Integrating comparative effectiveness design elements and endpoints into a phase III, randomized clinical trial (SWOG S1007) evaluating oncotypeDX-guided management for women with breast cancer involving lymph nodes

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Abstract

Women with breast cancer involving the lymph nodes are typically treated with cytotoxic chemotherapy. Retrospective evaluations of prior studies suggest that the 21-gene test (OncotypeDX®), may allow identification of those who can safely avoid chemotherapy. To better understand the performance of the 21-gene test, the RxPONDER (Rx for Positive Node, Endocrine Responsive breast cancer) study was designed, a multicenter Phase III trial randomizing women with hormone receptor-positive and HER2-negative breast cancer involving 1–3 lymph nodes and a 21-gene assay recurrence score (RS) of 25 or less to endocrine therapy alone versus chemotherapy followed by endocrine therapy. As one of the first large-scale comparative-effectiveness studies in oncology, RxPONDER utilized an external stakeholder group to help inform the design of the trial. Stakeholders met with representatives of SWOG over several months through a structured discussion process. The stakeholder engagement process resulted in several changes being made to the trial design. In addition, stakeholder representatives from the health insurance industry provided guidance regarding a mechanism whereby the costs of OncotypeDX® would be paid by the majority of health insurers as part of the trial. The process may serve as a template for future studies evaluating the comparative effectiveness of genomic tests in oncology, particularly those that are conducted within cooperative clinical trials groups.

Introduction

Women with early stage breast cancer involving the lymph nodes are routinely offered chemotherapy in addition to surgery and radiation therapy. Although these recommendations are based on evidence from multiple randomized trials and a worldwide meta-analysis showing improvements in overall survival with chemotherapy [1], there is also evidence that some, and perhaps many, patients do not benefit from chemotherapy; specifically, those with tumors that are well-differentiated, low grade, and with estrogen receptor positivity. In a retrospective evaluation of subsets of patients with hormone-receptor-positive tumors who received adjuvant endocrine therapy in two randomized clinical trials evaluating adjuvant endocrine therapy regimens, the 21-gene assay (OncotypeDX®) recurrence score (RS) combined with pathologic assessment was shown to have predictive value in identifying women who will benefit from chemotherapy with either node-positive [2] or node-negative breast cancer [3].

OncotypeDX® is now being marketed as an option for patients with hormone-receptor-positive breast cancer involving 0–3 positive nodes, although genomic predictors such as OncotypeDX® are not yet widely employed in node-positive disease. Testing could potentially spare thousands of women from chemotherapy-related morbidity while also reducing chemotherapy expenditures by millions of dollars. However, it is not clear whether the RS can be calibrated to provide a balance between the benefits and harms of chemotherapy that would be acceptable to women and providers [4].

The comparative effectiveness of management using OncotypeDX® versus current practice is an important question for this population. The Institute of Medicine defines comparative effectiveness research (CER) as “the generation and synthesis of evidence that compares the benefits and harms of alternative methods to prevent, diagnose, treat and monitor a clinical condition, or to improve the delivery of care” [5]. The inclusion of stakeholders to provide real-world insights into unmet information needs and inform the prioritization and design of clinical studies is considered to be a crucial feature of CER.

In this manuscript, we describe the design of SWOG S1007 (clinical trial registry: NCT01272037) given the acronym RxPONDER (Rx for Positive Node, Endocrine Responsive breast cancer). This multicenter Phase III trial randomizes to endocrine therapy alone versus chemotherapy followed by endocrine therapy for women with hormone receptor-positive and HER2-negative breast cancer involving 1–3 lymph nodes and a 21-gene assay RS of 25 or less. We also describe a unique aspect of this SWOG-led cancer cooperative group study: the participation of an external stakeholder group prior to finalizing the trial design and endpoints for the purpose of ensuring that the study results would be informative to patients, clinicians and payers while balancing considerations such as internal validity and trial feasibility. In addition, because reimbursement for genomic tests in the context of a clinical trial is unclear, we describe how a joint funding arrangement involving health insurers and the National Cancer Institute (NCI) was created for the RxPONDER study. The process we describe may serve as a template for future studies evaluating the comparative effectiveness of genomic tests in oncology, particularly those that are conducted within cooperative clinical trials groups.

Section snippets

Initial designs of RxPONDER Trial

The initial RxPONDER trial design was developed by SWOG and submitted to the NCI's Breast Cancer Steering Committee for review, comment, and approval. Genomic Health, the manufacturer of the 21-gene assay (OncotypeDX®) had no role in the conception or design of the study. Reviewers included representatives of the Cancer Clinical Trials Cooperative Groups, the advocacy community, and other scientific personnel involved in breast cancer research. This study proposal involved a 2 × 2 factorial

Incorporation of comparative effectiveness research elements into the trial

From a comparative-effectiveness perspective, it could be argued that the preferable design is one that randomizes patients to one of two management options: “treat all” with chemotherapy (current standard of care) versus 21-gene assay RS-guided treatment. While this approach provides a direct test of the 21-gene assay versus the current standard of care, such designs are inefficient [8], [9], in this case increasing the sample size requirements to randomize 9000 women and to screen over

ESAG input and trial modifications

The ESAG acknowledged the importance of the study and many felt, after discussing the rationale behind the design choices made for the trial (as approved by the Breast Cancer Steering Committee), that the objectives, study design, exclusion and inclusion criteria, and endpoints were appropriate. Many initial comments raised by the ESAG were considered and discussed by the Steering Committee during the formative stage of the design [e.g., randomizing to usual care (chemotherapy) vs. management

Funding sources

Trials of the size of RxPONDER are very costly. A potential advantage of CER is in leveraging trial funds through the participation and support of multiple stakeholder groups, including health insurers and the manufacturers of the technologies of interest. An important issue was finding funds to pay for the test itself (at a retail price of approximately $4000, the 21-gene assay is the largest single component of the study after study personnel costs). OncotypeDX® has been developed and

Sample size and power analyses

The primary hypothesis tests an interaction of randomized treatment (chemotherapy versus no chemotherapy) and RS. The actual statistical model for the test uses a Cox regression model and a test of this interaction. The underlying model and sample size computations are too lengthy to be included here, but are described in the following handbook [15]. The sample size yields 81% power to test the interaction and to determine the optimal cutpoint for recommending chemotherapy.

Discussion

Prospective experimental studies are a crucial source of CER information, and for questions that can be addressed effectively with these methods, study designs and infrastructure must be available to generate credible and relevant information as quickly, efficiently, and inexpensively as possible [16]. The Cancer Cooperative Clinical Trials Program offers a compelling infrastructure for meeting these goals; however, several challenges must be addressed before the full potential of this network

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    Funding Source: This work was funded by the Center for Comparative Effectiveness Research in Cancer Genomics (CANCERGEN) through the American Recovery and Reinvestment Act of 2009 by the National Cancer Institute, National Institutes of Health under Agency Award #5UC2CA148570-02 and by PHS Cooperative Agreement grants CA32102 and CA38926 awarded to SWOG by the National Cancer Institute. The content of this manuscript is solely the responsibility of the authors and does not necessarily reflect the views or policies of the National Cancer Institute, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.

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