[Skip to Content]
[Skip to Content Landing]

Surrogacy of Pathologic Complete Response in Trials of Neoadjuvant Therapy for Early Breast CancerCritical Analysis of Strengths, Weaknesses, and Misinterpretations

To identify the key insights or developments described in this article
1 Credit CME
Abstract

Importance  The pathologic complete response (pCR) is supported by regulatory agencies as a surrogate end point for long-term patients’ clinical outcomes in the accelerated approval process of new drugs tested in neoadjuvant randomized clinical trials (RCTs) for early breast cancer (BC). However, a meaningful association between pCR and patients’ survival has been proven only at the patient level (ie, significantly better survival of patients who achieved pCR compared with those who did not), but not at trial level (ie, poor association between degree of improvement in pCR rate and survival reported across trials).

Observations  We critically discuss the potential reasons of such discrepancy between pCR surrogacy value at the patient and trial level, as well as the relevant implications for both clinical research and drug regulatory policy. We also describe alternative surrogate end points, including combined end points that jointly analyzed pathological response and event-free survival data, or the assessment of circulating tumor DNA (ctDNA). Such proposed surrogate end points could overcome limits of pCR and provide a reasonable trade-off between the 2 conflicting needs to have access to effective therapies rapidly, and to reliably assess patients’ clinical benefit.

Conclusions and Relevance  Using surrogate end points to grant drug approvals is justified only when they can provide accurate prediction of a drug’s effect on the long-term patient outcomes. Evidence currently available does not support pCR used alone as a reliable surrogate end point in regulatory neoadjuvant RCTs for BC. The surrogacy value at trial level of potentially more robust surrogate end points needs to be urgently tested.

Sign in to take quiz and track your certificates

Buy This Activity

JN Learning™ is the home for CME and MOC from the JAMA Network. Search by specialty or US state and earn AMA PRA Category 1 Credit(s)™ from articles, audio, Clinical Challenges and more. Learn more about CME/MOC

CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.

Article Information

Accepted for Publication: June 7, 2022.

Published Online: October 6, 2022. doi:10.1001/jamaoncol.2022.3755

Corresponding Author: Fabio Conforti, MD, Division of Medical Oncology for Melanoma & Sarcoma, European Institute of Oncology, Via Ripamonti 435, 20141, Milan, Italy (fabio.conforti@ieo.it).

Author Contributions: Dr Conforti had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Authors Conforti, Pala, Viale, and Gelber contributed equally to the work.

Concept and design: Conforti, Pala, Bagnardi, De Pas, Colleoni, Buyse, Gianni, Winer, Loibl, Cortés, Viale.

Acquisition, analysis, or interpretation of data: Conforti, Bagnardi, Hortobagyi, Loibl, Piccart-Gebhart, Wolff, Gelber.

Drafting of the manuscript: Conforti, Pala, Bagnardi, De Pas, Colleoni, Buyse.

Critical revision of the manuscript for important intellectual content: Conforti, Pala, Bagnardi, De Pas, Hortobagyi, Gianni, Winer, Loibl, Cortés, Piccart-Gebhart, Wolff, Viale, Gelber.

Statistical analysis: Conforti, Bagnardi.

Administrative, technical, or material support: ConfortI, Gelber.

Supervision: Conforti, Pala, Bagnardi, Gianni, Loibl, Cortés, Piccart-Gebhart, Viale.

Other: Winer.

