arm B) or concurrent trastuzumab (arm C) in the phase III early-stage human epidermal growth factor receptor 2 (HER2) –positive trial—North Central Cancer Treatment Group (NCCTG) N9831. Patients and Methods The intensity and percentage of invasive cells with cytoplasmic PTEN staining were determined in tissue microarray sections containing three cores per block (n = 1,286) or in whole tissue sections (WS; n = 516) by using standard immunohistochemistry (138G6 monoclonal antibody). Tumors were considered positive for PTEN (PTEN-positive) if any core or WS had any invasive cells with ≥ 1+ staining. Median follow-up was 6.0 years. Results Of 1,802 patients included in this analysis (of 3,505 patients registered to N9831), 1,342 (74%) had PTEN-positive tumors. PTEN positivity was associated with hormone receptor negativity (χ2 P < .001) and nodal positivity (χ2 P = .04). PTEN did not have an impact on DFS within the various arms. Comparing DFS of arm C to arm A, patients with PTEN-positive and PTEN-negative tumors had hazard ratios (HRs) of 0.65 (P = .003) and 0.47 (P = .005), respectively (interaction P = .16). For arm B versus arm A, patients with PTEN-positive and PTEN-negative tumors had HRs of 0.70 (P = .009) and 0.85 (P = .44), respectively (interaction P = .47). Conclusion In contrast to selected preclinical and limited clinical studies suggesting a decrease in trastuzumab sensitivity in patients with PTEN-negative tumors, our data show benefit of adjuvant trastuzumab for patients with HER2-positive breast cancer, independent of tumor PTEN status.

scholarly journals C-MYC Alterations and Association With Patient Outcome in Early-Stage HER2-Positive Breast Cancer From the North Central Cancer Treatment Group N9831 Adjuvant Trastuzumab Trial

2011 ◽  
Vol 29 (6) ◽  
pp. 651-659 ◽  
Author(s):  
Edith A. Perez ◽  
Robert B. Jenkins ◽  
Amylou C. Dueck ◽  
Anne E. Wiktor ◽  
Patrick P. Bedroske ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Treatment Group ◽  
Cancer Treatment ◽  
Copy Number ◽  
Early Stage ◽  
Chromosome 8 ◽  
Her2 Positive ◽  
Adjuvant Trastuzumab ◽  
North Central ◽  
Positive Breast Cancer

Purpose Findings from the human epidermal growth factor receptor 2 (HER2) –positive National Surgical Adjuvant Breast and Bowel Project (NSABP) B31 trial suggested that MYC/HER2 coamplification (> 5.0 copies/nucleus) was associated with additional benefit from adjuvant trastuzumab in patients with early-stage breast cancer. To further explore this relationship, we investigated associations between MYC amplification and disease-free survival (DFS) in a similar adjuvant trastuzumab HER2-positive breast cancer trial—North Central Cancer Treatment Group (NCCTG) N9831. Patients and Methods This analysis included 799 patients randomly assigned to receive chemotherapy alone or with concurrent trastuzumab on N9831. Fluorescence in situ hybridization (FISH) was performed by using a dual-probe mixture for MYC and centromere 8 (MYC:CEP8) on tissue microarrays. MYC amplification was prespecified as MYC:CEP8 ratio > 2.2 or average MYC copies/nucleus > 5.0. Exploratory variables included polysomy 8. Results In comparing DFS (median follow-up, 4.0 years) between treatments, patients with MYC:CEP8 ratio ≤ 2.2 (n = 618; 77%) and > 2.2 (n = 181; 23%) had hazard ratios (HRs) of 0.46 (P < .001) and 0.67 (P = .33), respectively (interaction P = .38). Patients with MYC copies/nucleus ≤ 5.0 (n = 534; 67%) and > 5.0 (n = 265; 33%) had HRs of 0.52 (P = .002) and 0.48 (P = .02), respectively (interaction P = .94). Patients with MYC:CEP8 ratio < 1.3 with normal chromosome 8 copy number (n = 141; 18%) and ≥ 1.3 or < 1.3 with polysomy 8 (n = 658; 82%) had HRs of 0.66 (P = .28) and 0.44 (P < .001), respectively (interaction P = .23). Patients with MYC copies/nucleus < 2.5 (n = 130; 16%) and ≥ 2.5 (n = 669; 84%) had HRs of 1.07 (P = .87) and 0.42 (P < .001), respectively (interaction P = .05). Conclusion We did not confirm the B31 association between MYC amplification and additional trastuzumab benefit. Exploratory analyses revealed potential associations between alternative MYC/chromosome 8 copy number alterations and differential benefit of adjuvant trastuzumab.

scholarly journals Immunotherapy Implication of Signature-Guided Biomarker Discovery for Trastuzumab-Resistant HER2-Positive Breast Cancer

2020 ◽  
Author(s):  
Andrea Sand ◽  
Aspen T. Duffin ◽  
Geoffrey T. Riddell ◽  
Mitchel Piacsek ◽  
Brittany Last ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Biomarker Discovery ◽  
Early Stage ◽  
Cytotoxic T Cell ◽  
Her2 Positive ◽  
Adjuvant Trastuzumab ◽  
Early Stage Disease ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

AbstractDespite the great improvement of patient outcomes by trastuzumab, a monoclonal antibody targeted on HER2-positive breast cancer, approximately 23% of patients with early-stage disease treated with adjuvant trastuzumab either fail to respond or experience recurrence within 10 years, highlighting the importance of identifying which HER2-positive patients would benefit from trastuzumab upfront. Efforts to identify biomarkers predictive of response to trastuzumab in initial breast tumor core biopsies have been complicated by the clinical and biological heterogeneity of HER2-positive tumors. Therefore, we identified a trastuzumab-resistant (TrR) signature that accurately predicts response to trastuzumab quantitively and qualitatively in vitro and in vivo, via repurposing transcriptome profiles in an engineered cell line model. We additionally demonstrated that our TrR signature was associated with tumor progression and capable of stratifying patient prognosis. Our study further illustrated the possible mechanism of this resistance as being less inherited cytotoxic T cell infiltration and failure to secrete Interferon-γ upon trastuzumab treatment in TrR tumors. These findings highlight the potential clinical application of TrR signature in treatment management and identifying possible immunotherapy interventions.

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