Preoperative therapy allows for a higher rate of breast conserving surgery and has been shown equivalent to adjuvant therapy. Preoperative therapy provides an opportunity to obtain insights into breast cancer biology and to accelerate the evaluation of new therapies. Clinical trials have shown that women who achieve a pathologic complete response (pCR) have substantially improved outcomes compared with those who do not achieve a pCR. The U.S. Food and Drug Administration (FDA) meta-analysis demonstrated that the association of pCR and long-term outcomes is greater in women with aggressive breast cancer subtypes. In patients with HER2+ breast cancer, the addition of trastuzumab to chemotherapy in the neoadjuvant setting has doubled pCR and correlated with improved outcomes. Clinical trials will evaluate tailoring the use of radiation therapy in patients who have received neoadjuvant therapy. Trials have established neoadjuvant endocrine therapy as a valid treatment and research option for ER-rich breast cancer. The neoadjuvant setting allows for evaluation of endocrine therapies in combination with newer targeted therapies in the appropriate patient populations. The neoadjuvant setting provides opportunity to accelerate the evaluation of new agents, improve pCR rates, and identify predictive biomarkers for response. This setting provides the opportunity for screening new agents in combination with chemotherapy while obtaining serial biopsies to understand biology of response and resistance. Although current standard therapies provide substantial benefits for patients with a pCR, patients with residual disease are at substantial risk for disease recurrence. New agents are being evaluated in patients with high-risk residual disease following standard treatment regimens.
Preoperative or neoadjuvant therapy, initially used for locally advanced breast cancers, has become more commonly used for patients with operable disease, particularly those with larger primary tumors. By reducing the size of the primary tumor, preoperative therapy allows a higher rate of breast conserving surgery.1-10 The neoadjuvant setting also provides opportunities to obtain insights into breast cancer biology and accelerate evaluation of new therapies.
CLINICAL RATIONALE FOR PREOPERATIVE (NEOADJUVANT) THERAPY
Hortobagyi and colleagues demonstrated in the 1980s that women with locally advanced breast cancer who achieved a pathologic complete response (pCR) after neoadjuvant chemotherapy (NACT) had substantially improved outcomes compared with historic controls.11 Use of NACT in operable breast cancer was evaluated in the National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol B-18 clinical trial in which 1,523 women with operable breast cancer were randomized to four cycles of AC (doxorubicin 60 mg/m2, cyclophosphamide 600 mg/m2) every 21 days either before or after definitive surgery.5-7,10 A pCR in the breast was documented in 13% of patients, who had substantially improved outcomes relative to the larger group without pCR (disease-free survival (DFS) hazard ratio [HR] = 0.47, p < 0.0001; overall survival (OS) HR = 0.32, p < 0.0001). Pathologically negative nodes were identified in 58% of women receiving the neoadjuvant therapy compared with 42% among women undergoing initial surgery (p < 0.0001). A higher rate of breast conserving surgery was also observed in women receiving preoperative therapy (68% vs. 60%, respectively; p = 0.001). There were no statistically significant differences in DFS (HR = 0.93, p = 0.27) and OS (HR = 0.99, p = 0.90) between the two groups. This trial demonstrated that NACT was safe in operable breast cancer and that pCR status was associated with a favorable outcome.
PATHOLOGIC RESPONSE AS A SURROGATE FOR CLINICAL OUTCOME
The NSABP B-27 trial evaluated the incorporation of docetaxel into the neoadjuvant setting.8-10 Women with operable breast cancer were randomized to receive (1) preoperative AC followed by surgery, (2) preoperative AC followed by four cycles of preoperative docetaxel followed by surgery, or (3) preoperative AC followed by surgery and then four cycles of postoperative docetaxel. Preoperative docetaxel following AC increased the pCR rate (13% to 26%, p < 0.001), and the proportion of women with negative nodes (51% to 58%, p < 0.001) relative to AC alone. Although this larger group of women had a more favorable outcome (DFS HR = 0.49, p < 0.0001 and OS HR = 0.36, p < 0.0001), there were no statistically significant differences in DFS and OS demonstrated among the three overall treatment groups (p across all arms = 0.76).
