Clinical Trials of Precision Medicine through ...

PRECISION MEDICINE FOR BREAST CANCER

Clinical Trials of Precision Medicine through Molecular Profiling: Focus on Breast Cancer Dimitrios Zardavas, MD, and Martine Piccart-Gebhart, MD, PhD OVERVIEW High-throughput technologies of molecular profiling in cancer, such as gene-expression profiling and next-generation sequencing, are expanding our knowledge of the molecular landscapes of several cancer types. This increasing knowledge coupled with the development of several molecularly targeted agents hold the promise for personalized cancer medicine to be fully realized. Moreover, an expanding armamentarium of targeted agents has been approved for the treatment of specific molecular cancer subgroups in different diagnoses. According to this paradigm, treatment selection should be dictated by the specific molecular aberrations found in each patient’s tumor. The classical clinical trials paradigm of patients’ eligibility being based on clinicopathologic parameters is being abandoned, with current clinical trials enrolling patients on the basis of specific molecular aberrations. New, innovative trial designs have been generated to better tackle the multiple challenges induced by the increasing molecular fragmentation of cancer, namely: (1) longitudinal cohort studies with or without downstream trials, (2) studies assessing the clinical utility of molecular profiling, (3) master or umbrella trials, (4) basket trials, (5) N-of-1 trials, and (6) adaptive design trials. This article provides an overview of the challenges for clinical trials in the era of molecular profiling of cancer. Subsequently, innovative trial designs with respective examples and their potential to expedite efficient clinical development of targeted anticancer agents is discussed.

P

ersonalized medicine is defıned by the National Cancer Institute (NCI) as “a form of medicine that uses information about a person’s genes, proteins and environment to prevent, diagnose and treat disease.”1 In oncology, this is a dynamically evolving fıeld, with an increasing list of molecular markers from tumor tissue dictating the treatment selection of patients with several cancer diagnoses (Table 1). In the setting of breast cancer, personalized medicine was fırst exemplifıed with the introduction of hormone receptor (HR) assessment and the subsequent use of endocrine treatment changing the natural history of HR-positive breast cancer.2 Interestingly, the fırst clinical trials demonstrating clinical benefıt deriving from the use of tamoxifen in the setting of breast cancer were performed for all cancers, irrespective of HR positivity.3,4 As a result of the high frequency of this overexpression in breast cancer, effıcacy signals were captured even within this unselected patient population. On the contrary, the success story of trastuzumab for patients with HER2 positivity, defıned as protein overexpression and/or gene amplifıcation, used a different route: the respective clinical trials in both metastatic and early-stage disease recruited exclusively patients with HER2-positive breast cancer.5,6 Subsequent studies assessing other HER2 blocking agents have been conducted within this particular molecular niche of breast cancer, for which four different tar-

geted agents have been approved at present.7 Other tumor entities provide similar examples of how molecular preselection of patients for study enrolment can accelerate effıcient clinical development of molecularly targeted agents. In the case of non–small cell lung cancer (NSCLC), the IPASS (Iressa Pan-Asia Study) study randomly assigned 1,217 unselected patients with previously untreated advanced disease to receive gefıtinib or carboplatin/paclitaxel. In the fınal analysis performed according to epidermal growth factor receptor (EGFR) biomarker status, it was reported that progressionfree survival (PFS) was signifıcantly longer with gefıtinib for patients whose tumors had both high EGFR gene copy number and EGFR mutation (hazard ratio [HR], 0.48; 95% CI, 0.34 to 0.67, p ⬍ 0.001) but signifıcantly shorter when high EGFR gene copy number was not accompanied by EGFR mutation (HR, 3.85; 95% CI, 2.09 to 7.09, p ⬍ 0.001).8 This fınding confırmed the previously established knowledge that administration of EGFR-blocking agents should be dictated by the presence of EGFR mutations in NSCLC. In the setting of breast cancer, multiple oncogenic signaling pathways have been identifıed as promoters of the malignant progression with numerous aberrations, such as mutations and/or copy number variations affecting their molecular components. Such pathways operate in (1) bulk tumor cells, (2) a subset of tumor initiating cells, and/or (3)

From the Breast International Group, Brussels, Belgium; Institut Jules Bordet, Brussels, Belgium. Disclosures of potential conflicts of interest are found at the end of this article. Corresponding author: Martine Piccart-Gebhart, MD, PhD, Institut Jules Bordet, Blvd de Waterloo, 121, 1000 Brussels, Belgium; email: [email protected]. © 2015 by American Society of Clinical Oncology.

