Breast cancer represents a heterogeneous group of diseases with varied biological features, behavior, and response to therapy; thus, management of breast cancer relies on the availability of robust predictive and prognostic factors to support therapy decision-making. Traditionally, neoadjuvant treatment for breast cancer was preserved for locally advanced, converting an inoperable to a surgical resectable cancer. Neoadjuvant trials, additionally, offer: 1) the opportunity to evaluate new treatment options in a faster way and with fewer patients than large adjuvant trials; 2) to identify and validate the prognostic and predictive value of a marker with its association with clinical outcome in relation to the administered treatment. In this setting, thanks to new, affordable technologies which help to detail the molecular profiles of tumors, new trial designs based on new target therapies, like window-of-opportunity, are also suggested, as they represent the chance to identify tumor sensitivity or to overcome tumor resistance to the treatment used, based on its interaction with tumor biology in early tumor stages. However, clinicians and researchers should pay particular attention: In this setting, the safety of patients is paramount, given the exposure of potentially curable patients to investigational agents with limited safety experience, the definition of the study population and the study design, such as adaptive strategies, should limit patient exposure to ineffective agents, and intensify safety monitoring in the course of the treatment. Here, issues related to outcome determination in breast cancer, including some critical points of view, are presented.
Breast cancer is the most common cancer among women in industrialized countries and it is still the most common cause of cancer death worldwide. Two major advances in breast cancer treatment have recently changed the oncologist’s perspective of breast cancer treatment: Firstly, the molecular profile of the tumor is helping to avoid overtreatment; successively, the availability of targeted therapies has added new bullets in the breast cancer therapy armamentarium (1).
As breast cancer comprises several molecular breast cancer subtypes with different clinical and therapeutic implications, oncological treatments are becoming more and more personalized (2). In addition to these new targets for research and clinicians are the development of predictive diagnostic tools or biomarkers able to predict resistance/sensitivity to a given therapy, or likelihood of side effects. It is hoped that predictive parameters will provide further stratification as part of a more individualized treatment approach.
The neoadjuvant approach in early or locally advanced cancer provides a unique and powerful opportunity to examine the efficacy of investigational agents and to identify the patients and tumors in which they would be most effective, without compromising curability (3,4). Thus, compared to the classical adjuvant treatment, the neoadjuvant approach offers several advantages:
1) It provides the opportunity to monitor response during treatment and allows changing or discontinuing treatment in case of nonresponsiveness. Even if an advantage of changing therapy has not yet been proven, toxicity of an ineffective treatment can be avoided. The demonstration of treatment efficacy, conversely, motivates patients to continue therapy despite toxicities.
2) The rate of breast conservation can be increased, and in cases of breast conserving therapy, the extent of surgery can be reduced. Additionally, primarily inoperable tumors can be downsized, allowing a curative intervention.
3) The residual cancer burden is a powerful prognostic marker, sometimes changing the initial prognostic profile in either way.
4) In neoadjuvant trials, predictive markers, tumor biology, mechanisms of resistance, and new treatment approaches could be investigated more rapidly and with fewer patients than in adjuvant studies. The in vivo assessment provides real-time examination of tumor response and pharmacodynamics while the tumor remains in its microenvironment. The primary tumor is accessible for concurrent biomarker assessment and development of companion diagnostics needed to provide predictive markers of response.
The American Society of Clinical Oncology publishing “Blueprint for Transforming Clinical and Translational Cancer Research” highlights the importance of designing and conducting clinical trials along with new strategies to accelerate drug development to reduce the time of drug-related research, costs, and resources necessary to identify and optimize active agents. In this scenario, the neoadjuvant setting helps to accelerate drug development (5). To accelerate drug approval, the US Food and Drug Administration supports the use of neoadjuvant studies in which the surrogate biological endpoint and/or pathological response can be used to identify active drugs and shorten the time to their approval, and to identify biomarkers which help to stratify patients most likely to respond (6,7).
However, while performing neoadjuvant treatment, different aspects of breast cancer treatment should be taken into account, in order to answer clinical questions to optimize decision-making.
The Profile of the Tumor and Its Therapeutic Implication
Molecular profiling studies have established that breast cancer is highly heterogeneous and encompasses diverse histological and molecular subtypes with distinct biological and clinical implications, particularly, in relation to the incidence of progression to metastasis (8,9). This has led to identification of the proper treatment for the subtypes of breast cancer—thus introducing the concept of personalized medicine, which has become a highly-regarded development in tailoring approaches to prevention and treatment for specific patient subpopulations. The basic concept consists of identifying genetic, phenotypic, or environmental factors, which affect the subpopulation’s health risks, and help to find the most appropriate type of intervention and/or dose of medication. Thanks to this new molecular profiling, technologies to assess DNA, RNA, protein, etc., provide the potential to tailor treatment, both at tumor and patient levels. These approaches try to fulfill the promise of delivering the right dose for the right indication to the right patient at the right time.
