TAILORx: A Trial Design Toward Our Goal of Personalized Medicine

M. Janakiram, MD

Breast Cancer

Dr Janakiram is a postdoctoral fellow in immunology and breast cancer at the Albert Einstein College of Medicine. He completed his oncology fellowship at the Albert Einstein College of Medicine/Montefiore Medical Center and his internal medicine residency at Case Western Reserve University. His research interests include investigating and role of coinhibitory B7 molecules in human malignancies.

Dr Assal received his medical degree at New York University School of Medicine. He completed an internal medicine residency at New York University, Langone Medical Center. He is currently a fellow in hematology and medical oncology at Albert Einstein College of Medicine and is active in clinical research. His research interests include tumor immunology and immunotherapies.
Dr Sparano is Professor of Medicine and Professor of Obstetrics, Gynecology, and Women’s Health at the Albert Einstein College of Medicine and Associate Chairman of the Department of Oncology at Montefiore Medical Center. He also serves as Associate Director for Clinical Research at the Einstein Cancer Center and leads the Einstein Breast Cancer Working Group, a multidisciplinary group of physicians and scientists focused on translational breast cancer research. He currently serves as the study chair of TAILORx.

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Breast cancer is a significant public health problem; in 2009 (the most recent year for which numbers are available), 211,731 women were diagnosed with breast cancer and 40,676 died of breast cancer in the United States.1 Breast cancer mortality rates have decreased by 2.2% per year from 1990 to 2007, and the decline has been more prominent (3.2% per year) in women older than 50 years.2 Statistical modeling indicates that this decline is due to screening mammography and improved adjuvant therapy.3 The absolute benefit of adjuvant chemotherapy for early- stage disease varies depending on recurrence risk. The Early Breast Cancer Trialists’ Collaborative Group showed that the mortality benefit derived from adjuvant chemotherapy was little affected by age, nodal status, tumor differentiation, estrogen receptor (ER) expression, or tamoxifen use.4 On the other hand, a large proportion of patients with operable breast cancer, especially if associated with ER-positive, lymph node–negative disease, may be cured with primary local therapy and endocrine therapy, resulting in overtreatment with chemotherapy in many patients who may otherwise have been cured without it.5 Hence there is a compelling need to develop assays predictive of chemotherapy benefit and to evaluate and refine their clinical utility in prospective clinical trials.

Risk Assessment in ER-Positive Disease
Classic Clinicopathologic Prognostic Factors
The traditional method for assessing prognosis has been the TNM staging,6 which is based upon the premise that prognosis is determined by the anatomic extent of disease (ie, tumor size, nodal status). The disadvantage of TNM staging is that even within the same stage, tumors can have variable prognosis, and it provides no predictive information about benefit from systemic therapy. The Nottingham grading system7 classifies breast tumors into 3 grades based on degree of tubule formation, nuclear pleomorphism, and mitotic counts and is independently correlated with prognosis in ER-positive breast cancer.8 A limitation of grading is that this suffers from interobserver variability,9 and the prognosis is variable for grade 2 tumors, which account for most tumors.

Online decision-making tools – Adjuvant! Online10 and PREDICT11 – were later developed, and Adjuvant! Online is popular in the United States. This web-based decision aid estimates the risk of recurrence with and without adjuvant systemic therapy based on Surveillance, Epidemiology, and End Results estimates on disease-free and overall survival, and hence provides information regarding the absolute benefit likely to be achieved with systemic endocrine therapy, chemotherapy, or both. The estimates from Adjuvant! have been validated in a population-based study, although estimates may be less reliable in certain patient subsets.12 While Adjuvant! accurately predicts recurrence risk in patient populations, it does not accurately identify a benefit from adjuvant systemic therapy in individual patients. Hence, other tools are required to assist in making more informed decisions for individual patients.

