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Published in: BMC Medicine 1/2015

Open Access 01-12-2015 | Opinion

Neoadjuvant trials in early breast cancer: pathological response at surgery and correlation to longer term outcomes – what does it all mean?

Authors: Helena Earl, Elena Provenzano, Jean Abraham, Janet Dunn, Anne-Laure Vallier, Ioannis Gounaris, Louise Hiller

Published in: BMC Medicine | Issue 1/2015

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Abstract

Background

Neoadjuvant breast cancer trials are important for speeding up the introduction of new treatments for patients with early breast cancer and for the highly productive translational research which they facilitate. Meta-analysis of trial data shows clear correlation between pathological response at surgery after neoadjuvant chemotherapy and longer-term outcomes at an individual patient level. However, this does not appear to be present on individual trial level analysis, when correlating improved outcome for the investigational arm for the primary endpoint (pathological response) with longer-term outcomes.

Discussion

The correlation between pathological response and longer-term outcomes in trials is dependent on many factors. These include definitions of pathological response, both complete and partial; assessment methods for pathological response at surgery; subtype and prognosis of breast cancer at diagnosis; number of patients recruited; adjuvant treatments; the mechanism of action of the investigational drug; the length of follow-up at the time of reporting; the definitions used in longer-term outcomes analysis; clonal heterogeneity; and new adaptive trial designs with additional neo/adjuvant treatments. Future developments of neoadjuvant breast cancer trials are discussed. With so many factors influencing the correlation of longer-term outcomes for trial-level data, we conclude that the main focus of neoadjuvant trials should remain the primary endpoint of pathological response.