Recently an international working group, in collaboration with the FDA, conducted a large meta-analysis of 12,993 patients treated on 12 early, randomized NACT trials with available long-term follow-up for DFS and OS. Improved outcomes in patients with pCR compared with those without were again demonstrated (event-free survival HR = 0.48, p < 0.001 and OS HR = 0.36, p < 0.001). Moreover, the magnitude of the association between pCR and event-free survival was greater in patients with aggressive breast cancer subtypes (hormone receptor (HR) +/HER2-HR = 0.49, p < 0.001 and HR+/HER2+ HR = 0.58, p = 0.001vs. HR-/HER2+ HR = 0.25, p < 0.001 and HR-/HER2-HR = 0.24, p < 0.001). However, correlation of improvement in long-term outcomes with increased pCR rates could not be established. The authors suggested this may be due to relatively low pCR rates in these early trials, the heterogeneity of the populations accrued, and the lack of targeted therapy in the majority of patients.12
The German Breast Group (GBG) and Arbeitsgemeinschaft Gynäkologische Onkologie-Breast Group (AGO-B) conducted a pooled analysis of seven randomized NACTs conducted by the groups, involving 4,193 patients, to determine whether pCR predicts improved outcomes across the intrinsic subtypes. Estrogen receptor (ER), progesterone receptor (PR), HER2 and histologic grade determined by local pathologists were used to classify patients by intrinsic subtypes according to clinicopathologic criteria recently recommended by the St. Gallen panelists, with the exception that grade was substituted for Ki-67.13 In the luminal B/HER2-, ER-/HER2+ and triple negative groups, pCR was associated with improved outcomes. However in luminal A and luminal B/HER2+ patient groups, no correlations were identified, suggesting that inclusion of these “low-risk” patients may have had a substantial adverse dilutional effect on the ability to demonstrate improved outcomes among the women with highly proliferative tumors with pCR. Analysis of the I-SPY TRIAL 1 (Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and Molecular Analysis 1) correlated pCR, residual cancer burden (RCB), intrinsic subtypes, and three-year RFS; the trial demonstrated similar findings in low-risk subsets defined by a variety of predictive profiles. Low-risk subsets had low pCR rates but favorable outcomes regardless of the degree of response.14
The hypothesis that the lack of correlation between pCR rates and long-term outcome could be on the basis of inclusion of low-risk patients is further supported by results of the NOAH (NeoAdjuvant Herceptin) trial.15 In this study, 235 women with HER2+ locally advanced or inflammatory breast cancer were treated with NACT with or without trastuzumab. For women receiving chemotherapy and trastuzumab, the pCR rate was 38%, compared with 19% for women receiving chemotherapy alone. The doubling of pCR in this more homogeneous population with high proliferation rates correlated with improved three-year event-free survival (71% vs. 56%; HR = 0.59, p = 0.013). In aggregate, these findings support the contention that pCR is a meaningful short-term surrogate of outcome in more aggressive tumors (particularly HER2+ and triple negative tumors) and provide a strong rationale for testing new agents targeting highly proliferative tumors in the neoadjuvant setting using pCR as a primary end point.