Conflict of Interest Disclosures: Dr Colleoni reported grants from Roche outside the submitted work. Dr Buyse reported nonfinancial support from IDDI, stockholder outside the submitted work. Dr Hortobagyi reported personal fees from Novartis outside the submitted work. Dr Gianni reported advisory board membership, consultancy fees, or support to institution from AstraZeneca, Celgene, Eli Lilly, Roche, Pfizer, Seattle Genetics, Artemida Pharma Ltd, Zymeworks; from METIS Precision Medecine, Novartis, Revolution Medicines, Synaffix, Menarini Ricerche, Amgen, Biomedical Insights, and Denali Therapeutics, outside the submitted work; in addition, Dr Gianni had a patent for European Patent Application n. 12195182.6 and 12196177.5; Roche; no compensation was provided. Dr Winer reported consultancy fees from Carrick Therapeutics; honoraria from Genentech/Roche; consultancy fees for advisory board membership, lectures or writing fees, or fees paid to institution from Genomic Helath, GSK, Jounce Therapeutics, and Leap Therapeutics outside the submitted work. Dr Loibl reported honoraria for advisory board membership, lecture and/or writing fees, and/or fees paid to institution from Abbvie, Amgen, AstraZeneca, BMS, Celgene, EirGenix, GSK, Gilead, Lilly, Merck, Novartis, Pfizer, Pierre Fabre, Seagen, DSI, Sanofi, Roche, outside the submitted work; in addition, Dr Loibl had a patent for EP14153692.0 pending Immunsignature in TNBC, paid to institute, a patent for EP21152186.9 pending Signature for CDK 4/6 Inhibitor, paid to institute, a patent for EP15702464.7 issued predicting response to an Anti–HER2-containing therapy, paid to institute, a patent for EP19808852.8 pending GeparNuevo, paid to institute, and a patent for Digital Ki67 Evaluator with royalties paid VM Scope GmbH, paid to institute. Dr Cortés reported personal fees, honoraria for advisory board membership, lecture and/or writing fees, travel expenses, reasearch funding, stock holdings, and/or fees paid to institution from Roche, Celgene, Cellestia Consulting, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Merck Sharp & Dohme, GSK, Leuko, Bioasis, Clovis Oncology, Boehringer, Ellipses, Hibercell, Gemoab, Gilead, Menarini, Zymeworks, Reveal Genomics, Novartis, Eisai, Pfizer, Samsung, Roche, Ariad Pharmaceuticals, AstraZeneca, Baxalta, Bayer Healthcare, Guardanth Health, Merck Sharp & Dohme, Piqur Therapeutics, Puma C, Queen Mary University of London, Medsir Nektar Therapeutics, Leuko, during the conduct of the study; personal fees, honoraria for advisory board membership, lecture and/or writing fees, travel expenses, reasearch funding, stock holdings, and/or fees paid to institution Roche, Celgene, Cellestia, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Merck Sharp & Dohme, GSK, Leuko, Bioasis, Clovis Oncology, Boehringer, Ellipses, Hibercell, Gemoab, Gilead, Menarini, Zymeworks, Reveal Genomics, Novartis, Eisai, Pfizer, Samsung Bioepis, Roche, Ariad Pharmaceuticals, AstraZeneca, Baxalta, Bayer Healthcare, Guardanth Health, Merck Sharp & Dohme, Piqur Therapeutics, Puma C, Queen Mary University of London, Medsir, Nektar Therapeutics, and Leuko, outside the submitted work; in addition, Dr Cortés had a patent for Pharmaceutical Combinations of A Pi3k Inhibitor And A Microtubule Destabilizing Agent. Javier Cortés Castán, Alejandro Piris Giménez, Violeta Serra Elizalde issued WO 2014/199294 A and a patent for Her2 as a predictor of response to dual HER2 blockade in the absence of cytotoxic therapy. Aleix Prat, Antonio Llombart, Javier Cortés issued US 2019/0338368 A1. Dr Piccart-Gebhart reported personal fees, honoraria for advisory board membership, lecture and/or writing fees, travel expenses, reasearch funding, stock holdings, and/or fees paid to institution from AstraZeneca, Camel-IDS/Precirix, Frame Therapeutics, Gilead, Immunomedics, Immutep, Lilly, Menarini, MSD, NBE Therapeutics, Novartis, Odonate, Pfizer, Roche-Genentech, SeaGen, Seattle Genetics, Oncolytics, AstraZeneca, Immunomedics, Menarini, Radius, Servier, and Synthon outside the submitted work. Dr Viale reported personal, advisory board, and/or consultancy fees from Roche, AstraZeneca, MSD, Daichii Sankyo, Agilent, Ventana, and Pfizer outside the submitted work. Dr Gelber reported grants from Roche, AstraZeneca, Merck, and Novartis to institution outside the submitted work. No other disclosures were reported.