Summary

Neoadjuvant breast cancer trials are very important investigational studies that will continue to increase our understanding of the disease and offer the potential of more rapid introduction of new treatments for women with high-risk early breast cancer. In the future, we are likely to see both novel trial designs adopted in the neoadjuvant context and modifications of neo/adjuvant treatments for pathological non-responders within clinical trials. Both of these have the intention of improving longer-term outcomes for patients who do not have a good pathological response to first-line neoadjuvant treatment. If successful, these developments are likely to reduce further any positive correlation between pathological response and longer-term outcomes.
Literature
1.
Killelea BK, Yang VQ, Mougalian S, Horowitz NR, Pusztai L, Chagpar AB, et al. Neoadjuvant chemotherapy for breast cancer increases the rate of breast conservation: results from the National Cancer Database. J Am Coll Surg. 2015;220:1063–9.CrossRefPubMed
2.
Fisher B, Brown A, Mamounas E, Wieand S, Robidoux A, Margolese RG, et al. Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18. J Clin Oncol. 1997;15:2483–93.PubMed
3.
Gianni L, Baselga J, Eiermann W, Porta VG, Semiglazov V, Lluch A, et al. Phase III trial evaluating the addition of paclitaxel to doxorubicin followed by cyclophosphamide, methotrexate, and fluorouracil, as adjuvant or primary systemic therapy: European Cooperative Trial in Operable Breast Cancer. J Clin Oncol. 2009;27:2474–81.CrossRefPubMed
4.
Earl HM, Hiller L, Dunn JA, Blenkinsop C, Grybowicz L, Vallier AL, et al. Efficacy of neoadjuvant bevacizumab added to docetaxel followed by fluorouracil, epirubicin and cyclophosphamide, for women with HER2 negative early breast cancer (ARTemis): an open-label randomised phase 3 trial. Lancet Oncol. 2015;16:656–66.CrossRefPubMed
5.
Cortazar P, Zhang L, Untch M, Mehta K, Costantino JP, Wolmark N, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 2014;384:164–72.CrossRefPubMed
6.
Berruti A, Amoroso V, Gallo F, Bertaglia V, Simoncini E, Pedersini R, et al. Pathologic complete response as a potential surrogate for the clinical outcome in patients with breast cancer after neoadjuvant therapy: a meta-regression of 29 randomized prospective studies. J Clin Oncol. 2014;32:3883–91.CrossRefPubMed
7.
Earl HM, Vallier A-L, Hiller L, Fenwick N, Young J, Iddawela M, et al. Effect of the addition of gemcitabine, and paclitaxel-first sequencing, in neoadjuvant sequential epirubicin, cyclophosphamide, and paclitaxel for women with high-risk early breast cancer (Neo-tAnGo): an open-label, 2 x 2 factorial randomised phase 3 trial. Lancet Oncol. 2014;15:201–12.CrossRefPubMed
8.
von Minckwitz G, Loibl S, Untch M, Eidtmann H, Rezai M, Fasching PA, et al. Survival after neoadjuvant chemotherapy with or without bevacizumab or everolimus for HER2-negative primary breast cancer (GBG 44-GeparQuinto). Ann Oncol. 2014;25:2363–72.CrossRef
9.
Bear HD, Tang G, Rastogi P, Geyer CE Jr, Liu Q, Robidoux A, et al. Neoadjuvant plus adjuvant bevacizumab in early breast cancer (NSABP B-40 [NRG Oncology]): secondary outcomes of a phase 3, randomised controlled trial. Lancet Oncol. 2015 Aug 10. [Epub ahead of print].
10.
Gianni L, Eiermann W, Semiglazov V, Lluch A, Tjulandin S, Zambetti M, et al. Neoadjuvant and adjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer (NOAH): follow-up of a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet Oncol. 2014;15:640–7.CrossRefPubMed
11.
US Department of Health and Human Services, 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. Published October 2014 (Clinical/Medical).
12.
Prowell TM, Pazdur R. Perspective: pathological complete response and accelerated drug approval in early breast cancer. N Engl J Med. 2012;366:2438–41.CrossRefPubMed
13.
Rouzier R, Extra JM, Klijanienko J, Falcou MC, Asselain B, Vincent-Salomon A, et al. Incidence and prognostic significance of complete axillary downstaging after primary chemotherapy in breast cancer patients with T1 to T3 tumors and cytologically proven axillary metastatic lymph nodes. J Clin Oncol. 2002;20:1304–10.CrossRefPubMed
14.
McCready DR, Hortobagyi GN, Kau SW, Smith TL, Buzdar AU, Balch CM. The prognostic significance of lymph node metastases after preoperative chemotherapy for locally advanced breast cancer. Arch Surg. 1989;124:21–5.CrossRefPubMed
15.
Hennessy BT, Hortobagyi GN, Rouzier R, Kuerer H, Sneige N, Buzdar AU, et al. Outcome after pathologic complete eradication of cytologically proven breast cancer axillary node metastases following primary chemotherapy. J Clin Oncol. 2005;23:9304–11.CrossRefPubMed
16.
Provenzano E, Brown JP, Pinder SE. Pathological controversies in breast cancer: classification of ductal carcinoma in situ, sentinel lymph nodes and low volume metastatic disease and reporting of neoadjuvant chemotherapy specimens. Clin Oncol (R Coll Radiol). 2013;25:80–92.CrossRef
17.
Mazouni C, Peintinger F, Wan-Kau S, Andre F, Gonzalez-Angulo AM, Symmans WF, et al. Residual ductal carcinoma in situ in patients with complete eradication of invasive breast cancer after neoadjuvant chemotherapy does not adversely affect patient outcome. J Clin Oncol. 2007;25:2650–5.CrossRefPubMed
18.
von Minckwitz G, Untch M, Blohmer JU, Costa SD, Eidtmann H, Fasching PA, et al. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol. 2012;30:1796–804.CrossRef
19.
Provenzano E, Bossuyt V, Viale G, Cameron D, Badve S, Denkert C. Standardization of pathologic evaluation and reporting of post-neoadjuvant specimens in clinical trials of breast cancer: Recommendations from an international working group. Mod Pathol. 2015;28:1185–201.CrossRefPubMed
20.
Marchio C, Sapino A. The pathologic complete response open question in primary therapy. J Natl Cancer Inst Monogr. 2011;43:86–90.CrossRef
21.
