Are we HER-ting for innovation in neoadjuvant breast cancer trial design?
© BioMed Central Ltd 2009
Published: 16 January 2009
Through the use of surrogate markers of efficacy, neoadjuvant studies may facilitate the implementation of new treatments into clinical practice. However, disease-free survival is the current standard outcome endpoint for registration of a novel treatment. The coupling of smaller neoadjuvant 'proof of principle' studies with larger adjuvant registration trials offers the promise of speeding up the time to market of new therapies. Clever new designs, such as the 'biological window' and 'learn on the way', can provide valuable insight regarding mechanisms of action and resistance of these novel drugs by identifying patients who are most likely to respond to a novel therapy early in the drug development process. Using the ongoing neoadjuvant trials with HER2 (human epidermal growth factor receptor 2)-directed therapy as a paradigm, this article discusses recent innovations in study design and the challenges of conducting translational research in the neoadjuvant setting.
Neoadjuvant chemotherapy is the standard of care for patients with locally advanced and inflammatory breast cancer (IBC) , with the goal of improving operability and eradicating micrometastatic disease. In primary operable breast cancer, neoadjuvant chemotherapy increases the rate of breast conservation  and achieves similar overall survival (OS) as adjuvant chemotherapy  without compromising local control provided that careful multidisciplinary coordination is planned from the outset . Currently, the same regimens used for adjuvant treatment are recommended for neoadjuvant therapy . The initiation of chemotherapy prior to surgery allows for the identification of two distinct prognostic groups: patients able to attain a pathologic complete response (pCR) with a favourable long-term outcome and those with residual disease at surgery who are at a high risk of relapse . Unfortunately, there is no additional therapy that has been shown to improve survival for patients failing to achieve a pCR to an anthracycline-taxane regimen  and this group of chemoresistant patients is desperately in need of novel therapeutic options.
There are many unresolved clinical questions regarding the use of neoadjuvant chemotherapy and additional locoregional treatment [5, 6]. Well-designed neoadjuvant studies can quickly generate important preliminary data on the efficacy of novel therapies based on short-term endpoints such as pCR. They also offer an excellent opportunity to study the impact of systemic therapies on breast cancer biology, to explore surrogate markers of response (such as functional imaging), and to select promising biomarkers for future validation studies. The traditional model of conducting initial trials in metastatic breast cancer patients with refractory disease following standard therapy has been disappointing, as it demands a lot of effort and requires a long time before the drug reaches adjuvant registration. In addition, many new agents thought to be successful at controlling minimal residual disease have failed to demonstrate the efficacy for patients with advanced disease. As a result, a new pathway to accelerate the clinical development of emerging therapies is sorely needed.
The identification of the central role of the human epidermal growth factor receptor 2 (HER2) protein in the pathogenesis of HER2-overexpressing breast cancer is one of the greatest successes of modern oncology. Over the last 10 years, trastuzumab, a monoclonal antibody against the HER2 protein, has been approved for the treatment of HER2+ breast cancer, and a variety of exciting novel anti-HER2-directed therapies that are entering clinical testing have been developed. As such, HER2+ breast cancer represents the ideal paradigm for a discussion of targeted neoadjuvant breast cancer therapy. The purpose of this article is to review ongoing neoadjuvant randomised clinical trials in HER2+ breast cancer evaluating novel HER2-directed agents, with an emphasis on recent innovations in trial design, platforms for the evaluation of surrogate endpoints and translational research, and the challenges in conducting neoadjuvant research.
Ongoing randomised neoadjuvant studies targeting HER2 with new agents
Sponsor and participating groups
Patient eligibility (all HER2+)
July 2007 to July 2014a
- pCR (breast only)
Vanderbilt-Ingram Cancer Center (Nashville, TN, USA) NCI
July 2007 to July 2010
- Change in percentage of Ki67+ tumour cells – pCR
ER+ and/or PR+
Feb. 2007 to Dec. 2009
- pCRc – Safety and tolerability –
RR – Phdinam.
ER+/- PR+/- Inflammatory BC Included
NCT00567554 GeparQuinto 
GBG AGO Ovarian Cancer Study Group
2,547 (all patients)
Oct. 2007 to Dec. 2015
Biomarkers CTCs Imaging Phgen.