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TABLE 1. Molecular Aberrations Defining Administration of Approved Targeted Agents in Different Solid Tumor Diagnoses Cancer Type

Molecular Target

Aberration

Method of Assessment

Approved Targeted Agent

Breast Cancer

ER

Overexpression

IHC

Tamoxifen AIs Fulvestrant

PgR

Overexpression

IHC

Tamoxifen AIs Fulvestrant

HER2

Overexpression and/or amplification

IHC

Trastuzumab

FISH

Lapatinib

Pertuzumab T-DM1 Colorectal Cancer

KRAS*

Mutation

DNA

Cetuximab Panitumumab

Gastric Cancer

HER2

Overexpression and/or amplification

IHC

Trastuzumab

FISH GIST

KIT

Mutation

IHC

Imatinib

Melanoma

BRAF

Mutation

DNA

Vemurafenib Dabrafenib

Non-Small Cell Lung Cancer

EGFR

Mutation

DNA

Gefitinib Erlotinib

ALK

Rearrangement

FISH

Crizotinib

RET

Rearrangement

FISH

Vandetanib

ROS

Rearrangement

FISH

Crizotinib

Abbreviations: AI, aromatase inhibitor; ALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor; ER, estrogen receptor; FISH, fluorescent in situ hybridization; GIST, gastrointestinal stromal tumor; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; PgR, progesterone receptor; T-DM1, trastuzumab DM1. *KRAS mutations predict lack of benefit derived from EGFR-blocking agents.

the tumor microenvironment. An expanding arsenal of targeted agents is currently under clinical development, aiming to block specifıc molecular aberrations9 ; however, the extended tumor heterogeneity seen poses impediments to their success.10 The increasing number of targeted agents warranting clinical assessment, coupled with the increasing molecu-

KEY POINTS 䡠 The success stories of trastuzumab and endocrine treatment for patients with HER2-positive and hormone receptor-positive breast cancer exemplify the potential of personalized cancer medicine. 䡠 High-throughput molecular profiling techniques reveal the extensive molecular diversity of breast cancer, leading to an increased molecular fragmentation. 䡠 There is an increasing number of targeted agents that need to be assessed in the setting of breast cancer. 䡠 Clinical assessment of targeted agents within small molecularly defined breast cancer segments poses challenges to the design and conduct of clinical trials. 䡠 New, innovative study designs are being introduced to overcome these challenges.

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lar fragmentation of breast cancer and thus the respective decrease in prevalence of putative predictive biomarkers, render the current clinical trial paradigm ineffıcient. New study designs are needed to facilitate the successful clinical development of targeted agents within specifıc molecular niches of breast cancer.11

MOLECULAR PROFILING IN BREAST CANCER The advent of gene-expression profıling analysis led to the identifıcation of four intrinsic subtypes of breast cancer, associated with different prognostication and sensitivity profıles to treatment,12 namely: (1) luminal A, being HR-positive with low proliferation rates, (2) luminal B, HR-positive with higher proliferation rates, (3) HER2-like, characterized by amplifıcation of the ERBB2 gene as well as other genes in the same amplicon, and (4) basal-like, largely showing a triple phenotype with lack of expression of estrogen receptor, progesterone receptor, and HER2. Of note, these subtypes show distinct molecular profıles, as indicated by studies that coupled gene expression profıling with genome copy number analysis.13,14 Subsequent studies, implementing this powerful technique to larger collections of primary breast tumors, have led to further molecular fragmentation of this common


TABLE 2. Approaches of Next-Generation Sequencing Approach

Advantages

Disadvantages

Whole-Genome Sequencing

䡠 Potential for identification of previously unrecognized cancer related genes and aberrations 䡠 More efficient interrogation of structural variations

䡠䡠䡠䡠䡠䡠

Targeted Sequencing

䡠 Lower costs

䡠 Limited potential for identification of previously unrecognized cancer-related genes