References
1.
Lenzer  J , Brownlee  S .  Should regulatory authorities approve drugs based on surrogate endpoints?   BMJ. 2021;374(2059):n2059. doi:10.1136/bmj.n2059 PubMedGoogle ScholarCrossref
2.
Dawoud  D , Naci  H , Ciani  O , Bujkiewicz  S .  Raising the bar for using surrogate endpoints in drug regulation and health technology assessment.   BMJ. 2021;374(2191):n2191. doi:10.1136/bmj.n2191 PubMedGoogle ScholarCrossref
3.
Buyse  M , Molenberghs  G .  Criteria for the validation of surrogate endpoints in randomized experiments.   Biometrics. 1998;54(3):1014-1029. doi:10.2307/2533853 PubMedGoogle ScholarCrossref
4.
Buyse  M , Molenberghs  G , Burzykowski  T , Renard  D , Geys  H .  The validation of surrogate endpoints in meta-analyses of randomized experiments.   Biostatistics. 2000;1(1):49-67. doi:10.1093/biostatistics/1.1.49 PubMedGoogle ScholarCrossref
5.
Xie  W , Halabi  S , Tierney  JF ,  et al.  A systematic review and Recommendation for reporting of surrogate endpoint evaluation using meta-analyses.   JNCI Cancer Spectr. 2019;3(1):pkz002. doi:10.1093/jncics/pkz002PubMedGoogle ScholarCrossref
6.
Institute for Quality and Efficiency in Health Care (IQWiG). Validity of surrogate endpoints in oncology. Version 1.1, 2011. www.ncbi.nlm.nih.gov/books/NBK198799/
7.
Gyawali  B , Hey  SP , Kesselheim  AS .  Evaluating the evidence behind the surrogate measures included in the FDA’s table of surrogate endpoints as supporting approval of cancer drugs.   EClinicalMedicine. 2020;21:100332. doi:10.1016/j.eclinm.2020.100332 PubMedGoogle ScholarCrossref
8.
US Department of Health and Human Services. US Food and Drug Administration, Center for Drug Evaluation and Research (CDER): Guidance for Industry: Pathological Complete Response in Neoadjuvant Treatment of High-Risk Early-Stage Breast Cancer—Use as an Endpoint to Support Accelerated Approval. www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm305501.pdf
9.
European Medicines Agency.  EMA/CHMP/ 151853 /2014: Draft guideline on the role of the pathological complete response as an endpoint in neoadjuvant breast cancer studies. www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/04/ WC500165781.pdf.
10.
Cortazar  P , Zhang  L , Untch  M ,  et al.  Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis.   Lancet. 2014;384(9938):164-172. doi:10.1016/S0140-6736(13)62422-8 PubMedGoogle ScholarCrossref
11.
Prowell  TM , Pazdur  R .  Pathological complete response and accelerated drug approval in early breast cancer.   N Engl J Med. 2012;366(26):2438-2441. doi:10.1056/NEJMp1205737 PubMedGoogle ScholarCrossref
12.
Gianni  L , Pienkowski  T , Im  YH ,  et al.  Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial.   Lancet Oncol. 2012;13(1):25-32. doi:10.1016/S1470-2045(11)70336-9 PubMedGoogle ScholarCrossref
13.
Piccart  M , Procter  M , Fumagalli  D ,  et al; APHINITY Steering Committee and Investigators.  Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years’ Follow-Up.   J Clin Oncol. 2021;39(13):1448-1457. doi:10.1200/JCO.20.01204 PubMedGoogle ScholarCrossref
14.
