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

BMC Medicine

Louise Hiller¹  Ioannis Gounaris³  Anne-Laure Vallier²  Janet Dunn¹  Jean Abraham²  Elena Provenzano²  Helena Earl² 

[1] Warwick Clinical Trials Unit, University of Warwick, Coventry, UK;Cambridge University Hospital NHS Foundation Trust, Cambridge, UK;Cancer Research UK Cambridge Institute, Cambridge, UK

关键词: Pathological response;    Neoadjuvant trials;    Longer-term outcomes;    Early breast cancer;   

Others  :  1226296
DOI  :  10.1186/s12916-015-0472-7

 received in 2015-05-14, accepted in 2015-09-01,  发布年份 2015

【 摘 要 】

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.

【 授权许可】

   
2015 Earl et al.

【 图 表 】

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【 参考文献 】

• [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.
• [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.
• [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.
• [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.
• [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.
• [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.
• [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.
• [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.
• [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.
• [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.
• [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.
• [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.
• [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.
• [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.
• [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.
• [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.
• [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.
• [20]Marchio C, Sapino A. The pathologic complete response open question in primary therapy. J Natl Cancer Inst Monogr. 2011; 43:86-90.
• [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.
• [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.
• [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.
• [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.
• [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.
• [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.
• [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.
• [28]http://www3.mdanderson.org/app/medcalc/index.cfm?pagename=jsconvert3
• [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.
• [30]Earl HM. Reporting of adjuvant breast cancer trials – when is the right time? J Clin Oncol. 2012; 30:1-2.
• [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.
• [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.
• [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.
• [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.
• [35]Bear HD, Tang G, Rastogi P, Geyer CE, Robidoux A, Atkins JN et al.. Bevacizumab added to neoadjuvant chemotherapy for breast cancer. N Engl J Med. 2012; 366:310-20.
• [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.
• [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.
• [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.
• [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.
• [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.
• [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 CE, Davidson NE et al.. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005; 353:1673-84.
• [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.
• [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.
• [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.