Pinder SE, Provenzano E, Earl HM, Ellis IO. Laboratory handling and reporting of breast specimens from patients who have received neo-adjuvant chemotherapy. Histopathology. 2007;50:409–17.CrossRefPubMed
22.
Sahoo S, Lester SC. Pathology of breast carcinomas after neoadjuvant chemotherapy: an overview with recommendations on specimen processing and reporting. Arch Pathol Lab Med. 2009;133:633–42.PubMed
23.
Provenzano E, Vallier A-L, Champ R, Walland K, Bowden S, Grier A, et al. A central review of histopathology reports after breast cancer neoadjuvant chemotherapy in the Neo-tAnGo trial. Br J Cancer. 2013;108:866–72.CrossRefPubMedPubMedCentral
24.
Sataloff DM, Mason BA, Prestipino AJ, Seinige UL, Lieber CP, Baloch Z. Pathologic response to induction chemotherapy in locally advanced carcinoma of the breast: a determinant of outcome. J Am Coll Surg. 1995;180:297–306.PubMed
25.
Ogston KN, Miller ID, Payne S, Hutcheon AW, Sarkar TK, Smith I, et al. A new histological grading system to assess response of breast cancers to primary chemotherapy: prognostic significance and survival. Breast. 2003;12:320–7.CrossRefPubMed
26.
Chevallier B, Roche H, Olivier JP, Chollet P, Hurteloup P. Inflammatory breast cancer. Pilot study of intensive induction chemotherapy (FEC-HD) results in a high histologic response rate. Am J Clin Oncol. 1993;16:223–8.CrossRefPubMed
27.
Symmans WF, Peintinger F, Hatzis C, Rajan R, Kuerer H, Valero V, et al. Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol. 2007;25:4414–22.CrossRefPubMed
28.
29.
Peintinger F, Kuerer HM, McGuire SE, Bassett R, Pusztai L, Symmans WF. Residual specimen cellularity after neoadjuvant chemotherapy for breast cancer. Br J Surg. 2008;95:433–7.CrossRefPubMed
30.
Earl HM. Reporting of adjuvant breast cancer trials – when is the right time? J Clin Oncol. 2012;30:1–2.CrossRefPubMed
31.
Dawson SJ, Rueda OM, Aparicio S, Caldas C. A new genome-driven integrated classification of breast cancer and its implications. EMBO J. 2013;32:617–28.CrossRefPubMedPubMedCentral
32.
Goldie JH, Coldman AJ. A mathematic model for relating the drug sensitivity of tumours to their spontaneous mutation rate. Cancer Treat Rep. 1979;63:1727–33.PubMed
33.
Dawson SJ, Tsui DW, Murtaza M, Biggs H, Rueda OM, Chin SF, et al. Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med. 2013;368:1199–209.CrossRefPubMed
34.
von Minckwitz G, Eidtmann H, Rezai M, Fasching PA, Tesch H, Eggemann H, et al. Neoadjuvant chemotherapy and bevacizumab for HER2-negative breast cancer. N Engl J Med. 2012;366:299–309.CrossRef
35.
Bear HD, Tang G, Rastogi P, Geyer Jr CE, Robidoux A, Atkins JN, et al. Bevacizumab added to neoadjuvant chemotherapy for breast cancer. N Engl J Med. 2012;366:310–20.CrossRefPubMedPubMedCentral
36.
Sikov WM, Berry DA, Perou CM, Singh B, Cirrincione CT, Tolaney SM, et al. Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance). J Clin Oncol. 2015;33:13–21.CrossRefPubMed
37.
Cameron D, Brown J, Dent R, Jackisch C, Mackey J, Pivot X, et al. Adjuvant bevacizumab-containing therapy in triple-negative breast cancer (BEATRICE): primary results of a randomised, phase 3 trial. Lancet Oncol. 2013;14:933–42.CrossRefPubMed
38.
Miller K, O’Neill AM, Dang CT, Northfelt DW, Gradishar WJ, Goldstein LJ, et al. Bevacizumab (Bv) in the adjuvant treatment of HER2-negative breast cancer: Final results from Eastern Cooperative Oncology Group E5103. J Clin Oncol. 2014;32:5s. suppl; abstr 500.CrossRef
39.
Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012;379:633–40.CrossRefPubMed
40.
Piccart-Gebhart MJ, Holmes AP, Baselga J, Azambuja E, Dueck AC, Viale G, et al. First results from the phase III ALTTO trial (BIG 2-06; NCCTG [Alliance] N063D) comparing one year of anti-HER2 therapy with Lapatinib alone (L), trastuzumab alone (T), their sequence (T then L), or their combinations (T + L) in the adjuvant treatment of HER2-positive early breast cancer (EBC) [abstract]. J Clin Oncol. 2014;32 Suppl 5:LBA4.
41.
DeMichele A, Yee D, Berry DA, Albain KS, Benz CC, Boughey J, et al. The neoadjuvant model is still the future for drug development in breast cancer. Clin Cancer Res. 2015;21:2911–5.CrossRefPubMedPubMedCentral
42.
Hatzis C, Gould RE, Zhang Y, Chung G, Sanft T, Hofstatter E, et al. Predicting improvements in survival based on improvements in pathologic response rate to neoadjuvant chemotherapy in different breast cancer subtypes. San Antonio Breast Cancer Symposium. Cancer Res. 2013;73(24 Suppl):Abstract P6-06–37.
43.
Romond EH, Perez EA, Bryant J, Suman VJ, Geyer Jr CE, Davidson NE, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353:1673–84.CrossRefPubMed
44.
Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353:1659–72.CrossRefPubMed
45.
Esserman LJ, Berry DA, DeMichele A, Carey L, Davis SE, Buxton M, et al. Pathologic complete response predicts recurrence-free survival more effectively by cancer subset: results from the I-SPY 1 TRIAL--CALGB 150007/150012, ACRIN 6657. J Clin Oncol. 2012;30:3242–9.CrossRefPubMedPubMedCentral
46.
Rugo HS, Olopade O, DeMichele A, et al. Veliparib/carboplatin plus standard neoadjuvant therapy for high-risk breast cancer: first efficacy results from the I-SPY 2 TRIAL. San Antonio Breast Cancer Symposium. Cancer Res. 2013;73(24Suppl):Abstract: S5–02.
47.
Wason JMS, Abraham JE, Baird RD, Gournaris I, Vallier AL, Brenton JD, et al. Bayesian adaptive designs for biomarker trials with biomarker discovery. Br J Cancer. 2015;113(5):699–705.CrossRefPubMedPubMedCentral
Metadata
Title
Neoadjuvant trials in early breast cancer: pathological response at surgery and correlation to longer term outcomes – what does it all mean?
Authors
Helena Earl
Elena Provenzano
Jean Abraham
Janet Dunn
Anne-Laure Vallier
Ioannis Gounaris
Louise Hiller
Publication date
01-12-2015
Publisher
BioMed Central
Published in
BMC Medicine / Issue 1/2015
Electronic ISSN: 1741-7015
DOI
https://doi.org/10.1186/s12916-015-0472-7

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