Burstein  HJ , Curigliano  G , Thürlimann  B ,  et al; Panelists of the St Gallen Consensus Conference.  Customizing local and systemic therapies for women with early breast cancer: the St. Gallen International Consensus Guidelines for treatment of early breast cancer 2021.   Ann Oncol. 2021;32(10):1216-1235. doi:10.1016/j.annonc.2021.06.023 PubMedGoogle ScholarCrossref
15.
Schmid  P , Cortes  J , Pusztai  L ,  et al; KEYNOTE-522 Investigators.  Pembrolizumab for early triple-negative breast cancer.   N Engl J Med. 2020;382(9):810-821. doi:10.1056/NEJMoa1910549 PubMedGoogle ScholarCrossref
16.
Oncologic Drugs Advisory Committee (ODAC) Meeting February 9, 2021. Accessed September 9, 2022. https://www.fda.gov/media/145654/download
17.
Prowell  TM , Beaver  JA , Pazdur  R .  Residual disease after neoadjuvant therapy—developing drugs for high-risk early breast cancer.   N Engl J Med. 2019;380(7):612-615. doi:10.1056/NEJMp1900079 PubMedGoogle ScholarCrossref
18.
Conforti  F , Pala  L , Sala  I ,  et al.  Evaluation of pathological complete response as surrogate endpoint in neoadjuvant randomised clinical trials of early stage breast cancer: systematic review and meta-analysis.   BMJ. 2021;375:e066381. doi:10.1136/bmj-2021-066381 PubMedGoogle ScholarCrossref
19.
von Minckwitz  G , Huang  C-S , Mano  MS ,  et al; KATHERINE Investigators.  Trastuzumab emtansine for residual invasive HER2-positive breast cancer.   N Engl J Med. 2019;380(7):617-628. doi:10.1056/NEJMoa1814017 PubMedGoogle ScholarCrossref
20.
Masuda  N , Lee  S-J , Ohtani  S ,  et al.  Adjuvant capecitabine for breast cancer after preoperative chemotherapy.   N Engl J Med. 2017;376(22):2147-2159. doi:10.1056/NEJMoa1612645 PubMedGoogle ScholarCrossref
21.
Loibl  S , Marmé  F , Martin  M ,  et al.  Palbociclib for residual high-risk invasive HR-positive and HER2-Negative Early Breast Cancer-The Penelope-B Trial.   J Clin Oncol. 2021;39(14):1518-1530. doi:10.1200/JCO.20.03639 PubMedGoogle ScholarCrossref
22.
Hayes  DF , Schott  AF .  Neoadjuvant chemotherapy: what are the benefits for the patient and for the investigator?   J Natl Cancer Inst Monogr. 2015;2015(51):36-39. doi:10.1093/jncimonographs/lgv004 PubMedGoogle ScholarCrossref
23.
Rose  BS , Winer  EP , Mamon  HJ .  Perils of the pathologic complete response.   J Clin Oncol. 2016;34(33):3959-3962. doi:10.1200/JCO.2016.68.1718 PubMedGoogle ScholarCrossref
24.
Menzies  AM , Amaria  RN , Rozeman  EA ,  et al.  Pathological response and survival with neoadjuvant therapy in melanoma: a pooled analysis from the International Neoadjuvant Melanoma Consortium (INMC).   Nat Med. 2021;27(2):301-309. doi:10.1038/s41591-020-01188-3 PubMedGoogle ScholarCrossref
25.
Feldman  LD , Hortobagyi  GN , Buzdar  AU , Ames  FC , Blumenschein  GR .  Pathological assessment of response to induction chemotherapy in breast cancer.   Cancer Res. 1986;46(5):2578-2581.PubMedGoogle Scholar
26.
Earl  HM , Hiller  L , Dunn  JA ,  et al; ARTemis Investigators Group.  Disease-free and overall survival at 3.5 years for neoadjuvant bevacizumab added to docetaxel followed by fluorouracil, epirubicin and cyclophosphamide, for women with HER2 negative early breast cancer: ARTemis Trial.   Ann Oncol. 2017;28(8):1817-1824. doi:10.1093/annonc/mdx173 PubMedGoogle ScholarCrossref