TAILORING LOCOREGIONAL THERAPY WITH NEOADJUVANT CHEMOTHERAPY
Response to NACT allows for less extensive surgery to the breast and may provide similar benefits in tailoring the extent of surgical resection in the axilla (with the use of sentinel node biopsy), as well as decreasing the need and extent of postoperative radiotherapy in patients who achieve pCR. The utility of downstaging of axillary nodes with NACT has been demonstrated in several studies that have evaluated the role of node status in prognosis after neoadjuvant therapy. Historically, definitions of pCR vary across studies, ranging from the most stringent, ypT0 ypN0 (absence of invasive cancer in the breast and axillary nodes and absence of DCIS), to ypT0/Tis ypN0 (absence of invasive cancer in the breast and axillary nodes; DCIS allowed), to the most liberal, ypT0/Tis (absence of invasive cancer in the breast and DCIS allowed; regardless of nodal involvement). The pooled analysis of seven randomized neoadjuvant trials conducted by GBG and AGO found that patients with no invasive or noninvasive disease in the breast and negative axillary nodes had significantly better DFS than the group with either residual noninvasive or microinvasive breast disease or residual positive nodes.13 Hazard ratios for DFS comparing patients with or without pCR were lowest when defined as no invasive and no in situ residuals (0.446) and increased monotonously when in situ residuals (0.523), no invasive breast residuals but involved nodes (0.623), and focal-invasive disease (0.727) were included in the definition. However the FDA-led meta-analysis, which included the German studies, demonstrated no difference in the hazard of recurrence or death regardless of presence or absence of residual DCIS in the breast.12 These data suggest that clearing the nodes has prognostic significance, and therefore accurate assessment of the residual nodal burden is necessary.
An additional advantage of rendering the axillary nodes free of disease with NACT is the potential reduction in surgical morbidity and late lymphedema from the use of sentinel node evaluation. However, this advantage is predicated on the accuracy of sentinel node biopsy following NACT. Because NACT can have an adverse effect on the integrity of axillary nodal tissue (with or without eradication of disease), the accuracy of sentinel lymph node evaluation in the patient who has undergone NACT must be established independently of its validation in patients who are chemotherapy-naive. Several retrospective and prospective, single-institution and multicenter trials, as well as two meta-analyses, have shown that sentinel node biopsy after NACT has lower identification rates but similar false-negative rates as sentinel node biopsy before NACT (about10%).16-18 It is important to emphasize that the available data on the performance of sentinel node biopsy after NACT are only applicable to patients who present with operable breast cancers (T1–3N0–1) and should not be extrapolated to those who present with locally advanced disease (T4, N2). Similarly, caution is required for patients who present with documented tumor involvement of the axilla (by fine needle aspiration or core biopsy) and undergo NACT. Two prospective trials presented at the 2012 San Antonio Breast Cancer Symposium demonstrated false-negative rates of 12.6% and 14.2%, respectively, slightly higher than in the upfront setting.19,20 Moreover, the number of resected sentinel nodes inversely correlated with the false-negative rate, and the data suggested that the removal of at least two sentinel nodes in this setting is important to keep the accuracy of sentinel node biopsy similar to that in the upfront setting.
A pCR to NACT may identify subsets of patients with lower risk for locoregional recurrences (LRR) that may not justify regional chest wall and/or regional nodal radiation. This approach is predicated on the demonstration that downstaging substantially lowers the rates of locoregional recurrence. The NSABP B-18 and B-27 trials provide an important data set to address these questions. In both trials, regional nodal radiation after lumpectomy or chest wall and regional nodal radiation after mastectomy were not permitted per protocol, thus avoiding the confounding effects of selective use of radiation in patients with positive nodes or other high-risk features. Data from a combined analysis of these two trials were recently published.21 The 10-year cumulative incidence of LRR was 12.3% for patients treated with mastectomy (8.9% local; 3.4% regional) and 10.3% for those treated with lumpectomy plus breast radiation (8.1% local; 2.2% regional). Independent predictors of LRR in patients treated with lumpectomy were age, clinical node status (before NACT), and pathologic node status/pathologic breast tumor response. In patients treated with mastectomy, independent predictors of LRR were clinical tumor size (before NACT), clinical node status (before NACT), and pathologic node status/pathologic breast tumor response. By using these independent predictors, risk of LRR can be tailored, and the need for postoperative radiotherapy could be individualized.
