Long-term outcomes for neoadjuvant versus adjuvant chemotherapy in early breast cancer: meta-analysis of individual patient data from ten randomised trials

Abstract

Background: Neoadjuvant chemotherapy (NACT) for early breast cancer can make breast-conserving surgery more feasible and might be more likely to eradicate micrometastatic disease than might the same chemotherapy given after surgery. We investigated the long-term benefits and risks of NACT and the influence of tumour characteristics on outcome with a collaborative meta-analysis of individual patient data from relevant randomised trials.

Methods: We obtained information about prerandomisation tumour characteristics, clinical tumour response, surgery, recurrence, and mortality for 4756 women in ten randomised trials in early breast cancer that began before 2005 and compared NACT with the same chemotherapy given postoperatively. Primary outcomes were tumour response, extent of local therapy, local and distant recurrence, breast cancer death, and overall mortality. Analyses by intention-to-treat used standard regression (for response and frequency of breast-conserving therapy) and log-rank methods (for recurrence and mortality).

Findings: Patients entered the trials from 1983 to 2002 and median follow-up was 9 years (IQR 5-14), with the last follow-up in 2013. Most chemotherapy was anthracycline based (3838 [81%] of 4756 women). More than two thirds (1349 [69%] of 1947) of women allocated NACT had a complete or partial clinical response. Patients allocated NACT had an increased frequency of breast-conserving therapy (1504 [65%] of 2320 treated with NACT vs 1135 [49%] of 2318 treated with adjuvant chemotherapy). NACT was associated with more frequent local recurrence than was adjuvant chemotherapy: the 15 year local recurrence was 21·4% for NACT versus 15·9% for adjuvant chemotherapy (5·5% increase [95% CI 2·4-8·6]; rate ratio 1·37 [95% CI 1·17-1·61]; p=0·0001). No significant difference between NACT and adjuvant chemotherapy was noted for distant recurrence (15 year risk 38·2% for NACT vs 38·0% for adjuvant chemotherapy; rate ratio 1·02 [95% CI 0·92-1·14]; p=0·66), breast cancer mortality (34·4% vs 33·7%; 1·06 [0·95-1·18]; p=0·31), or death from any cause (40·9% vs 41·2%; 1·04 [0·94-1·15]; p=0·45).

Interpretation: Tumours downsized by NACT might have higher local recurrence after breast-conserving therapy than might tumours of the same dimensions in women who have not received NACT. Strategies to mitigate the increased local recurrence after breast-conserving therapy in tumours downsized by NACT should be considered-eg, careful tumour localisation, detailed pathological assessment, and appropriate radiotherapy.

Funding: Cancer Research UK, British Heart Foundation, UK Medical Research Council, and UK Department of Health.

Figure 1

BCT rate ratios Numbers with BCT or mastectomy after chemotherapy. Excludes local therapy unknown (67 patients with NACT and 51 with adjuvant chemotherapies). BCT=breast-conserving therapy. ER=oestrogen receptor. PR=progesterone receptor. NACT=neoadjuvant chemotherapy.

Figure 2

Effect of neoadjuvant versus adjuvant chemotherapy on recurrence and mortality Local recurrence (A), distant recurrence (B), breast cancer mortality (C), and death from any cause (D). Three trials recorded causes of any deaths but only the first breast cancer event. Hence, for these trials, distant recurrence includes the first distant recurrence as the first event and death from breast cancer. Error bars are 95% CIs. NACT=neoadjuvant chemotherapy. O–E=observed minus expected. RR=rate ratio. V=variance of O–E.

Figure 3

Time to recurrence and breast cancer mortality Local recurrence for surgery commonly used (A) and less commonly used (B), distant recurrence for surgery commonly used (C) and less commonly used (D), and breast cancer mortality for surgery commonly used (E) and less commonly used (F). Heterogeneity by surgery use: local recurrence p=0·19, distant recurrence p=0·29, and breast cancer mortality p=0·24. Error bars are 95% CIs. NACT=neoadjuvant chemotherapy. O–E=observed minus expected. RR=rate ratio. V=variance of O–E. Three trials recorded causes of any deaths but only the first breast cancer event. Hence, for these trials, distant recurrence includes the first distant recurrence as the first event and death from breast cancer. *Includes Institut Bergonié Bordeaux (in NACT group, 33% had radiotherapy alone) and Institut Curie S6 (in NACT group, 51% had radiotherapy alone; in adjuvant chemotherapy group, 46% had radiotherapy alone) trials.

Figure 4

Rate ratios for the effect of neoadjuvant versus adjuvant chemotherapy on recurrence by trial (A) Local recurrence. (B) Distant recurrence. Three trials recorded causes of any deaths but only the first breast cancer event. Hence, for these trials, distant recurrence includes the first distant recurrence as the first event and death from breast cancer. The appendix (pp 3–4) contains a full description of each trial's chemotherapy regimen. A=doxorubicin (adriamycin). BCCA=British Columbia Cancer Agency. BCSG=Breast Cancer Study Group. C=cyclophosphamide. E=epirubicin. ECTO=European Cooperative Trial in Operable Breast Cancer. EORTC=European Organisation for Research and Treatment of Cancer. F=fluorouracil. Fol=folinic acid. IB=Institut Bergonié. M=methotrexate. Mit=mitomycin-C. Mz=mitoxantrone. NCI=National Cancer Institute. NSABP=National Surgical Adjuvant Breast and Bowel Project. O–E=observed minus expected. P=paclitaxel. Tt=thiotepa. Vc=vincristine. Vd=vindesine. *Chemotherapy regimens given preoperatively in those allocated neoadjuvant and postoperatively in those allocated adjuvant chemotherapy. The number of cycles, agents, and drug doses (in mg/m²) per cycle are given. †The Austrian BCSG VII trial8 has two entries to take into account the two postoperative chemotherapies given to both randomised groups (appendix pp 3–4).

Figure 5

Local recurrence rate ratios For lumpectomy versus mastectomy, χ²₁=3·3; p=0·07. ER=oestrogen receptor. PR=progesterone receptor. *408 women with missing data had planned local therapy imputed (appendix p 9). †Refers to Institut Curie S6 (appendix p 9).

Figure 6

Clinical complete response rate ratios Three trials are excluded, as individual responses are not available; 440 women have missing clinical response data. CIs are group specific. Rate ratios are scaled such that, within each category, their inverse variance-weighted sum is 1—ie, ratios are with respect to the mean CR. The appendix (p 6) contains data available for each trial. CR=complete response. ER=oestrogen receptor. PR=progesterone receptor.