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Cited by 170Breast Cancer Treatment StudiesStatistical Methods in Clinical TrialsGastric Cancer Management and Outcomes

Evaluation of pathological complete response as surrogate endpoint in neoadjuvant randomised clinical trials of early stage breast cancer: systematic review and meta-analysis

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Conforti, Fabio, Pala, Laura, Sala, Isabella, Oriecuia, Chiara, De Pas, Tommaso, Specchia, Claudia, Graffeo, Rossella, Pagan, Eleonora +6 more·2021·BMJ
DOI 10.1136/bmj-2021-066381PMC PMC8689398
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Abstract

Objective: To evaluate pathological complete response as a surrogate endpoint for disease-free survival and overall survival in regulatory neoadjuvant trials of early stage breast cancer. Design: Systematic review and meta-analysis. Data sources: Medline, Embase, and Scopus to 1 December 2020. Eligibility criteria for study selection: Randomised clinical trials that tested neoadjuvant chemotherapy given alone or combined with other treatments, including anti-human epidermal growth factor 2 (anti-HER2) drugs, targeted treatments, antivascular agents, bisphosphonates, and immune checkpoint inhibitors. Data extraction and synthesis: Trial level associations between the surrogate endpoint pathological complete response and disease-free survival and overall survival. Methods: A weighted regression analysis was performed on log transformed treatment effect estimates (hazard ratio for disease-free survival and overall survival and relative risk for pathological complete response), and the coefficient of determination (R 2) was used to quantify the association. The secondary objective was to explore heterogeneity of results in preplanned subgroups analysis, stratifying trials according treatment type in the experimental arm, definition used for pathological complete response (breast and lymph nodes v breast only), and biological features of the disease (HER2 positive or triple negative breast cancer). The surrogate threshold effect was also evaluated, indicating the minimum value of the relative risk for pathological complete response necessary to confidently predict a non-null effect on hazard ratio for disease-free survival or overall survival. Results: 54 randomised clinical trials comprising a total of 32 611 patients were included in the analysis. A weak association was observed between the log(relative risk) for pathological complete response and log(hazard ratio) for both disease-free survival (R 2=0.14, 95% confidence interval 0.00 to 0.29) and overall survival (R 2=0.08, 0.00 to 0.22). Similar results were found across all subgroups evaluated, independently of the definition used for pathological complete response, treatment type in the experimental arm, and biological features of the disease. The surrogate threshold effect was 5.19 for disease-free survival but was not estimable for overall survival. Consistent results were confirmed in three sensitivity analyses: excluding small trials (<200 patients enrolled), excluding trials with short median follow-up (<24 months), and replacing the relative risk for pathological complete response with the absolute difference of pathological complete response rates between treatment arms. Conclusion: A lack of surrogacy of pathological complete response was identified at trial level for both disease-free survival and overall survival. The findings suggest that pathological complete response should not be used as primary endpoint in regulatory neoadjuvant trials of early stage breast cancer.

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  • Evolving experience from the use of systemic anticancer therapy in solid tumours suggests that a pathologically demonstrated response in resected specimens predicts improved chances of complete remission in patients with various oncological diagnoses, including breast cancer, non-small-cell lung cancer, and bladder cancer.

    “Evolving experience from the use of systemic anticancer therapy in solid tumours suggests that a pathologically demonstrated response in resected specimens predicts improved chances of complete remission in patients with various oncological diagnoses, including breast cancer, non-small-cell lung cancer, and bladder cancer.15–17”

    From Pathological response following neoadjuvant immune checkpoint inhibitors in patients with hepatocellular carcinoma: a cross-trial, patient-level analysis (2024) · cites this paper as [15]

    The Discussion (page unavailable) reports a strong patient-level association between pathological complete response and overall survival in breast cancer, and discusses pathological response and long-term outcomes in lung cancer. It does not establish the claim for bladder cancer or show that pathological response predicts a later complete remission; its reported outcomes are survival and relapse risk. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • In other cancer types, the endpoint to define response to neoadjuvant therapy has been pathological complete response (100%) or near-pathological complete response (>90%).

    “In other cancer types, the endpoint to define response to neoadjuvant therapy has been pathological complete response (100%)13,15 or near-pathological complete response (>90%).29”

    From Pathological response following neoadjuvant immune checkpoint inhibitors in patients with hepatocellular carcinoma: a cross-trial, patient-level analysis (2024) · cites this paper as [15]

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Cited by

Sorted by citations

Authors
Conforti, F., Pala, L., Sala, I., Oriecuia, C., De Pas, T., Specchia, C., Graffeo, R., Pagan, E., Queirolo, P., Pennacchioli, E., Colleoni, M., Viale, G., Bagnardi, V., & Gelber, R. D.
Affiliations
  • European Institute of Oncology (IT)
  • University of Milano-Bicocca (IT)
  • University of Brescia (IT)
  • Istituto Oncologico della Svizzera Italiana (CH)
  • University of Milan (IT)
  • Harvard University (US)
ORCID
Venue
BMJ
Publisher
BMJ
Published
2021-12-21
Volume
375
Pages
e066381
ISSN
1756-1833 (ISSN-L)
DOI
10.1136/bmj-2021-066381
PMC
PMC8689398
OpenAlex
W4200089627
Cited by
170
References
6
Citations by year
2026: 27 · 2025: 47 · 2024: 38 · 2023: 39 · 2022: 19
FWCI
2.93
Type
journal article
Language
en
Open access
Licence
Locations
  • BMJ (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
  • BOA (University of Milano-Bicocca) (submittedVersion, other-oa)
  • Institutional Research Information System (Università degli Studi di Brescia) (submittedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
  • Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Gastric Cancer Management and Outcomes
Keywords
pathological complete response, surrogate endpoints, early breast cancer, neoadjuvant therapy, disease-free survival, overall survival, surrogate threshold effect, HER2-positive breast cancer, triple-negative breast cancer, neoadjuvant chemotherapy, HER2-targeted therapy, treatment effect heterogeneity, antivascular agents
MeSH terms
Breast Neoplasms, Female, Humans, Biomarkers, Randomized Controlled Trials as Topic, Chemotherapy, Adjuvant, Disease-Free Survival, Neoadjuvant Therapy

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