The other subtype in which a strong association is suspected between response to neoadjuvant therapy and overall outcome is triple-negative breast cancer. It is the subgroup with the largest difference in outcome when comparing patients with and without a pCR [1▪▪]. However, due to the high heterogeneity of the disease, it appears much more challenging to develop targeted agents that can add to the effect of chemotherapy. One compound that raised high interest due to promising results in pretreated metastatic breast cancer was iniparib . Initially considered to be a PARP inhibitor, it was combined with other DNA damaging agents such as carboplatin. However, a subsequent phase III study  failed to show significant results regarding the primary endpoints prompting a re-examination of the mode of action and revealing that in fact the compound was not inhibiting PARP. Only one neoadjuvant trial with iniparib was started at that time. Results on this NeoPARP study were published recently showing no change in pCR when iniparib was given at two different schedules together with paclitaxel to patients with early breast cancer . Therefore, it might be a better approach to target the host instead of this heterogenic subtype. In fact, the GeparQuinto trial showed a significant improvement of pCR when bevacizumab was added to chemotherapy in patients with HER2-negative breast cancer . Subgroup analysis suggested that this effect was derived mainly from patients with triple-negative breast cancer; pCR rates increased from 27.9% with chemotherapy alone to 39.3% with chemotherapy and bevacizumab . The sustainability of this result will be shown by the Beatrice study (NCT00528567) that examined various chemotherapy regimens with or without bevacizumab as an adjuvant treatment for patients with triple-negative breast cancer (Fig. 3d) . However, a first announcement by the sponsor claimed that the predefined endpoint invasive disease-free survival was not met (http://www.roche.com/hy12e02.pdf [Accessed 19 September 2012]).
Extent and characterization of residual disease after neoadjuvant chemotherapy raises increasingly more interest. The above-mentioned meta-analysis [1▪▪] showed that the extent of residual disease after neoadjuvant chemotherapy in the breast as well as in the nodes is associated with survival of patients. Worst prognosis with a median survival of around 5 years was observed for patients with posttreatment persisting inflammatory breast cancer, as well as large (>10) involvement of axillary nodes. Further biological characterization of residual disease was initiated by examining Ki-67 on the residual tumour. We determined Ki-67 on 1150 patients from the GeparTrio study for disease-free and overall survival . Patients were subdivided into four groups (pCR, Ki-67 0–15%, Ki-67 15.1–35%, Ki-67 >35%) having significantly different disease-free and overall survival prospects (Fig. 4) . In fact, posttreatment Ki-67 measurements were prognostically more relevant than pretreatment measurements or changes from before to after treatment. When analysing patients separately according to the hormone receptor status of their tumour, it became obvious that in hormone receptor positive disease, patients with low or moderate posttreatment Ki-67 levels had a comparable outcome with patients with a pCR, and only patients with high Ki-67 levels showed a very high risk of relapse. In hormone receptor negative disease, however, patients with a pCR did better than those with low or moderate Ki-67 levels, and again, patients with highly proliferating tumours had a most unfavourable outcome.
Developing treatment strategies for those patients with an unfavourable future outcome due to residual disease after neoadjuvant chemotherapy appears to be a major task for the future. The NATAN study has recruited (NCT00512993) over 800 patients with residual disease after anthracycline–taxane based chemotherapy and randomized them to 5 years treatment with zoledronic acid or observation. However, as 80% of the patients had hormone receptor positive disease and the patients were not otherwise selected for a high relapse risk, event rate was much lower than expected and a report of the results had to be postponed. Due to the unfavourable outcome of patients without a pCR after neoadjuvant treatment with chemotherapy and trastuzumab, patients with HER2-positive tumours might be better candidates for such a postneoadjuvant approach. A registration trial is currently under development, with the aim to compare postsurgical treatment with trastuzumab with postsurgical treatment with trastuzumab emtansine (T-DM1), a fusion molecule of trastuzumab and an antimicrotubule agent derived from maytansine.
The concept of response-guided neoadjuvant chemotherapy was explored by the GeparTrio study [15,16]. Patients received two cycles of docetaxel, doxorubicin, cyclophosphamide (TAC). Response was assessed predominantly by sonography, and patients without an early response randomized to either four further cycles of TAC or four cycles of vinorelbine/capecitabine. Patients with an early response were considered sensitive to this type of chemotherapy and were randomized to a further four or six cycles of TAC. Analysis of pCR did not show any significant differences between the randomized groups. However, after a median of 5 years of follow-up, patients treated with the experimental treatments showed a better disease-free and overall survival than patients treated with conventional six cycles of TAC . An analysis by subgroup was performed to reveal why pCR did not predict these long-term results. It could be shown that the treatment effects were restricted to patients with hormone receptor positive tumours in which pCR was not prognostic (Fig. 5a) . However, in patients with HER2-positive (nonluminal) and triple-negative breast cancers, no difference between response-guided and conventional treatment was observed (Fig. 5b) . As these are the subgroups, wherein pCR shows predominantly its prognostic impact, the forecast of the surrogate marker was correct. It therefore appears crucial to assess the relationship between the prognostic impact of pCR and the treatment effect on pCR and survival separately by subtypes.
Furthermore, the response-guided approach should be further examined in patients with hormone receptor positive disease. However, the findings do not recommend aggressive chemotherapy to all kind of Luminal A tumours, as the GeparTrio study excluded patients with a low risk profile. Those patients included, despite a Luminal A-type feature of the tumour, had other clinical risk factors qualifying them for anthracycline–taxane based chemotherapy.
