Neoadjuvant as Future for Drug Development in Breast Cancer—Letter

Buyse, Marc; Burzykowski, Tomasz; Saad, Everardo D.

doi:10.1158/1078-0432.ccr-15-1047

Cited by 4 publications

(6 citation statements)

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“…The perception that pCR may be a valid surrogate for long-term outcomes has generated controversy in the literature. 34,35 In some cases, it seems that incorrect conclusions have been drawn because of failure to consider the importance of triallevel associations when assessing the worth of pCR as a surrogate. 35 All our analyses of patient-level surrogacy of pCR have yielded statistically significant results, both for EFS and OS (Table 2).…”

Section: Discussionmentioning

confidence: 99%

“…34,35 In some cases, it seems that incorrect conclusions have been drawn because of failure to consider the importance of triallevel associations when assessing the worth of pCR as a surrogate. 35 All our analyses of patient-level surrogacy of pCR have yielded statistically significant results, both for EFS and OS (Table 2). Conversely, the observed values of R 2 indicated weak associations in the majority of cases, and although the 95% CIs of R 2 were very wide, they all excluded values of R 2 that would qualify pCR as a statistically valid surrogate end point (Table 2 and Fig 2).…”

Section: Discussionmentioning

confidence: 99%

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Re-Evaluation of Pathologic Complete Response as a Surrogate for Event-Free and Overall Survival in Human Epidermal Growth Factor Receptor 2–Positive, Early Breast Cancer Treated With Neoadjuvant Therapy Including Anti–Human Epidermal Growth Factor Receptor 2 Therapy

Squifflet

Saad

Loibl

et al. 2023

JCO

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PURPOSE Pathologic complete response (pCR) has prognostic importance and is frequently used as a primary end point, but doubts remain about its validity as a surrogate for event-free survival (EFS) and overall survival (OS) in human epidermal growth factor receptor 2 (HER2)–positive, early breast cancer. METHODS We obtained individual-patient data from randomized trials of neoadjuvant anti-HER2 therapy that enrolled at least 100 patients, had data for pCR, EFS, and OS, and a median follow-up of at least 3 years. We quantified the patient-level association between pCR (defined as ypT0/Tis ypN0) and both EFS and OS using odds ratios (ORs, with ORs >1.00 indicating a benefit from achieving a pCR). We quantified the trial-level association between treatment effects on pCR and on EFS and OS using R2 (with values above 0.75 considered as indicating strong associations). RESULTS Eleven of 15 eligible trials had data for analysis (3,980 patients, with a median follow-up of 62 months). Considering all trials, we found strong patient-level associations, with ORs of 2.64 (95% CI, 2.20 to 3.07) for EFS and 3.15 (95% CI, 2.38 to 3.91) for OS; however, trial-level associations were weak, with an unadjusted R2 of 0.23 (95% CI, 0 to 0.66) for EFS and 0.02 (95% CI, 0 to 0.17) for OS. We found qualitatively similar results when grouping trials according to different clinical questions, when analyzing only patients with hormone receptor–negative disease, and when using a more stringent definition of pCR (ypT0 ypN0). CONCLUSION Although pCR may be useful for patient management, it cannot be considered as a surrogate for EFS or OS in neoadjuvant trials of HER2-positive, operable breast cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Re-Evaluation of Pathologic Complete Response as a Surrogate for Event-Free and Overall Survival in Human Epidermal Growth Factor Receptor 2–Positive, Early Breast Cancer Treated With Neoadjuvant Therapy Including Anti–Human Epidermal Growth Factor Receptor 2 Therapy

Squifflet

Saad

Loibl

et al. 2023

JCO

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“…This assumes that any treatment difference in pCR leads to a beneficial change in survival. This is an assumption that is currently not yet verified and is the subject of recent debate . As such, this paper does not address the validity of pCR as a surrogate endpoint.…”

Section: Discussionmentioning

confidence: 96%

Assessment of effect size and power for survival analysis through a binary surrogate endpoint in clinical trials

Abberbock

Anderson

Tang

2018

Statistics in Medicine

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A strategy for early-stage breast cancer trials in recent years consists of a neoadjuvant trial with pathological complete response (pCR) at time of surgery as the efficacy endpoint, followed by the collection of long-term data to show efficacy in survival. To calculate an appropriate sample size to detect a survival difference based upon pCR data, it is necessary to relate the effect size in pCR with the effect size in survival. Here, we propose an exponential mixture model for survival time with parameters for the neoadjuvant pCR rates and an estimated benefit of achieving pCR to determine the treatment effect size. Through simulation studies, we demonstrated how to estimate the empirical power for detecting the survival efficacy under a parameter setting. We also showed a more efficient way to estimate the power for detecting the survival efficacy through estimated average hazard ratios and the Schoenfeld formula. Our method can be used to power future confirmatory adjuvant trials based on the preliminary data obtained from the neoadjuvant component.