Until to now, the classic immunohistochemical markers (ie, hormone receptor and Ki67 expression, as well as HER2 overexpression and/or amplification) have provided prognostic, and particularly predictive, information of substantial clinical relevance, and they are used to decide routine therapeutical strategies in breast cancer (10). Nomograms based on these biological variables, along with the classical parameters as grading, age, menopausal status, and so forth, are under construction to help clinicians in their treatment decision-making (11,12). Moreover, nowadays, several newly validated molecular tests performed in tumor tissue are introduced into clinical practice. The most commonly considered platforms are Mammaprint (Agendia), Oncotype Dx (Genomic Health), and PAM50 (13). However, these diagnostic assays have not yet fully been recognized as a tool for therapy decision-making by the international guidelines for breast cancer treatment.
So far, these molecular tests are only available for a small number of drugs and/or cancers, and if the goal of individualized medicine is to become a reality, a considerable number of predictive biomarkers needs to be developed with respect to any single drug or type of cancer. The predictive markers are thought to aid in deciding on a certain treatment approach rather than on the overall necessity of treatment. Ideally, predictive factors should provide information on the extent of response, as well as the side-effect profile that could be expected from a given treatment. A number of markers have been suggested for use in a novel, more-personalized treatment selection process, such as uPA or topoisomerase II, expression of single genes (ie, tau, etc.), CYP 2D6, multigene profiles, ratio of Ki67/Tunel, RNA disruption assay (RDA) index, or changes in Ki67.
In this scenario, neoadjuvant trials represent the emerging opportunity for the rapid validation of biomarkers either molecular or immunohistochemical in cancer. Ideally, a biomarker-driven trial should be designed in breast cancer in which multitumor biopsies should be mandatory to test patient tumors for the presence of specific genetic lesions in specific pathways, to deliver rationally designed therapy that targets the underlying aberrations in tumors as well as the potential bypass mechanisms. This approach must clearly be compared with the standard of care. Patients should be rebiopsied during therapy to monitor pharmacodynamic markers and at recurrence or progression to understand mechanisms of resistance. With this purpose, a great number of well-known and new substances are in clinical testing in phase-II and phase-III trials. The goals of these trials are not only to improve pathological complete response rates and survival, but also to individualize therapy through the identification of pathways involved in responsiveness/resistance and to reduce toxicity (14).
Also “window-of-opportunity” trials for tailored therapy, biomarkers in tumor tissue or circulation, predicting treatment response or resistance, should be considered in personalized medicine helping the experts in the field to understand how a single drug acts with respect to tumor biology. A short course of targeted therapy is given before surgical resection or before standard therapy. Sequential biopsies during treatment can be performed easily. Thereby, treatment-induced molecular changes can be monitored at an early timepoint. The endpoint of such trials is not necessarily response rate but changes of biological markers, for example, for apoptosis or proliferation. A hypothesis-generating trial like this was done with metformin in operable breast cancer, where metformin was given twice daily for a median of 18 days before surgery. Ki-67 staining in invasive tumor tissue decreased significantly (from 37% to 34%,) and TUNEL staining increased (from 0.56% to 1.05%) (15). Thus, window-of-opportunity studies can be initiated to prove the expected mechanism of action, to identify tumor resistance and sensitivity, or to establish a “biologically effective” dose of the investigated targeted agent.
However, the field of personalized medicine raises many challenges including the unexpected high failure rate of molecular-targeted therapeutics due to several molecular “reasons” and difficulties identifying and validating molecular markers. To improve our knowledge of cancer biology and targeting drugs, a multimodal approach, including a simultaneous assessment of DNA, RNA, proteomics, and metabolomics, along with the clinic, is needed to understand the patient tumor (16).