Whole-Exome Sequencing

䡠 Shorter turnaround time

䡠 Reduced capacity to interrogate of structural variations

Targeted Gene Sequencing

䡠䡠䡠䡠

Easier Lower Easier Ready

Higher costs Longer turnaround time Laborious bioinformatics work High storage capacity needed Challenging clinical interpretation/reporting Low reproducibility of FFPE tumor material analysis

data interpretation data storage capacity needed clinical interpretation/reporting to be used for FFPE

disease. An integrated analysis of almost 2,000 primary breast cancers combining copy number and gene expression data from the METABRIC (Molecular Taxonomy of Breast Cancer International Consortium) group revealed a total of 10 different subgroups with distinct prognoses.15 Further molecular classes have been identifıed within basal-like breast cancerbreast cancer, such as: (1) the claudin-low tumors characterized by a gene expression profıle similar to that of mammary stem cells and mesenchymal features,16 and (2) molecularapocrine tumors characterized by expression of androgen receptor and consecutive downstream signaling.17 More recently, there have been studies employing nextgeneration or massively parallel sequencing (NGS and MPS, respectively) in breast cancer, expanding further our understanding of the underlying molecular heterogeneity.18-22 NGS is a powerful molecular profıling tool, deciphering DNA sequences and informing us about a variety of different molecular aberrations, namely nucleotide substitution mutations, insertions and deletions, copy number variations, and structural rearrangements.23 Importantly, the ability of NGS to quantify the allelic frequency of any mutational event captured enables the reconstruction of the clonal architecture of any given tumor sequenced.24,25 These studies document the extensive intertumor heterogeneity of breast cancer, as exemplifıed by the study of Stephens et al, in which among the 100 sequenced breast cancers there were 73 different combination of possibilities of mutated cancer genes.22 Additionally, a repetitive fınding from these studies is that unlike some few commonly mutated cancer genes such as TP53 and PIK3CA, most of the gene mutations are seen in less than 10% of the cases that are sequenced.26,27 Last, the determination of the allelic frequencies indicates than not all mutated genes reported are of clonal nature, since some of them are found in a subclonal population of cancer cells. There has been an increasing availability of NGS techniques to many investigators thanks to a steep decrease in the fınancial costs involved that surpassed to what Moore’s law foresaw.28 Currently, different applications of NGS are under use that could be summarized as follows: (1) Whole-genome sequencing (WGS), with the fırst whole cancer genome to be

sequenced being that of a cytogenetically normal acute myeloid leukemia.29 Subsequently, several studies have employed this approach in the setting of breast cancer.22,30,31 However, the implementation of WGS in clinical practice has been questioned, since the use of archived formalin-fıxed paraffın-embedded tumor material is problematic. Additionally, high computational power and delicate bioinformatic tools are needed for data interpretation, posing further challenges in the clinical implementation of WGS.32 (2) Targeted sequencing, referring to either whole-exome sequencing, or targeted-gene sequencing, is conducted using panels of selected cancer-related genes. Such approaches have certain advantages (Table 2), such as shorter turn-around times, lower costs, and less laborious data interpretation; presently, they are available in several Clinical Laboratory Improvement Amendments (CLIA)– certifıed laboratories; however, there is a compromise in the ability to detect translocations and other structural rearrangements.33

INNOVATIVE CLINICAL TRIAL DESIGNS Currently, there is an increasing use of the afore-mentioned molecular profıling for patients with breast cancer, in particular in the setting of high-volume academic institutions, where extended profıling programs are being developed, sometimes in a CLIA environment.34 Such initiatives can be used to guide patients in clinical trials assessing targeted agents.35 However, several challenges can be identifıed, in regard to the success of trials assessing such experimental anticancer compounds (Table 3). To address these ever more frequently met challenges, new transformative clinical trial designs are needed. In such innovative trials, eligibility is based on the genotype of breast cancer, rather than the classic clinic-pathologic characteristic of the disease (Table 4). These study designs hold the promise to reduce the high attrition rates seen in oncology drug development, as well as to keep the number of patients recruited in the respective trials at reasonable levels. To this end, several innovative study designs are being developed. asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK

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TABLE 3. Challenges Encountered in Current Clinical Trials Assessing Targeted Anticancer Agents and Proposed Mechanisms to Circumvent Them Phenomenon

Consequence

Potential Solution 䡠 Innovative study designs such as master protocols to reduce screening failures 䡠 Statistical tools to reduce sample sizes needed (e.g., relaxing type I error) 䡠 Revisiting regulatory pathways for approval

Intertumor heterogeneity Molecular fragmentation of the disease

䡠 Increased costs for molecular profiling

䡠 Risk-sharing strategies 䡠 Greater pharmaceutical industry participation

䡠 Variable functional output of different aberrations

䡠 Functional validation 䡠 Well-characterized xenograft tumor models

Intratumor heterogeneity 䡠 Need to assess multiple molecular aberrations from one tumor sample 䡠 Multiplexed molecular profiling to reduce tissue requirements 䡠 “Liquid” biopsies/plasma-based molecular profiling 䡠 Increased costs for molecular profiling Clonal evolution

䡠 Risk-sharing strategies 䡠 Greater pharmaceutical industry participation

䡠 Emergence of treatment resistance

䡠 “Liquid” biopsies/plasma-based molecular profiling

䡠 Discordances of aberrations between primary and metastatic disease

䡠 Longitudinal cohorts of patients with profiling of both primary and metastatic tumor tissue 䡠 Biopsies/plasma-based molecular profiling

Longitudinal Cohort Studies with or without Downstream Clinical Trials

outcome. An already completed initiative from this category is the SAFIR01 program that recruited 423 patients with metastatic breast cancer.38 Patients were subjected to biopsy of metastatic site, with the tissue analyzed by comparative genomic hybridization as well as Sanger sequencing of the PIK3CA and AKT1 genes. This study, with a primary endpoint of the proportion of patients that could be entered into trials of targeted agents, demonstrated that personalization of treatment for patients with this disease is feasible in clinical practice. A subsequent effort, SAFIR02, is currently recruiting patients with HER2-negative metastatic breast cancer who have received no more than one line of chemotherapy. Metastatic tissue from these patients will be analyzed by NGS; after six to eight cycles of cytotoxic chemotherapy, patients with no progression of their disease will be randomly assigned to receive the standard of care or targeted therapy according to a list of 51 molecular alterations.

This study design can be exemplifıed by the AURORA (Aiming to Understand the Molecular Aberrations in Metastatic Breast Cancer) program initiated by the Breast International Group.36 This represents a collaborative effort of European hospitals to conduct large-scale molecular profıling of patients with metastatic breast cancer who are prospectively followed (Fig. 1). This molecular profıling, of one metastatic lesion and of the primary tumor, can support the conduct of genotype-driven “nested” or “downstream” clinical trials,37 offering a dual benefıt: (1) facilitate the molecular preselection of patients eligible to be enrolled in genotype-driven clinical trials and (2) identify potential predictive biomarkers, through the coupling of the molecular and clinical outcome data captured for the patients enrolled in such a program. An important additional benefıt that can be expected through this approach is the fact that clinicians become familiarized to the reporting of genomic data. Furthermore, such programs can improve our knowledge of prognosis for molecularly defıned subsets of cancer, through the prospective follow-up of patients for clinical

Studies Assessing the Clinical Utility of Molecular Profiling The advent of molecular profıling in cancer has generated another study design, which assesses the clinical utility of

TABLE 4. Examples of Ongoing Genotype-Driven Clinical Trials in Breast Cancer Clinicaltrials.gov Identifier

Phase (No. of Patients)

Genotype Targeted

Agent

Molecular Target

Design

Primary Endpoint

NCT01277757

II (40)

AKT mutations, PIK3CA mutations, PTEN loss

MK2206

AKT

Single-arm, monotherapy

ORR

NCT01219699

I (200)

PIK3CA mutations

BYL719

Alpha-isoform PI3K

Single-arm, BYL719 combined with fulvestrant

MTD

NCT01589861

I/II (106)

PIK3CA mutations, PTEN loss

BKM120

All isoforms PI3K

Single-arm, BKM120 combined with lapatinib

MTD, ORR

NCT01670877

II (29)

ERBB2 mutation

Neratinib

EGFR/HER2/HER4

Single-arm, monotherapy

CBR

Abbreviations: CBR, clinical benefit rate; EGFR, epidermal growth factor receptor; MTD, maximum tolerated dose; ORR, objective response rate; PI3K, phosphatidylinositol-4,5-bisphosphate 3-kinase; PTEN, phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase.