On the basis of these findings, a prospective, randomized phase III clinical trial led by NSABP and RTOG (NSABP B-51/RTOG 1304) has been initiated to validate the approach of tailoring the use of radiation for patients who present with documented involvement of axillary nodes before NACT but are found to have histologically negative nodes afterward. Alternatively for patients who present with documented involvement of axillary nodes before NACT and are found to be pathologically node-positive based on sentinel node biopsy following NACT, the Alliance for Clinical Trials in Oncology is conducting a phase III trial (A011202) randomizing patients to completion axillary dissection plus regional RT compared with regional RT alone.
DEVELOPING NEW AGENTS IN THE NEOADJUVANT SETTING
Sequential taxane/anthracycline-based three-drug regimens have become standard for neoadjuvant therapy of patients who present with stage II or III breast cancer and are candidates for chemotherapy. Trastuzumab is incorporated into these regimens in HER2+ disease. These regimens result in pCR rates of 20% to 50% in patient populations with subtypes of breast cancer associated with high proliferative rates. Although current standard therapies provide substantial benefits for patients with a pCR at surgery, patients with residual disease are at substantial risk for disease recurrence, with the majority of patients with HER2+ or triple negative breast cancers who do not achieve pCR developing distant metastatic disease within the first three years after therapy.14 Attempts to improve pCR rates with additional standard chemotherapeutic agents have not been successful.22 Therefore efforts to improve pCR rates and develop alternative therapies for women with residual disease following standard therapy are clearly needed.
Insights into the heterogeneity and biology of breast cancer obtained through gene-sequencing and other technologies have identified a large number of potential targets in these tumors for newer, more selective investigational agents (so-called targeted therapies). Toxicity of many of these agents appears to be substantially less problematic than with more nonselective agents, and combination with chemotherapy appears to be feasible. The neoadjuvant setting provides an opportunity to accelerate evaluation of these agents and identify predictive biomarkers for response, as well as to gain insights into mechanisms of resistance. Other interventions, including immunotherapy and complementary approaches in the neoadjuvant setting, are also being used or are under consideration.
Because palpable or locally advanced breast cancer is readily accessible for serial biopsies and imaging assessment, the neoadjuvant setting provides opportunity for screening new agents in combination with chemotherapy, while also obtaining serial biopsies to understand biology of response and resistance as well as to develop early predictors of response. The prototype for this important step in drug development is the I-SPY TRIAL 2.23 This ambitious, multicenter, randomized phase II effort among academic cancer centers across the United States employs a standard regimen of weekly paclitaxel for 12 weeks followed by AC for four cycles. Trastuzumab is administered with paclitaxel for HER2+ breast cancer in the control arm and in several of the treatment arms. Potential candidates undergo biopsy for screening, which includes the 70-gene Mammaprint (MP) along with ER, PR, and HER2 assessment. Women with low-risk MP score and ER+/HER2 negative disease are excluded from entry and randomization.
Several agents (up to eight) are under evaluation at any time point, with assignment to control therapy or investigational therapy on the basis of results of the molecular profiling and an adaptive randomization design. The primary objective is to determine whether adding experimental agents to standard NACT (with or without trastuzumab) increases the probability of pCR over standard NACT for each biomarker signature established at trial entry, and to determine for each experimental agent used the predictive probability of success in a subsequent phase III trial for each possible biomarker signature. A data safety monitoring board (DSMB) meets monthly to assess toxicity and review performance of the adaptive randomization, given the potential curability of patients receiving investigational therapy. A biopsy for pharmacodynamic markers is obtained after three weeks of therapy, and serial imaging is performed throughout the trial using automated dynamic contrast enhanced MRI. As information accumulates on each agent, it is either “graduated” or “dropped for futility,” and new agents enter the trial. The basic design of the study remains unchanged so that additional agents and potential biomarkers can be more rapidly and efficiently evaluated. Although the I-SPY TRIAL 2 will not provide definitive information on a new investigational agent, it is hoped that promising agents will be quickly identified and moved into phase III trials with a much higher probability for success than has been seen in the past.
