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

Saad, Everardo D.; Squifflet, Pierre; Burzykowski, Tomasz; Quinaux, Emmanuel; Delaloge, Suzette; Mavroudis, Dimitris; Perez, Edith A.; Piccart‐Gebhart, Martine; Schneider, Bryan; Slamon, Dennis J.; Wolmark, Norman; Buyse, Marc

doi:10.1016/s1470-2045(18)30750-2

Cited by 63 publications

(57 citation statements)

References 27 publications

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“…At least four large, randomized, controlled clinical trials have demonstrated that women with early human epidermal growth factor receptor 2 (HER2)-positive breast cancer receiving 12-month adjuvant trastuzumab show improved disease-free survival (DFS) compared with those who did not receive this treatment 1 . Overall survival (OS) improved in agreement with DFS 2 . Although a longer duration of trastuzumab treatment of 24 months seems to add toxicity without additional survival benefit 3 , the shorter duration of a 9-week trastuzumab regimen only exhibited a borderline significant improvement in DFS 4 .…”

Section: Introductionmentioning

confidence: 62%

Tailored duration of adjuvant trastuzumab for human epidermal growth factor receptor 2-positive breast cancer

Wang

Chen

et al. 2020

npj Precis. Onc.

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We assumed that the effect of adjuvant trastuzumab on survival is mediated by the treatment time and we conducted this trial-level meta-regression to determine the appropriate length of treatment. Twelve adjuvant trastuzumab trials (from January 2000 to June 2019, consisting of 20,271 patients) were included. We considered 12-month trastuzumab treatment as the standard. The primary study endpoint was disease-free survival (DFS). By quantifying the relationship between shortened treatment time (month) and altered recurrence risk (expressed as hazard ratio), we found the regression coefficient β was 0.05 (95% confidence interval: 0.02–0.08, P = 0.002), indicating the recurrence risk would increase 5.1% for each month that treatment was shortened. Accordingly, 3, 6, and 9-month reductions in treatment time resulted in 16%, 35%, and 57% increases in recurrence risk, respectively. We revealed a significant linear association between shortened treatment time of trastuzumab and recurrence risk. The clinical duration of adjuvant trastuzumab should be tailored.

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Section: Introductionmentioning

confidence: 62%

Tailored duration of adjuvant trastuzumab for human epidermal growth factor receptor 2-positive breast cancer

Wang

Chen

et al. 2020

npj Precis. Onc.

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“…However, this approach has been commonly used for surrogate validation, especially when the number of included trials was limited. 13,17,37 Furthermore, although our study focused on the trial-level association, the validity of a surrogate endpoint should be supported by both trial-level and individual-level associations. Additional analyses are warranted to reassess the individuallevel association between pCR and long-term outcomes in TNBC using updated data.…”

Section: Discussionmentioning

confidence: 98%

Evaluation of Pathologic Complete Response as a Surrogate for Long-Term Survival Outcomes in Triple-Negative Breast Cancer

Huang

O’Shaughnessy

Zhao

et al. 2020

Journal of the National Comprehensive Cancer Network

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Background: Pathologic complete response (pCR) is a common efficacy endpoint in neoadjuvant therapy trials for triple-negative breast cancer (TNBC). Previous studies have shown that pCR is strongly associated with improved long-term survival outcomes, including event-free survival (EFS) and overall survival (OS). However, the trial-level associations between treatment effect on pCR and long-term survival outcomes are not well established. This study sought to evaluate these associations by incorporating more recent clinical trials in TNBC. Methods: A literature review identified published randomized controlled trials (RCTs) of neoadjuvant therapy for TNBC that reported results for both pCR and EFS/OS. Meta-regression models were performed to evaluate the association of treatment effect on pCR and EFS/OS. Sensitivity analyses were conducted to assess the impact of divergent study designs. Results: Ten comparisons from 8 RCTs (N=2,478 patients) were identified from the literature review. The log (odds ratio) of pCR was a significant predictor of the log (hazard ratio) of EFS (P=.003), with a coefficient of determination of 0.68 (95% CI, 0.41–0.95). There was a weaker association between pCR and OS (P=.18), with a coefficient of determination of 0.24 (95% CI, 0.01–0.77). Consistent results were found in the exploratory analysis and sensitivity analyses. Conclusions: This is the first study that has shown a trial-level association between pCR and survival outcomes in TNBC. By incorporating the most up-to-date RCTs, this study showed a significant trial-level association between pCR and EFS. A positive association between pCR and OS was also recorded.

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“…No included trial had separate non-inferiority margin for OS and in applying our same predefined DFS non-inferiority margin to OS results we are assuming we accept the same difference, which is debatable. While OS in our analysis did not meet our calculated non-inferiority threshold, DFS has been shown to be a good surrogate for OS in adjuvant HER2 positive breast cancer and longer follow up is needed to confirm [ 30 ]. GRADE recommendation for OS results is moderate due to serious imprecision of these results evidenced by wide 95%CI margins in the included trials.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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One year of adjuvant trastuzumab is considered the standard treatment for patients with HER2 positive breast cancer. However, a shorter duration of trastuzumab may be associated with reduced costs and side effects. Results from randomized trials with diverse non-inferiority margins comparing one year to a shorter duration of adjuvant trastuzumab are not consistent and have not been systematically reviewed using a non-inferiority meta-analysis approach. We conducted a systematic review and meta-analysis of randomized trials to assess whether a shorter duration of adjuvant trastuzumab was non-inferior to one year of treatment or not. The non-inferiority margin for the meta-analysis was pre-defined as the median of the margins of all the trials included. Data of 11,376 patients from 5 trials were analyzed. Non-inferiority margins in included studies varied from 1.15 to 1.53 with median of 1.29 for HR of DFS. A shorter duration of trastuzumab was non-inferior to one year of therapy for DFS (HR 1.13, 95%CI 1.03–1.24) but inconclusive for OS (HR 1.14, 95%CI 1.00–1.30). In a subgroup analysis for DFS outcome, shorter therapy was non-inferior in patients with ER positive disease (HR 1.10, 95%CI 0.95–1.28) and those with sequential therapy (HR 0.97, 95%CI 0.75–1.27) and when the duration of treatment was 6 months (HR 1.09, 95%CI 0.98–1.22). Although a shorter duration of adjuvant trastuzumab was non-inferior to one year of therapy for DFS in patients with HER2 positive breast cancer based on our HR margin of 1.29, any benefit of a shorter duration comes at a loss of efficacy with an increase in absolute risk up to 3.9% for 5 year DFS. Whether the potential increased risk is clinically acceptable for the benefits of a shorter duration remains debatable.

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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

Cited by 63 publications

References 27 publications

Tailored duration of adjuvant trastuzumab for human epidermal growth factor receptor 2-positive breast cancer

Tailored duration of adjuvant trastuzumab for human epidermal growth factor receptor 2-positive breast cancer

Evaluation of Pathologic Complete Response as a Surrogate for Long-Term Survival Outcomes in Triple-Negative Breast Cancer

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

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