The majority of ongoing HER2-targeted trials are investigating the efficacy of lapatinib in the neoadjuvant setting for HER2+
breast cancer (Table ) [16
]. Most of these studies use pCR as a primary endpoint. pCR has been proven to correlate with survival endpoints (DFS and OS) in neoadjuvant chemotherapeutic trials [25
] but its precise definition is still debated. Whereas early trials regarded pCR as the absence of tumour on pathologic slides in breast and axillary lymph nodes, some of the later trials defined pCR as the absence of tumour in breast only without considering nodal evaluation in the operative specimen. In addition, definitions of pCR in neoadjuvant trials do not consistently account for the presence of minimal residual cellularity and residual in situ
carcinoma. Recently, it was shown that the extent of residual breast cancer burden, calculated as a continuous index based on primary tumour measurements (size and cellularity) and lymph node metastases (number and size), correlates with survival outcomes [27
]. Therefore, it is clear that a unified definition of pathologic response for neoadjuvant trials is required, much like the recent consensus statement regarding standard efficacy endpoints (STEEP) for adjuvant trials in early-stage disease [28
]. Unfortunately, the definitions of response endpoints in the ongoing neoadjuvant trials with novel anti-HER2 agents are inconsistent (Table ). It should be noted that there is even less evidence regarding the correlation between the extent of residual breast cancer burden following neoadjuvant targeted therapy (with or without chemotherapy) and survival [12
At the present time, pCR is not robust enough to replace survival as an endpoint for the registration of novel therapies. Even though pCR appears to identify a subgroup with a favourable prognosis [6
], therapies that improve the rate of pCR do not necessarily translate into long-term differences in survival, as demonstrated by the addition of taxane therapy in the NSABP (National Surgical Adjuvant Breast and Bowel Project) B-27 trial [6
]. However, the evaluation of pCR in neoadjuvant studies can provide a critical early marker of efficacy, especially if a neoadjuvant study is coupled with a larger adjuvant registration trial using survival as its primary endpoint, such as in the case of the ongoing neoALTTO (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) and the ALTTO (Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) trials. A similar model has been employed by the recently completed neo-tAnGo and tAnGo trials in nonselected populations [31
]. Adjuvant registration trials require an enormous financial and patient investment to detect small differences in long-term outcome. A well-designed neoadjuvant study can rapidly provide a 'go/no go' decision for an emerging therapy. Invaluable data for the appropriate selection of patients and the evaluation of endpoints for a subsequent adjuvant registration trial can be generated by a well-designed neoadjuvant pilot trial: this concept is currently being developed and explored by the Breast International Group (Brussels, Belgium).
The proliferation marker Ki67 is another marker of interest to be used as a surrogate marker for efficacy, especially with endocrine therapy [17
]. Declines in Ki67 after 2 weeks of neoadjuvant treatment showed no difference between tamoxifen and the combination of tamoxifen and anastrozole in the IMPACT (Immediate Preoperative 'Arimidex' [anastro-zole], Tamoxifen, or Arimidex Combined with Tamoxifen) trial, while a significantly greater drop was found in the anastrazole-alone arm [33
], mirroring the DFS results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial [34
]. If these findings had been known before the launch of the ATAC trial, the combination arm likely would have been dropped from the study design from the outset, thereby saving considerable financial and patient resources.
The eligibility criteria for the ongoing neoadjuvant anti-HER2 studies are similar. With the exception of the National Cancer Institute study [35
] that includes only patients with hormone receptor-positive (HR+
) and HER2+
breast cancer, all other studies include HR+
disease. Although HR+
breast cancer may exhibit different clinical behaviour [36
], the joint inclusion of HER2+
disease regardless of HR status in the evaluation of novel anti-HER2 therapy is justified, as trastuzumab has been shown to be effective regardless of the expression of hormonal receptors [37
Perhaps more controversial is the joint inclusion of IBC together with locally advanced disease in the same study, as IBC represents a separate entity with distinct epidemiology, biology, and long-term outcome [38
]. Although gene expression profiling (GEP) has identified the same five subtypes of IBC as originally described for noninflammatory breast cancer, differences in several key pathways and proteins do exist [39
]. IBC should be evaluated in separate clinical trials or at least stratification should be planned at the time of randomisation.