NEOADJUVANT TRIALS POWERED FOR DISEASE-FREE AND OVERALL SURVIVAL
In the potentially curative situation, it is likely that regulatory agencies will continue to require trials to conclusively demonstrate improvement in DFS and perhaps OS for approval of new agents in this setting. The FDA released a draft guidance in May 201224,25 stating that the agency would consider granting accelerated approval on the basis of a surrogate end point that is likely to predict clinical benefit, and it proposed pCR as such an end point in the neoadjuvant setting for high-risk early stage breast cancer. Confirmation of clinical benefit with an improvement in DFS or OS would still be required or the indication could be withdrawn if confirmatory trials do not show a benefit.
A potential approach would be to use a two-step design in which only neoadjuvant patients were entered in the first stage to determine whether a prespecified improvement in pCR could be demonstrated. If so, the second stage would allow entry of patients in both the neoadjuvant and adjuvant setting to achieve the sample size needed for determining DFS and OS. Interim analyses of pCR rates could be used to determine whether an accrual hiatus between the two stages was necessary. Accrual to this type of trial could be readily accomplished in cooperative group and community settings.
POSTNEOADJUVANT RESIDUAL DISEASE TRIALS
Because patients with pCR following standard adjuvant therapies have a low risk for recurrence, it may not be appropriate to evaluate newer agents with moderate toxicities or which do not combine well with standard therapies in these patients. In this situation an alternative development approach would be to study new agents in patients with high-risk residual disease following standard treatment regimens.
The NSABP, GBG, and other investigators are collaborating on a global trial (KATHERINE NCT 01772474) evaluating T-DM1 as an alternative to continuation of trastuzumab in women with residual disease following neoadjuvant chemotherapy combined with HER2 targeted therapy that includes trastuzumab. Patients with residual disease following NACT and trastuzumab have a three-year RFS of only 70%,26 so they are appropriate candidates for evaluating promising new therapeutic agents such as T-DM1. If successful this trial would establish a new approach for drug development.
Two innovative trials are in progress to address residual disease in patients with triple-negative breast cancer. The Hoosier Oncology Group is currently evaluating the benefit of cisplatin with or without a PARP inhibitor, rucaparib (Clovis) in women with triple negative or ER+/BRCA-mutant breast cancer who have residual disease in the breast after neoadjuvant chemotherapy with an anthracycline and/or taxane-based regimen (NCT01074970).27 The primary end point of this trial is two-year DFS. The ABCDE trial (Adjuvant Bevacizumab, Metronomic Chemotherapy Diet and Exercise)28 being conducted within the Translational Breast Cancer Research Consortium (TBCRC) enrolls patients with triple negative or high-stage ER+ disease who have received anthracycline and/or taxane-containing neoadjuvant chemotherapy and have residual disease at surgery. In this 2 x 2 design, patients are initially randomly assigned to either “observation” (standard of care, including endocrine therapy), or “treatment” (six months of bevacizumab with metronomic chemotherapy, followed by an additional 18 months of intermittent bevacizumab alone). Patients are additionally randomized to one of two telephone-based lifestyle interventions: diet alone or diet plus exercise.
NEOADJUVANT ENDOCRINE THERAPY TRIALS
Development of multigene expression profiles to predict the degree of benefit from specific therapeutic agents has been challenging; to date, a profile for defining benefit from specific agents has not been established. However the Oncotype DX Recurrence Score assay derived from an algorithm based on expression level of 16 breast cancer-related genes and five reference genes has been shown to consistently identify large subsets of patients with early stage, ER+ breast cancer who have a low-risk for recurrence with endocrine therapy alone.29 The assay also has apparent utility for defining potential benefit from the addition of chemotherapy in node-negative ER+ breast cancers.30 The utility of the assay in this population will be better defined by results of the TAILORx study, which has completed accrual and is in follow-up.31 SWOG is leading an effort (RxSPONDER) to evaluate the utility of the Recurrence Score for defining chemotherapy benefit in women with node-positive, ER+ breast cancers as well.32 Studies evaluating the Recurrence Score as well as other predictive assays have shown many women with early stage, ER+ breast cancer derive little or no benefit from the addition of chemotherapy to endocrine therapy. In view of these findings, it is not surprising that pCR rates in response to chemotherapy are low in these populations and that outcome is not associated with pCR.