The database on the German neoadjuvant studies was further analysed regarding locoregional tumour relapses , as early neoadjuvant trials showed a higher relapse risk for this approach. It was demonstrated that in general, patients with a pCR showed a lower locoregional relapse risk. These patients are therefore candidates to further reduce extent of locoregional treatment. It was further shown that patients treated by breast cancer conserving techniques had a lower locoregional relapse risk. This was also the case for patients with locally advanced tumours before the start of treatment. Even patients with inflammatory breast cancer showed a lower locoregional relapse risk when treated with breast cancer conservation than those treated with mastectomy (Fig. 1) [6▪▪,7,8▪,9]. As this is not a randomized comparison, it can only state that in case the investigator and the patient had chosen this nonstate-of-the-art approach (probably due to an extensive clinical response), it did not take patients at a high locoregional relapse risk.
The model of neoadjuvant chemotherapy has been improved over the last decade and is now successfully used to increase our knowledge on not only the pathophysiology of the disease but also on the activity of conventional and new treatment approaches. Due to this evolving evidence, a trend towards a more frequent use of this approach can be observed. Registration by authorities of new treatments in the neoadjuvant but as well in the postneoadjuvant setting further motivate to use this approach more frequently, as it will be the only option for patients to get early access to new and promising treatment options. The response-guided approach might be an option to further improve treatment, especially in hormone receptor positive tumours.
Papers of particular interest, published within the annual period of review, have been highlighted as:
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 88–89).
1▪▪. von Minckwitz G, Untch M, Blohmer JU, et al. Definition and impact of pathological complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol
A large meta-analysis exploring the impact of pCR in various breast cancer subtypes as well as which definition best separates patients with a poor and favourable outcome.
2. Goldhirsch A, Wood WC, Coates AS, et al. Strategies for subtypes: dealing with the diversity of breast cancer: highlights of the St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer. Ann Oncol
3. Rastogi P, Anderson SJ, Bear HD, et al. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol
4. Kaufmann M, Eiermann W, Schütte M, et al. Long term results form the neoadjuvant GeparDuo trial comparing a dose-dense regimen of adriamycin and docetaxel (ADoc) with a standard regimen of adriamycin /cyclophosphamide followed by docetaxel (AC–Doc) in patients (pts) with operable breast cancer (BC). J Clin Oncol
2010; 28 (15s):76s(Suppl; abstr 537).
5. von Minckwitz G, Blohmer JU, Costa SD, et al. Neoadjuvant chemotherapy adapted by interim response improves overall survival of primary breast cancer patients: results of the GeparTrio trial. Cancer Res
2011; 71 (Suppl 24):103s.
6▪▪. Gianni L, Eiermann W, Semiglazov V, et al. Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet
A landmark study leading to registration of trastuzumab for use in combination with neoadjuvant anthracycline–taxane based chemotherapy in Europe.
7. Untch M, Loibl S, Bischoff J, et al. Lapatinib versus trastuzumab in combination with neoadjuvant anthracycline-taxane-based chemotherapy (GeparQuinto, GBG 44): a randomised phase 3 trial. Lancet Oncol
8▪. 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
The first study using a double HER2 blockage together with a full-dose anthracycline–taxane based neoadjuvant chemotherapy.
9. von Minckwitz G, Eidtmann H, Rezai M, et al. Neoadjuvant chemotherapy and bevacizumab for HER2-negative breast cancer. N Engl J Med
10. O'Shaughnessy J, Osborne C, Pippen JE, et al. Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N Engl J Med
11. O'Shaughnessy J, Schwartzberg MA, Danso HS, et al.
A randomized phase III study of iniparib (BSI-201) in combination with gemcitabine/carboplatin (G/C) in metastatic triple-negative breast cancer (TNBC). J Clin Oncol 2011; 29(Suppl):abstr 1007.
12. Llombard A, Lluch A, Villanueva C, et al.
SOLTI NeoPARP: a phase II, randomized study of two schedules of iniparib plus paclitaxel and paclitaxel alone as neoadjuvant therapy in patients with triple-negative breast cancer (TNBC). J Clin Oncol 2012; 30(Suppl):abstr 1011.
13. Gerber B, Eidtman H, Rezai M, et al.
Neoadjuvant bevacizumab and anthracycline–taxane-based chemotherapry in 686 triple-negative primary breast cancers: secondary endpoint analysis of the GeparQuinto study (GBG 44). J Clin Oncol 2011; 29(Suppl):abstr 1006.
14. von Minckwitz G, Müller B, Blohmer JU, et al.
Prognostic and predictive impact of Ki-67 before and after neoadjuvant chemotherapy on PCR and survival: results of the GeparTrio trial. J Clin Oncol 2012; 30(Suppl):abstr 1023.
15. von Minckwitz G, Kummel S, Vogel P, et al. Intensified neoadjuvant chemotherapy in early-responding breast cancer: phase III randomized GeparTrio study. J Natl Cancer Inst
16. von Minckwitz G, Kümmel S, Vogel P, et al. Neoadjuvant vinorelbine-capecitabine versus docetaxel-doxorubicin-cyclophosphamide in early nonresponsive breast cancer: phase III randomized GeparTrio trial. J Natl Cancer Inst
17. von Minckwitz G, Kaufmann M, Kümmel S, et al. Local recurrence risk after neoadjuvant chemotherapy. Pooled analysis on 5477 breast cancer patients. Cancer Res
2011; 71 (Suppl 24):142s.