Genomic Testing in the Management of Early-Stage Breast Cancer

Ki-67 and the preoperative endocrine prognostic index (PEPI) score have been explored in the neoadjuvant setting to separate postmenopausal women with endocrine-sensitive versus intrinsically resistant disease and identify patients at risk for recurrent disease [17]. The on-treatment levels of Ki-67 in response to endocrine therapy have been shown to be more prognostic than baseline values, and a decrease in Ki-67 as early as 2 weeks after initiation of neoadjuvant endocrine therapy is associated with endocrine-sensitive tumors and improved outcome. The PEPI score was developed through retrospective analysis of the P024 trial [18] to evaluate the relationship between post-neoadjuvant endocrine therapy tumor characteristics and risk for early relapse. This was subsequently validated in an independent data set from the IMPACT trial [19]. Patients with low pathological stage (0 or 1) and a favorable biomarker profile (PEPI score 0) at surgery had the best prognosis in the absence of chemotherapy. On the other hand, higher pathological stage at surgery and a poor biomarker profile with loss of ER positivity or persistently elevated Ki-67 (PEPI score of 3) identified de novo endocrine-resistant tumors which are at higher risk for early relapse [20]. The ongoing Alliance A011106 ALTERNATE trial (ALTernate approaches for clinical stage II or III Estrogen Receptor positive breast cancer NeoAdjuvant TrEatment in postmenopausal women, NCT01953588) is a phase 3 study to prospectively test this hypothesis.

21-Gene Recurrence Score (Oncotype DX Assay)

The 21-gene Oncotype DX assay is conducted on paraffin-embedded tumor tissue and measures the expression of 16 cancer-related genes and 5 reference genes using quantitative polymerase chain reaction. The genes included in this assay are mainly related to proliferation (including Ki-67), invasion, and HER2 or estrogen signaling [21]. Originally, the 21-gene recurrence score assay was analyzed as a prognostic biomarker tool in a prospective-retrospective biomarker substudy of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 clinical trial in which patients with node-negative, ER-positive tumors were randomly assigned to receive tamoxifen or placebo without chemotherapy [22]. Using the standard reported values of low risk (< 18), intermediate risk (18–30), or high risk (≥ 31) for recurrence, among the tamoxifen-treated patients, cancers with a high-risk recurrence score had a significantly worse rate of distant recurrence and overall survival [21]. Inferior breast cancer survival with a high recurrence score was also confirmed in other series of endocrine-treated patients with node-negative and node-positive disease [23–25].

The predictive utility of the 21-gene recurrence score for endocrine therapy has also been evaluated. A comparison of the placebo- and tamoxifen-treated patients from the NSABP B-14 trial demonstrated that the 21-gene recurrence score predicted benefit from tamoxifen in cancers with low- or intermediate-risk recurrence scores [26]. However, there was no benefit from the use of tamoxifen over placebo in cancers with high-risk recurrence scores. To date, this intriguing data has not been prospectively confirmed, and thus the 21-gene recurrence score is not used to avoid endocrine therapy.

The 21-gene recurrence score is primarily used by oncologists to aid in decision-making regarding adjuvant chemotherapy in patients with node-negative and node-positive (with up to 3 positive lymph nodes), HR-positive/HER2-negative breast cancers. The predictive utility of the 21-gene recurrence score for adjuvant chemotherapy was initially tested using tumor samples from the NSABP B-20 study. This study initially compared adjuvant tamoxifen alone with tamoxifen plus chemotherapy in patients with node-negative, HR-positive tumors. The prospective-retrospective biomarker analysis showed that the patients with high-risk 21-gene recurrence scores benefited from the addition of chemotherapy, whereas those with low- or intermediate-risk did not have an improved freedom from distant recurrence with chemotherapy [27]. Similarly, an analysis from the prospective phase 3 Southwest Oncology Group (SWOG) 8814 trial comparing tamoxifen to tamoxifen with chemotherapy showed that for node-positive tumors, chemotherapy benefit was only seen in those with high 21-gene recurrence scores [24].