development and the RT-PCR and clinical data used in the development of 21-Gene RS are not publicly available.4

The test was locked down prior to clinical validation. The investigators reported that “the prospectively defined assay methods and endpoints were finalized in a protocol signed on August 27, 2003, and RT-PCR data were transferred to the NSABP for analysis on September 29, 2003” (Paik et al., 2004, p. 2820). Genomic Health was blinded to the clinical outcome data until the RT-PCR data were locked and transferred to NSABP.5

Clinical/Biological Validation

Archival tissue from breast cancer patients in three studies was used to clinically validate the prognostic value of Oncotype DX (Table A-2). Paik et al. (2004) found that the Recurrence Score quantified the likelihood of distant recurrence in tamoxifen-treated patients with lymph-node-negative, estrogen-receptor-positive breast cancer. Investigators prospectively defined the endpoints for validation and prespecified the cut-off values for low, intermediate, and high risk of recurrence. They had a large number of patient samples on which to clinically validate the prognostic value of the Recurrence Score, and did not use samples from the discovery phase in the validation studies. Although this study was not a true prospective clinical validation, many assert the prospective–retrospective study design has evidentiary value close to a prospective study (AHRQ, 2008; Harris et al., 2007; Simon et al., 2009).

The second study, Habel et al. (2006), assessed the prognostic value of the Recurrence Score using archival tissue from patients treated within the Northern California Kaiser Permanente health plan. Investigators found that the Recurrence Score was associated with the risk of breast cancer death among patients with estrogen-receptor-positive breast cancer who were treated with tamoxifen or were not treated with systemic adjuvant therapy.

The third study, Esteva et al. (2005), used a smaller number of archival tissue samples and did not find an association between the Recurrence Score and risk of distant recurrence. Investigators hypothesized that this result could be due to potential selection bias or confounding factors. However, investigators did find a high degree of concordance between RT-PCR and immunohistochemical assays for estrogen receptor, progesterone receptor, and HER2.

Chemotherapy benefit In an exploratory analysis designed to assess the test’s ability to predict the benefit of chemotherapy treatment, investigators


4 Personal communication, Steven Shak, Genomic Health, December 13, 2011.

5 Personal communication, Steven Shak, Genomic Health, December 13, 2011.

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