Given these observations, the neoadjuvant setting is ideal for evaluating endocrine therapies in combination with newer targeted therapies in appropriate patient populations. Ellis and colleagues conducted a randomized phase II study of four months of neoadjuvant endocrine therapy with tamoxifen vs. letrozole and evaluated post-therapy pathology findings to derive a response-based preoperative endocrine prognostic index (PEPI) to define a subset of patients who do well with endocrine therapy alone.33 The index was validated in an independent cohort of patients from another neoadjuvant endocrine study, the IMPACT trial.34 The authors concluded that “patients with breast cancer with pathologic stage I or 0 disease after neoadjuvant endocrine therapy and a low-risk biomarker profile in the surgical specimen (PEPI score 0) have an extremely low risk of relapse and are therefore unlikely to benefit from adjuvant chemotherapy.“
ACOSOG conducted a follow-up randomized phase II neoadjuvant trial (Z1031) comparing the three approved aromatase inhibitors in postmenopausal women with ER–rich stage II to III breast cancers. They demonstrated an overall clinical response rate of 63% and that breast-conserving surgery could be performed in 50% of patients who presented with disease that would have required mastectomy at presentation. They also demonstrated that a favorable PEPI score was more common in luminal A than luminal B tumors (27.1% v 10.7%; P = 0.004).35
The ALTERNATE trial (ACOSOG Z11103) will be a phase III study comparing anastrozole vs. fulvestrant vs. the combination as neoadjuvant endocrine therapy in postmenopausal women with ER-rich stage II and III breast cancer. The study will also prospectively evaluate the PEPI score as a predictive factor for favorable outcome with endocrine therapy alone. This innovative series of trials has established neoadjuvant endocrine therapy as a valid treatment and research option for ER-rich early breast cancer and will likely be further exploited in the future for combination endocrine/targeted therapy trials.
Neoadjuvant therapy for breast cancer has an established role in the management of women with inoperable disease and for those in whom breast conservation is a goal of therapy. Early randomized trials established pCR as a surrogate for survival outcomes, and more recent trials have refined our understanding of this relationship for different molecular subtypes of disease. Clinical management to minimize LRR continues to evolve, with recent studies evaluating the applicability of sentinel node evaluation after NACT, the relative contribution of nodal response to predicting outcome, and ongoing trials designed to optimize radiotherapy.
From a research standpoint, the neoadjuvant setting provides several important opportunities for translational drug development. Phase II randomized “screening studies” to improve pCR rates in high-risk patients with the addition of targeted therapies to standard chemotherapy are ongoing and will contribute important information on both drug activity and biomarkers identifying those patients most likely to respond. Such studies will contribute to the pipeline of agents for testing in phase III trials, with the ability to potentially accelerate approval of successful therapies by using the new FDA guidance that provides a roadmap for the use of pCR as a surrogate end point and smaller, more focused trial designs in specific biologically-defined subgroups to assess survival. Molecular and genetic profiling of residual disease after neoadjuvant therapy is an active avenue of investigation into potential targets of resistant disease, and trials of agents against these targets have the potential to improve outcome for patients with poor prognosis after standard therapy. The recognition that ER+ low-proliferation tumors are often intrinsically unresponsive to chemotherapy (and thus show low pCR rates) has led to a parallel pathway of investigation into neoadjuvant endocrine therapy, in which Ki-67 is being validated as a surrogate for response and outcome. Taken together, the advances brought about by neoadjuvant therapy in both standard and investigational settings have ushered in a more personalized approach to breast cancer therapy that could result in a reduced burden of toxicities and recurrent disease and in improved survival.
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