Trial Design Process
Due to the molecular heterogeneity of breast cancer, only a subset of treated patients would have benefit from a given therapy. This is particularly relevant for the new generation of anticancer agents that target specific molecular pathways (17,18). Even before personalized medicine is developed, new trial designs will be needed to address the goal of metastasis prevention, both in the adjuvant setting and for prevention of additional metastases in the limited metastatic setting. The clinician’s aim is to administer the best treatment with the respect to tumor’s characteristics. To understand which molecular target corresponds to the proper drug and vice versa we need to design a clinical trial considering all these aspects. The development of a reliable diagnostic classifier using nonrandomized phase II data or conducting a phase III randomized clinical trial is often not feasible, as it requires considerable time and resources. Therefore, clinical trial designs that allow combining the evaluation of a new agent with the development of an adequate diagnostic test are needed. Given the need to limit patient exposure to potentially harmful agents in neoadjuvant trials, adaptive study designs that minimize exposure without compromising statistical power are best suited to these studies. The adaptive trial-based design is based on the signature development and validation on the mutually exclusive subgroups of patients (eg, half of the study population is used to develop a signature and another half to validate it) even it could be its limits as it consider only half of the patients used for signature development and half for validation. In the adaptive randomization design, the randomization ratio changes during a period of time on the basis of the current (Bayesian) probability that an arm is the better treatment (19). Thus, the sample size needed to complete the study is reduced while patients preferentially receive assignment to more efficacious arms as the study progresses, thereby further optimizing the ratio of benefits to risks (20,21). This kind of approach was used in the I-SPY trial series, which is based on neoadjuvant treatment. The I-SPY 2 trial uses biomarkers (hormone receptor status, HER2 status, and the MammaPrint 70-gene signature status) to stratify patients based on their predicted potential response to treatment, and evaluates phase II drugs in combination with standard chemotherapy (22). An adaptive trial can use more than one type of adaptation, such as stopping a treatment early, changing or dropping arms or doses, and changing the proportion of patients randomized to each arm. This approach allows a rapid identification of effective new agents and drug combinations, as well as identification of the breast cancer subtypes that will benefit from the new therapy. It is hoped that this trial design will also reduce adverse effects and spare patients from enrolling in trials from which they will not benefit. In the new era, high-throughput technologies, such as microarray gene expression profiling and comparative genomic hybridization array, and next-generation sequencing are used for the personalization of treatment and to identify breast cancer patients whose tumors present specific molecular alterations to add a targeted regimen to the standard treatment. This approach attempts to improve personalized medicine and to lower risk, compared to a single-biomarker trial. However, the high cost of high-throughput technologies and the small size that a personalized approach can reach must be considered as limitations (21,23).
Patient Advocate Perspective
The approaches of personalized medicine in neoadjuvant setting could raise several ethical concerns (24–26). The measures of adequately implementing informed consent for biomarker studies should be discussed as well as issues of confidentiality, data protection, and the individuals’ right to know/not to know. Furthermore, when looking at the clinical usage of molecular test–based measures, concerns are expressed that predictive test results may influence individual well-being negatively, increase individual responsibility for one’s health, or lead to (genetic) discrimination of persons with predispositions for certain diseases. Moreover, it could be possible that establishing small patient subgroups may lead to insufficient drug testing before their application and, thus, may result in higher risks for patients when used in a larger setting or indication. Successively, it is argued that molecular test–based measures may lead to significant costs increases and thus result in an additional financial burden for health-care systems. This could further exacerbate problems of equal access to health-care services. Finally, even the neoadjuvant setting is a good model to test the interaction in vivo between the tumor, its microenvironment, and the administered drug, helping oncologists to a better understanding of tumor behaviors; we do not need to forget that the patient is curable and must not be used to test new therapeutic strategies without a strong rationale. Thus, fully, clearly informed consent of patients about their prognosis, known risks and benefits of standard therapy, and risks and benefits of participating in a trial of investigational therapy is absolutely mandatory. We also need to take into account that in these new trials based on new drugs focused on molecular markers, all the procedures should be well-described in the informed consent form and they should follow proper standard operating procedures, recognized worldwide. Further, new clinical trial designs to identify and validate biomarkers and targeted therapeutics require education of regulatory committees in institutions to ensure that effective approaches reach patients efficiently without compromising their safety. The ethical concerns for biomarker and/or new drug-related studies should take confidential protection of data into consideration (27).
A systems-biology approach to apply new high-throughput technologies will be required to efficiently fulfill the promise of personalized molecular medicine, along with new clinical trial designs which are needed to rapidly evaluate the hundreds of targeted therapies and potential biomarkers that are under preclinical evaluation. In this scenario, the neoadjuvant setting is the proper approach able to provide a unique opportunity to speed drug development by enabling in vivo examination of tumor response and proximate outcomes, including pathological response and relapse in high-risk patients. However, to accelerate drug development in this setting, new approaches and ethical procedures are needed to assure the safety and well-being of potentially curable patients. Given the recent US Food and Drug Administration guidance outlining a path to regulatory approval for agents screened and active in the neoadjuvant setting, these issues will require close attention as more patients enter such kinds trials with the use of new drugs and biomarker discovery.