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“…We thank Buyse and colleagues (1) for their letter and agree with much of their perspective, most importantly the need to continue to test new regimens in the neoadjuvant setting to further elucidate the relationship between pathologic complete response (pCR) and event-free survival (EFS).…”

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confidence: 94%

Neoadjuvant as Future for Drug Development in Breast Cancer—Response

DeMichele

Yee

Paoloni

et al. 2016

Clinical Cancer Research

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on behalf of the I-SPY2 InvestigatorsWe thank Buyse and colleagues (1) for their letter and agree with much of their perspective, most importantly the need to continue to test new regimens in the neoadjuvant setting to further elucidate the relationship between pathologic complete response (pCR) and event-free survival (EFS).However, we disagree with the comment that there is "no justification for equating" individual-level surrogacy with triallevel surrogacy in the FDA-led meta-analysis. For HER2 þ breast cancer, the meta-analysis "trial-level" analysis of six trial results actually depends upon patient-level data ( Fig. S1 "bubble plot" in Supplementary Appendix; ref.2). Indeed, one can derive the distributions of the 6 EFS HRs in these trials from the KaplanMeier curves describing the relationship between EFS and pCR in the patient-level analysis and the treatment-specific pCR rates within the six trials; the resulting means of these distributions closely mirror the respective bubbles in the plot. Evaluating the data at the "trial level" introduces variability (always present in clinical trials) and loses important information regarding the relationship between pCR and EFS. In the extreme case, if all six trials had the same pCR OR, there would be no information about the slope of the regression line or the correlation between OR and HR. Indeed, the actual plot shows less than 10% treatment difference in improvements in pCR rates in a cluster of five of the six trials. The lone outlier is NOAH, which therefore determines the slope of the regression line. NOAH was predicted to land where it did by the patient-level analysis, but regardless, there is no power to show statistical significance for the slope of a line through two points.Although the trial-level analysis reduces the information from the patient-level analysis, it provides an important service. Impressive HRs of EFS by pCR could lead to the erroneous conclusion that statistical significance in pCR will lead to significance in EFS. But the HR of 0.39 for HER2 þ disease applies only to a treatment that changes the pCR rate from 0% in the control group to 100% in the intervention group (3). NeoALTTO's improvement in pCR rate moves only 19.2% of the patients from the non-pCR curve to the pCR curve, which implies a more realistic but less impressive HR of 0.83. We agree that the accuracy of this prediction may be a coincidence; one example is hardly conclusive. Our point was simply that the NeoALTTO/ALTTO results were not inconsistent with the FDA's patient-level meta-analysis and therefore were not cause for reconsidering the utility of taking a neoadjuvant approach to drug development. It is also important to recognize that a new therapy may have an entirely different relationship between pCR and EFS. The need for validating or suitably modifying the FDA's patient-level analysis will be essential for any particular therapy, which is precisely what the FDA's guidance requires. Randomized neoadjuvant trials incorporating both pCR and EFS endpoints in the...

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Neoadjuvant as Future for Drug Development in Breast Cancer—Letter

Cited by 4 publications

References 4 publications

Re-Evaluation of Pathologic Complete Response as a Surrogate for Event-Free and Overall Survival in Human Epidermal Growth Factor Receptor 2–Positive, Early Breast Cancer Treated With Neoadjuvant Therapy Including Anti–Human Epidermal Growth Factor Receptor 2 Therapy

Re-Evaluation of Pathologic Complete Response as a Surrogate for Event-Free and Overall Survival in Human Epidermal Growth Factor Receptor 2–Positive, Early Breast Cancer Treated With Neoadjuvant Therapy Including Anti–Human Epidermal Growth Factor Receptor 2 Therapy

Assessment of effect size and power for survival analysis through a binary surrogate endpoint in clinical trials

Neoadjuvant as Future for Drug Development in Breast Cancer—Response

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