27.
von Minckwitz  G , Loibl  S , Untch  M ,  et al; GBG/AGO-B study groups.  Survival after neoadjuvant chemotherapy with or without bevacizumab or everolimus for HER2-negative primary breast cancer (GBG 44-GeparQuinto).   Ann Oncol. 2014;25(12):2363-2372. doi:10.1093/annonc/mdu455 PubMedGoogle ScholarCrossref
28.
Untch  M , Jackisch  C , Schneeweiss  A ,  et al.  NAB-paclitaxel improves disease-free survival in early breast cancer: GBG 69-GeparSepto.   J Clin Oncol. 2019;37(25):2226-2234. doi:10.1200/JCO.18.01842 PubMedGoogle ScholarCrossref
29.
Burstein  HJ .  Systemic therapy for estrogen receptor-positive, HER2-negative breast cancer.   N Engl J Med. 2020;383(26):2557-2570. doi:10.1056/NEJMra1307118 PubMedGoogle ScholarCrossref
30.
von Minckwitz  G , Blohmer  JU , Costa  SD ,  et al.  Response-guided neoadjuvant chemotherapy for breast cancer.   J Clin Oncol. 2013;31(29):3623-3630. doi:10.1200/JCO.2012.45.0940 PubMedGoogle ScholarCrossref
31.
Loibl  S , Schneeweiss  A , Huober  J ,  et al.  Durvalumab improves long-term outcome in TNBC: results from the phase II randomized GeparNUEVO study investigating neodjuvant durvalumab in addition to an anthracycline/taxane based neoadjuvant chemotherapy in early triple-negative breast cancer (TNBC).   J Clin Oncol. 2021;39:505-506. doi:10.1200/JCO.2021.39.15_suppl.506 Google ScholarCrossref
32.
Hellmann  MD , Chaft  JE , William  WN  Jr ,  et al; University of Texas MD Anderson Lung Cancer Collaborative Group.  Pathological response after neoadjuvant chemotherapy in resectable non-small-cell lung cancers: proposal for the use of major pathological response as a surrogate endpoint.   Lancet Oncol. 2014;15(1):e42-e50. doi:10.1016/S1470-2045(13)70334-6PubMedGoogle ScholarCrossref
33.
Hurvitz  SA , Martin  M , Jung  KH ,  et al.  Neoadjuvant trastuzumab emtansine and pertuzumab in human epidermal growth factor receptor 2-positive breast cancer: three-year outcomes from the phase III KRISTINE Study.   J Clin Oncol. 2019;37(25):2206-2216. doi:10.1200/JCO.19.00882 PubMedGoogle ScholarCrossref
34.
Symmans  WF , Yau  C , Chen  YY ,  et al.  Assessment of Residual Cancer Burden and Event-Free Survival in Neoadjuvant Treatment for High-risk Breast Cancer: An Analysis of Data From the I-SPY2 Randomized Clinical Trial.   JAMA Oncol. 2021;7(11):1654-1663. doi:10.1001/jamaoncol.2021.3690 PubMedGoogle ScholarCrossref
35.
Yau  C , Osdoit  M , van der Noordaa  M ,  et al; I-SPY 2 Trial Consortium.  Residual cancer burden after neoadjuvant chemotherapy and long-term survival outcomes in breast cancer: a multicentre pooled analysis of 5161 patients.   Lancet Oncol. 2022;23(1):149-160. doi:10.1016/S1470-2045(21)00589-1 PubMedGoogle Scholar
36.
Bujkiewicz  S , Thompson  JR , Riley  RD , Abrams  KR .  Bayesian meta-analytical methods to incorporate multiple surrogate endpoints in drug development process.   Stat Med. 2016;35(7):1063-1089. doi:10.1002/sim.6776 PubMedGoogle Scholar
37.