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FIGURE 1. The AURORA Initiative for Metastatic Breast Cancer

The AURORA Program A prospecve, longitudinal study of 1,300 women with Metastac Breast Cancer recruited at 81 centers across 15 European countries Dynamics of the subdonal tumor architecture over me

Improved understanding

Can “driver” mutaons be captured by plasma tumour DNA?

Relave importance of “driver” mutaons in the “trunk” or in the branches Which clones are going to play a major role in the lethal evoluon of the disease?

of the disease

Up-scaling of the number of MBC paents candidate for clinical trials with new targeted therapies

NIF Trust

choosing targeted therapeutics based on the molecular profıling as compared with conventional treatment. This design does not assess individual targeted agents and should be therefore perceived as proof of concept. Tsimberidou et al reported promising results from a nonrandomized, phase I clinical trials program, according to which tumor tissue from patients with several advanced solid tumors diagnoses (1,144 tumors) were analyzed by molecular profıling: disease in patients having one molecular aberration who were treated based on the genotype of their disease (175 patients) demonstrated an increased overall response rate (27% vs. 5%; p ⬍ 0.0001), longer time-to-treatment failure (5.2 months vs. 2.2 months; p ⬍ 0.0001), and longer overall survival (13.4 vs. 9.0 months; p ⫽ 0.017) compared with patients who received conventional treatment (116 patients).35 Currently, there is an ongoing randomized, proof-of-concept, phase II trial comparing targeted therapy based on tumor tissue molecular profıling compared with conventional treatment for patients with several advanced cancer types called SHIVA (NCT01771458).39 This study incorporated a feasibility part, which demonstrated the feasibility and safety of incorporating biopsy of metastatic disease for the fırst 100 patients who enrolled.40

Master-Protocol Trials This study design can assess different targeted agents in parallel within independent cohorts of patients defıned by specifıc molecular aberrations that could predict sensitivity to the investigational agent under assessment. This approach

reduces the percentage of screening failures, since patients with different aberrations can be enrolled in one of the different molecularly-defıned cohorts. An important effort using this approach, recently initiated by the NCI, is the master protocol for second-line treatment of squamous NSCLC. An important effort using this approach recently initiated by the NCI is the master protocol for second-line treatment of squamous NSCLC. This trial will evaluate targeted agents matched to specifıc molecular segments of this type of cancer, with frequencies ranging between 9.3% and 20%. This is an initiative that aims to establish a novel approach to the clinical development of targeted agents and their subsequent regulatory approval, according to which treatment selection will be based on the results of NGS from a panel of approximately 250 cancer-related genes.41 The study design that has been incorporated has fıve study strata with a total of 10 treatment arms; within each stratum a phase II/III study design has been adopted, with specifıc thresholds of effıcacy that have to be met before moving to the phase III component. An important aspect of this trial that is currently recruiting patients is its collaborative nature, with multiple major partners working together, including the Southwestern Oncology Group, NCI, the Foundation for the National Institutes of Health, the Friends of Cancer Research, and the U.S. Food and Drug Administration. In the setting of breast cancer, the Breast International Group currently is designing such a study with input from the North American Breast Cancer Group, assessing targeted agents for patients with aggressive metastatic asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK

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triple-negative breast cancer. In particular, patients with this breast cancer phenotype whose disease develop early systematic relapse will be eligible. Once metastatic tumor tissue has been analyzed by NGS and upon availability of these results, the patients will be entered into one of multiple parallel, molecularly-driven arms, randomly assigned between the standard of care or the respective targeted agent(s), dictated by the genotype of their disease.

and/or added, in cases where either predefıned thresholds of effıcacy are not reached or new promising data for new compounds emerge, respectively.48 Additionally, in trials having an adaptive design, the biomarker selection strategy can be changed, even when the treatment assignment remains the same, depending on emerging evidence associating new biomarkers not previously identifıed with (lack of) sensitivity to one or more of the treatments under assessment.