Gene Expression Profiling
Gene expression profiling quantitates the transcriptional expression of genes in a tumor and provides information about tumor biology that is not otherwise captured by classic clinicopathologic features.13,14 The most widely available gene expression assays are the Oncotype DX and MammaPrint for invasive cancer, and the Oncotype DX DCIS Score for ductal carcinoma in situ.15 Other validated available assays have been described elsewhere.16

Table

Figure 1

Oncotype DX and Rationale for TAILORx
Oncotype DX was developed and validated as a reverse transcriptase-polymerase chain reaction assay by Paik et al17 in 2004 in collaboration with Genomic Health, Inc. Prognostic genes were identified by evaluating a panel of 250 rationally selected candidate genes, and the expression was correlated with distant recurrence in a cohort of approximately 450 patients with localized breast cancer. The top-performing 16 genes with 5 reference genes for normalization were selected for a 21-gene assay (Figure 1), and an algorithm was developed that translated the gene expression profile into a quantitative “Recurrence Score” (RS). A prospective validation in 668 tamoxifen-treated patients with ER-positive, node-negative early breast cancer enrolled in National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B14 indicated that the RS provides prognostic information about the risk of distant recurrence independent of other clinical features, whether evaluated as a continuous variable or as a categorical variable of low (0-17), intermediate (18-30) or high (>30) RS. Additional validation was confirmed in a population-based study from Kaiser Permanente that included patients with early breast cancer treated with tamoxifen in which RS was significantly correlated with breast cancer mortality.18 In another prospective validation study that included a clinical trial population of patients with ER-positive, node-negative breast cancer randomized to receive tamoxifen alone or in combination with cyclophosphamide, methotrexate, and 5-fluorouracil chemotherapy,19 it was demonstrated that only the high RS group derived a large benefit from chemotherapy (hazard ratio [HR] 0.26; 95% CI, 0.13-0.53), whereas the benefit from chemotherapy was unlikely in the low-risk group and uncertain in the intermediate RS group (HR 0.61; 95% CI, 0.24-1.59). Similar results were found when the RS was evaluated in a cohort of 367 postmenopausal patients with ER-positive, node-positive disease enrolled in trial S8814 who were randomized to receive either tamoxifen or tamoxifen plus adjuvant chemotherapy consisting of cyclophosphamide, doxorubicin, and 5-fluorouracil.20 Similar to the NSABP B20 trial, there was no benefit from chemotherapy in the low and intermediate RS groups, whereas chemotherapy resulted in improvement in disease-free survival (HR 0.59; 95% CI, 0.35-1.01; log-rank P=.03) and overall survival (HR 0.56; 95% CI, 0.31-1.02; P=.057) in those with a high RS. Upon application of the assay in clinical practice in patients selected to have the test done because of therapeutic equipoise (eg, intermediate-grade tumors), it was found that a larger proportion of patents had an intermediate RS than originally observed in the validation studies.21 Based on these considerations, the North American Breast Cancer Intergroup designed the TAILORx (Trial Assigning Individualized Options for Treatment) to evaluate the effect of treatment in this intermediate RS group.

TAILORx: Design and Objectives
Trial Design
The TAILORx is a prospective, randomized, open label trial designed to evaluate the effect of adjuvant chemotherapy in ER-positive, HER2-negative, node negative patients who met established National Comprehensive Cancer Network guidelines for recommending adjuvant chemotherapy in addition to endocrine therapy. Patients were risk-stratified based on their RS according to the following 3 categories: Low risk with an RS of 0 to 10, intermediate risk with an RS of 11 to 25, and high risk with an RS above 25. The rationale for amending the RS cut points for defining low, intermediate, and high risk was to minimize the potential for undertreatment of high-risk patients. When these ranges were used to analyze the data in the NSABP B20 trial, the treatment effect for adjuvant chemotherapy was found to be similar for the high RS group, and the risk of recurrence was found to be 5% or less for the low and intermediate RS groups when treated with tamoxifen alone.19 In addition, when the risk of relapse is analyzed as a continuous variable, a trend favoring the addition of chemotherapy becomes evident when the RS is approximately 11 or higher, and the 95% confidence intervals overlap in the 11 to 25 RS range; hence this recurrence score range was selected. Patients in the intermediate-risk group (RS 11-25), the primary study group (Figure 2), were randomized to receive chemotherapy with hormonal therapy (the standard treatment arm) versus hormonal therapy alone (the experimental treatment arm). Randomization was stratified according to tumor size, menopausal status, planned chemotherapy (taxane-containing or not) or radiation therapy (whole breast irradiation with or without boost, partial breast irradiation, or no radiation therapy), and RS group (RS 11-15 vs 16-20 vs 21-25). The choice of hormone therapy and chemotherapy was at the discretion of the treating physician as long as it was consistent with one of the several standard treatment options described in the protocol. The final 1000 patients enrolled underwent quality-of-life assessments. The low-risk group (RS <11) was assigned to receive hormone therapy only, whereas the high-risk group (RS >25) was assigned to receive chemotherapy in addition to hormone therapy.