Elia  EG , Städler  N , Ciani  O , Taylor  RS , Bujkiewicz  S .  Combining tumour response and progression free survival as surrogate endpoints for overall survival in advanced colorectal cancer.   Cancer Epidemiol. 2020;64:101665. doi:10.1016/j.canep.2019.101665 PubMedGoogle Scholar
38.
Galbraith  S , Marschner  IC .  Interim analysis of continuous long-term endpoints in clinical trials with longitudinal outcomes.   Stat Med. 2003;22(11):1787-1805. doi:10.1002/sim.1311 PubMedGoogle Scholar
39.
Barrado  LG , Burzykowski  T , Legrand  T ,  et al.  Using an interim analysis based exclusively on an early outcome in a randomized clinical trial with a long-term clinical endpoint.   Pharm Stat. 2021:1-11.PubMedGoogle Scholar
40.
Marschner  IC , Becker  SL .  Interim monitoring of clinical trials based on long-term binary endpoints.   Stat Med. 2001;20(2):177-192. doi:10.1002/1097-0258(20010130)20:2<177::AID-SIM653>3.0.CO;2-K PubMedGoogle Scholar
41.
Pan  H , Gray  R , Braybrooke  J ,  et al; EBCTCG.  20-Year risks of breast-cancer recurrence after stopping endocrine therapy at 5 years.   N Engl J Med. 2017;377(19):1836-1846. doi:10.1056/NEJMoa1701830 PubMedGoogle Scholar
42.
Tie  J , Cohen  JD , Wang  Y ,  et al.  Circulating tumor DNA analyses as markers of recurrence risk and benefit of adjuvant therapy for stage III colon cancer.   JAMA Oncol. 2019;5(12):1710-1717. doi:10.1001/jamaoncol.2019.3616 PubMedGoogle Scholar
43.
Cullinane  C , Fleming  C , O’Leary  DP ,  et al.  Association of circulating tumor DNA with disease-free survival in breast cancer: a systematic review and meta-analysis.   JAMA Netw Open. 2020;3(11):e2026921. doi:10.1001/jamanetworkopen.2020.26921 PubMedGoogle Scholar
44.
Magbanua  MJM , Swigart  LB , Wu  HT ,  et al.  Circulating tumor DNA in neoadjuvant-treated breast cancer reflects response and survival.   Ann Oncol. 2021;32(2):229-239. doi:10.1016/j.annonc.2020.11.007 PubMedGoogle Scholar
45.
Turner  N , Swift  C , Jenkins  B ,  et al. Primary results of the cTRAK TN trial: A clinical trial utilising ctDNA mutation tracking to detect minimal residual disease and trigger intervention in patients with moderate and high risk early stage triple negative breast cancer. Presented at: 2021 San Antonio Breast Cancer Symposium; virtual. Abstract GS3-06.
46.
Braun  S , Vogl  FD , Naume  B ,  et al.  A pooled analysis of bone marrow micrometastasis in breast cancer.   N Engl J Med. 2005;353(8):793-802. doi:10.1056/NEJMoa050434PubMedGoogle Scholar
Close
Want full access to the AMA Ed Hub?
After you sign up for AMA Membership, make sure you sign in or create a Physician account with the AMA in order to access all learning activities on the AMA Ed Hub
Buy this activity
Close
Want full access to the AMA Ed Hub?
After you sign up for AMA Membership, make sure you sign in or create a Physician account with the AMA in order to access all learning activities on the AMA Ed Hub
Buy this activity
Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Close

Name Your Search

Save Search
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Close
Close

Lookup An Activity

or

My Saved Searches

You currently have no searches saved.

Close

My Saved Courses

You currently have no courses saved.

Close