Basket Trials

N-of-1 Trials

This is an innovative, histology-independent trial design, in which patients with cancer diagnoses of different histologies can be enrolled in the study protocol based on the presence of a specifıc molecular aberration. There is an ongoing clinical trial that aims to develop a small molecule HER2 blocking agent for patients with ERBB2-mutated cancers that exemplifıes this approach.42 The main disadvantage in this innovative design is a biology-driven one; in particular this is the issue of the potentially different functional outputs that a specifıc molecular aberration could have among different types of cancer. This has been reported in studies documenting lack of antitumor effıcacy of vemurafenib, a BRAF small molecule inhibitor, in the setting of BRAF-mutated metastatic colorectal cancer; these fındings are in direct contradiction with the dramatic antitumor activity seen among patients with metastatic melanoma bearing the V600E BRAF mutation.43 A major advantage of this study design is that it is very informative about which are the tumor types where single-agent therapy is worth pursuing in phase III trials versus other types where combination treatment strategies should be prioritized. Interestingly, there is an ongoing study by the NCI, called MATCH (Molecular Analysis for Therapy Choice) that combines elements from both master and basket trial design. In particular, this trial will assess molecularly targeted agents within specifıc molecular niches of cancer types such as erlotinib for EGFR-mutated NSCLC and crizotinib for cases with EML4-ALK translocations (master-trial component), as well as across different tumor types sharing a molecular aberration, e.g., vemurafenib in BRAF-mutated melanoma, thyroid cancer, and NSCLC (basket-trial component).

This is a study design that has been more frequently employed in fıelds of clinical research other than oncology, such as trials conducted for patients with musculoskeletal or pulmonary conditions.49,50 The defıning characteristic is the recruitment of patients exposed to different experimental agents or placebo in different sequencing, with washout periods in between.51 This type of design practically renders each involved patient to serve as his or her own comparator, through the comparison of the effıcacy seen for the different experimental agents that the patient receives. In oncology, a modifıed N-of-1 study design has been performed, which assessed the antitumor activity of different anticancer compounds matched to the genotype of the patients.52 This trial recruited 86 patients with different types of advanced tumor who had been heavily pretreated, that had molecular profıling. Sixty-six of these patients were treated according to these results. Concerning the effıcacy, 18 patients had a PFS ratio of 1.3 or higher (95% CI, 17% to 38%; one-sided, one-sample p ⫽ 0.007). The study met its primary endpoint, which was the comparison of PFS obtained by the targeted treatment with the PFS achieved by the previous systemic treatment within each individual patient. This is an approach that could be of help for molecular aberrations of really low prevalence, where randomized studies are extremely challenging.

Adaptive Trials Adaptive trials represent another transformative study design, recently exemplifıed by the BATTLE (BiomarkerIntegrated Approaches of Targeted Therapy for Lung Cancer Elimination)-1 and -2 clinical trials, focusing on patients with metastatic NSCLC,44 or the I-SPY (The Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and Biomarker Analysis) 1 and 2 trials conducted in the neoadjuvant setting of breast cancer.45-47 These are dynamically evolving trials, with the particular aspect of during the initial phase of the adaptive study patients are recruited in the different arms at an equal ratio; however, as more patients are enrolled and effıcacy data are being generated and pooled from the different treatment arms, the adaptive phase follows. During this second, adaptive phase, randomization ratios can be changed and treatment arms can be dropped e188


Window-of-Opportunity Trials Window-of-opportunity trials incorporate a design assessing the administration of an investigational agent over a short period of time, most often in the presurgical setting allowing serial tumor biopsies, though such studies can be conducted in the metastatic setting as well.53,54 These trials do not have an effıcacy endpoint, since it is the in vivo biologic effects of an experimental agent and not the antitumor activity with offıcially predefıned measures of outcome that they aim to assess. An ongoing study utilizing this innovative design is the D-beyond trial, a preoperative window study evaluating denosumab, a RANK ligand inhibitor, and its biologic effects for premenopausal women with early breast cancer.55 Patients entering this trial receive preoperatively two doses of 120 mg of denosumab subcutaneously 1 week apart that will be followed by surgery. Ten to 21 days after the fırst administration, surgical excision of the primary tumor will take place; the primary objective is the antiproliferative effect exerted by denosumab, as indicated by Ki67 immunohistochemistry-based assessment. Another example of a window-of-opportunity trial that will soon be initiated is the RHEA (Biomarker Research Study for PF-03084014 in


Chemoresistant Triple-Negative Breast Cancer) trial. This is a single-arm, phase II, open-label, preoperative study of a small-molecule NOTCH inhibitor that is administered for 9 days after completion of neoadjuvant chemotherapy in patients with triple-negative breast cancer that is chemotherapy-resistant.