Figure 2

After registration and informed consent, a tumor specimen was submitted to Genomic Health for determination of the RS by the Oncotype DX. Patients were asked to provide blood samples for the banking of plasma and peripheral mononuclear cells at the time of registration. The Eastern Cooperative Oncology Group Pathology Coordinating Office collected tissue specimens to allow for central testing and confirmation of ER and progesterone receptor expression, creation of tissue microarrays, and RNA extraction for future studies. By banking tumor RNA, formalin-fixed paraffin- embedded tissue microarrays, plasma, and germline DNA, future clinical cancer tests, such as genomic and epigenomic tests, tumor and serum proteomic patterns, and single nucleotide polymorphisms in drug and/or estrogen metabolizing enzymes, can be performed if the patients provided consent for future studies. A biospecimen repository was also established to study determinants of late relapse; blood samples are being collected from patients who are recurrence free at 4.5 to 7.5 years after registration. The samples will serve as a resource to define and/or validate biomarkers predictive of late relapse, including tumor-associated factors (eg, plasma tumor DNA) and host factors (eg, estrogen, insulin and/or IGF levels, and inflammatory cytokines).

Objectives and Outcome Measures
The primary objective of TAILORx was to determine whether adjuvant hormone therapy is noninferior to adjuvant chemotherapy plus hormone therapy in women in the primary study group (RS 11-25) whose tumors meet established clinical guidelines for adjuvant chemotherapy. The primary study end point was disease-free survival; other coprimary end points include distant recurrence-free interval, recurrence-free interval, and overall survival. Another objective of this trial was to establish a tissue and specimen bank for patients enrolled in this trial for use in future tests as they emerge. Secondary objectives of the trial were to determine whether hormone therapy is indeed sufficient to achieve a distant disease-free survival of 95% at 10 years for patients in the first secondary study group (RS ?10). The prognostic significance of the Oncotype DX RS as well as individual RS gene groups will be determined (proliferation group, HER2 gene group, ER gene group, invasion gene group, and other genes), and outcomes projected at 10 years by Adjuvant! (using classic pathologic parameters such as tumor size, hormone receptor status, and histologic grade) will be compared with those made by the Oncotype DX test. Failure rates as a function of the Oncotype DX RS are estimated separately in the chemotherapy and nonchemotherapy arms. The purpose is to develop more precise estimates of the relationship between RS and chemotherapy treatment effect at the upper range of the primary study group (RS 11-25).

Statistical Considerations
The trial, designed as a noninferiority trial, is powered to detect a 3% or greater difference between the randomized arms. The accrual goal of the primary study group (RS 11-25) was raised to 6860 patients from 4390 due to higher than expected rates of nonadherence to the treatment assignment (based on data as of October 30, 2008, 17% of patients in the hormone plus chemotherapy arm were not receiving chemotherapy, and 7% of the hormone therapy only arm were receiving chemotherapy). Disease-free survival will be compared using a stratified log-rank test, with the test stratified on the same factors used during randomization. It is estimated the primary trial results will be available in 2015 or later.

Current and Future Directions
Two other ongoing trials integrating gene expression profiles include the RxPONDER (Rx for Positive Node, Endocrine Responsive Breast Cancer) trial and the MINDACT (Microarray in Node-Negative Disease May Avoid Chemotherapy) trial; a comparison of the trials is presented in the Table. The RxPONDER trial integrates the Oncotype DX assay as a biomarker in ER-positive, HER2-negative breast cancer patients who have 1 to 3 positive axillary nodes. Patients with an RS >25 are assigned to chemotherapy plus endocrine therapy, whereas patients with an RS <25 are randomized to receive chemotherapy plus endocrine therapy or endocrine therapy alone.22 This study is currently open to accrual. The MINDACT trial integrates the MammaPrint assay as a biomarker to evaluate the benefit of chemotherapy in patients whose risk classification is discrepant between Adjuvant! and MammaPrint, with these patients being randomized to treatment by clinical criteria (Adjuvant!) versus genomic criteria (MammaPrint).23 By integrating biomarker-based information reflecting individual tumor biology, trials like TAILORx, RxPONDER, and MIND­ACT will refine the clinical utility of these assays that are already widely used in clinical practice.

References
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