In contrast to the classical design, in which an experimental therapy is compared with a standard therapy, examples of novel designs are available amongst the ongoing anti-HER2 neoadjuvant studies: the so-called 'biological window' design and 'learn on the way' design. The biological window design exposes the patients to a short period of therapy with the drug of interest alone to allow for the evaluation of biologic endpoints. This design can also provide valuable insight regarding drug pharmacodynamics and early evidence of drug activity and highlight potential mechanisms of resistance. As this phase of design is purely for research purposes and does not offer patients direct therapeutic benefit, there are ethical concerns that must be respected [40
]. A short biological window period can be followed by a more classical design comparing standard neoadjuvant therapy with new combinations, including targeted therapy with curative intent, such as in the neoALTTO trial (Figure ). In the future, these studies may lead to a reduction in overtreatment with chemotherapy, as they may identify patients with excellent response to targeted therapy alone that can be evaluated in a future chemotherapy-sparing study. Though feasible, such neoadjuvant studies require careful planning, enormous logistical support for material collection, and efficient screening systems to identify appropriate patients, all of which significantly increase the complexity and cost of conducting such research.
Figure 2 neoALTTO (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) study design. CTCs, circulating tumour cells; FEC, 5-fluoruracil-epirubicin-cyclophosphamide; PET, positron emission tomography. Note: In the combined Lapatinib + Trastuzumab + (more ...)
The 'learn on the way' design uses information gained from an initial treatment period to guide decisions regarding further therapy. A patient who does not demonstrate early clinical response at interim evaluation is unlikely to experience pCR with completion of standard neoadjuvant chemotherapy [41
]. Thus, early-response evaluation can identify a subgroup of patients with poor long-term outcome, providing the opportunity to explore a switch to an alternative therapy to improve the likelihood of pCR. To date, studies evaluating neoadjuvant taxane [41
] and capecitabine-vinca alkaloid [42
] combinations in nonselected populations have failed to demonstrate a benefit for patients who do not respond to anthracycline-based therapy. The GeparQuinto study described in Figures , , is an example of one such 'learn on the way' approach [7
]. The 'learn on the way' design is an excellent opportunity to reduce overtreatment and validate surrogate markers of response. Unfortunately, in the GeparQuinto study, only the nonresponding HER2-
cohort will undergo a second randomisation based upon early response, whereas in the HER2+
cohort early response is not used to inform further decision-making. In the future, 'learn on the way' designs based upon biomarker endpoints rather than tumour shrinkage may be employed, although there are important challenges regarding the standardisation of cutoff values and interlaboratory reproducibility, along with the need for prompt assessment must be addressed using such a dynamic approach.
Figure 3 Decision tree from GeparQuinto study. B, bevacizumab; EC, epirubicin-cyclophosphamide; H, trastuzumab; Her-2, human epidermal growth factor receptor 2; L, lapatinib; Pw, paclitaxel weekly; T, docetaxel. Reprinted with permission from GBG (German Breast (more ...)
Figure 4 GeparQuinto study design for HER2-negative cohort. B, bevacizumab (15 mg/kg intravenously: day 1 q day 21 for eight cycles); C, cyclophosphamide (600 mg/m2: day 1 q day 21 for four cycles); CR, complete response; E, epirubicin (90 mg/m2: every 3 weeks (more ...)
Figure 5 GeparQuinto study design for HER2-positive cohort. C, cyclophosphamide (600 mg/m2: day 1 q day 21 for four cycles); E, epirubicin (90 mg/m2: every 3 weeks for four cycles); H, trastuzumab (8 mg/kg: loading dose, 6 mg/kg: every 3 weeks); Her-2, human epidermal (more ...)