CONCLUSION To the present day, great progress has been made in the molecular profıling of breast cancer, with an expanding array of molecular aberrations being identifıed. The subsequent development of experimental targeted agents promises to improve cancer treatment for patients bearing specifıc molecular aberrations. A major challenge is the assessment of the functional signifıcance of such aberrations and the veri-

fıcation of their relevance as predictors of sensitivity to their matched targeted agents under development. The latter can be achieved through well-conducted clinical trials that match several specifıc genotypes of the disease with a number of targeted agents. To this end, innovative study designs must be implemented to expedite anticancer drug development. Such studies need to be coupled with next-generation molecular profıling techniques that have been validated to secure fındings’ reproducibility. The one-size-fıts-all paradigm of conventional study design must be abandoned, and the approval strategies revisited in some cases. More extensive collaboration between academia around the world, regulatory agencies, and pharmaceutical companies developing new anticancer compounds is becoming a necessity for these innovative study designs to be successfully implemented.

Disclosures of Potential Conflicts of Interest Relationships are considered self-held and compensated unless otherwise noted. Relationships marked “L” indicate leadership positions. Relationships marked “I” are those held by an immediate family member; those marked “B” are held by the author and an immediate family member. Institutional relationships are marked “Inst.” Relationships marked “U” are uncompensated.

Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: None. Consulting or Advisory Role: Martine J. Piccart-Gebhart, Amgen, Astellas, AstraZeneca, Bayer, Eli Lilly, Invivis, MSD, Novartis, Pfizer, Roche-Genentech, sanofi Aventis, Symphogen, Synthon, Verastem. Speakers’ Bureau: None. Research Funding: Martine J. Piccart-Gebhart, Amgen (Inst), Astellas (Inst), AstraZeneca (Inst), Bayer (Inst), Eli Lilly (Inst), Invivis (Inst), MSD (Inst), Novartis (Inst), Pfizer (Inst), Roche-Genentech (Inst), Sanofi Aventis (Inst), Symphogen (Inst), Synthon (Inst), Verastem (Inst). Patents, Royalties, or Other Intellectual Property: None. Expert Testimony: None. Travel, Accommodations, Expenses: None. Other Relationships: None.

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9. Zardavas D, Baselga J, Piccart M. Emerging targeted agents in metastatic breast cancer. Nat Rev Clin Oncol. 2013;10:191-210. 10. Zardavas D, Irrthum A, Swanton C, et al. Managing Breast Cancer Heterogeneity. Nat Rev Clin Oncol. In press. 11. Sleijfer S, Bogaerts J, Siu LL. Designing transformative clinical trials in the cancer genome era. J Clin Oncol. 2013;31:1834-1841. 12. Sotiriou C, Pusztai L. Gene-expression signatures in breast cancer. N Engl J Med. 2009;360:790-800. 13. Chin K, DeVries S, Fridlyand J, et al. Genomic and transcriptional aberrations linked to breast cancer pathophysiologies. Cancer Cell. 2006; 10:529-541. 14. Bergamaschi A, Kim YH, Wang P, et al. Distinct patterns of DNA copy number alteration are associated with different clinicopathological features and gene-expression subtypes of breast cancer. Genes Chromosomes Cancer. 2006;45:1033-1040. 15. Curtis C, Shah SP, Chin SF, et al. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature. 2012;486:346-352. 16. Prat A, Parker JS, Karginova O, et al. Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Res. 2010;12:R68. 17. Gucalp A, Traina TA. Triple-negative breast cancer: role of the androgen receptor. Cancer J. 2010;16:62-65. 18. Banerji S, Cibulskis K, Rangel-Escareno C, et al. Sequence analysis of

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