ER+/- PR+/- Inflammatory BC Included
Fédération Nationale des Centres de Lutte Contre le Cancer (Paris, France)
Apr. 2008 to Apr. 2014
- RR (clinical and echographic)
Phgen. Phdinam. Proteomics Biomarkers
Hoffmann-La Roche (Grenzach-Wyhlen, Germany)
Dec. 2007 to Oct. 2014
ER+/- PR+/- Inflammatory BC Included
Sept. 2007 to July 2013
- Pathologic RR
ER+/- PR+/- Inflammatory BC Included
GSK BIG Grupo Espaniol de Estudio Tratamiento y Otras Estrategias Experimentales en Tumores Solidos (Madrid, Spain)
Sept. 2007 to Sept. 2019
- pCR (breast only)
Biomarkers Imaging CTCs
Baylor Breast Cancer Center (Houston, TX, USA) GSK
Not yet recruiting
Jan. 2008 to Jan. 2012
Prior randomised neoadjuvant studies in HER2+disease
Reported randomised phase III trials with neoadjuvant trastuzumab
pCR rate, percentage (95% CI)
Number of patients
65% T2 40% N0/57% N1
P → FEC vs. P + H → FEC + H
IHC 3+ or FISH+
Gianni et al., 2007 
60% T4 85% N+
AP → P → CMF vs. AP + H → P + H → CMF + H
IHC 3+ or FISH
Untch et al., 2008 
EC → D or EC → DX or EC → D → X vs. EC → D + H or EC → DX + H or EC → D + H → X + H
Designs of the ongoing randomised neoadjuvant studies in HER2+disease
The majority of ongoing HER2-targeted trials are investigating the efficacy of lapatinib in the neoadjuvant setting for HER2+ breast cancer (Table 1) [16–24]. 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, 26] 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 . 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 . Unfortunately, the definitions of response endpoints in the ongoing neoadjuvant trials with novel anti-HER2 agents are inconsistent (Table 1). 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, 29].
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, 25, 30], 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 . 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 . 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, 32, 33]. 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 , mirroring the DFS results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial . 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  that includes only patients with hormone receptor-positive (HR+) and HER2+ breast cancer, all other studies include HR+ and HR-disease. Although HR+ and HR- HER2+ breast cancer may exhibit different clinical behaviour , 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 .
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 . 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 . IBC should be evaluated in separate clinical trials or at least stratification should be planned at the time of randomisation.
The neoadjuvant setting is an ideal platform to evaluate the predictive value of biomarkers using emerging technologies like GEP, proteomics, functional imaging, circulating tumour cells (CTCs), and the role of the host in the response to therapy (pharmacodynamic and pharmacogenetic substudies) (Table 1). Traditionally, translational research in breast cancer has been characterised by efforts to validate single predictive biomarkers using available tumour blocks from completed clinical trials, with largely disappointing results. With new techniques like GEP and biomarker models , several putative markers can be linked together to obtain a more powerful prognostic or predictive tool. The biological window design provides an especially valuable opportunity for the rapid evaluation of pharmacodynamic endpoints with biologic therapy.
Imaging modalities have not reliably been shown to predict the response to neoadjuvant therapy. This is, in part, because previous validation studies have been conducted in an incomplete and piecemeal manner. Given the rapidly expanding array of new imaging modalities, well-planned neoadjuvant studies with prospective integration of imaging endpoints are required to define and compare the role of molecular and functional imaging as early-response predictors. In contrast to traditional imaging modalities based upon anatomic evaluation of response, functional modalities such as magnetic resonance imaging [44–47], magnetic resonance spectroscopy , positron emission tomography [49, 50], single photon emission computed tomography , ultrasound with enhancement , and optical imaging  have all shown the ability to predict early response and warrant prospective evaluation in phase III clinical trials. In particular, their ability to predict an early response using anti-HER2 therapy still needs to be demonstrated prospectively.
CTCs can be identified in the blood of 10% to 30% of patients with early breast cancer and their detection is associated with poor long-term DFS [54–56]. Currently, their prognostic and predictive value is also being investigated in neoadjuvant trials exploring the efficacy of novel anti-HER2 drugs (Table 1). Several methods of CTC detection have been described, although reverse transcription-polymerase chain reaction and immunomagnetic/fluorescent approaches are the most advanced [57, 58].
Studies exploring the efficacy of novel anti-HER2 drugs not only are tumour-orientated but also will evaluate the role of the host with prospective pharmacogenetic and pharmacodynamic translational research studies. These studies will provide us with valuable knowledge regarding interindividual differences in drug metabolism and the efficacy of novel agents [59, 60].
Translational research rarely leads directly to the registration of novel therapies, making it difficult to justify the high costs of adequately powered translational research to industrial trial sponsors . However, innovative neoadjuvant translational research may identify patients likely to benefit from novel therapies that may ultimately reduce the number of participants needed for a subsequent registration study in the adjuvant setting as well as increase the probability of detecting a beneficial effect due to more accurate patient selection. As the examples of trastuzumab for breast cancer and gefitinib for lung cancer treatment illustrate, knowledge of the appropriate patient population for a novel targeted therapy can make the difference between a blockbuster drug and a drug that never makes it to market [62–66].
Ongoing neoadjuvant studies exploring the efficacy of novel anti-HER2 agents with innovative designs, like the 'biological window' and 'learn on the way', promise to deliver new knowledge of breast cancer biology and treatment. In the future, a greater collaborative effort between research groups is required to translate the new insights regarding the molecular heterogeneity of breast cancer into individualised therapies. Past failures have been marred by duplicative trial designs, poorly planned translational research, and overestimation of the benefit of experimental therapy in unselected populations. A new partnership between academic investigators, industry, patients, and policy-makers is needed, with a common understanding that properly conducted innovative neoadjuvant research can transform the dream of tailored therapy for breast cancer into reality.
Arimidex, Tamoxifen, Alone or in Combination
circulating tumour cell
gene expression profiling
human epidermal growth factor receptor 2
inflammatory breast cancer
Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation
pathologic complete response.
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