Clinical Validation

The initial study of the Oncotype DX® Breast Recurrence Score in a node-positive setting was from a cohort sample of 776 patients whose tumor blocks were collected in the course of the ECOG 2197 trial. An analysis of 465 patients with hormone receptor-positive disease, including both pre- and post-menopausal patients and both node-negative and node-positive (1-3 positive nodes) disease, all treated with anthracycline-based chemotherapy (AC or AT), was performed.1 Patients with a low Breast Recurrence Score result had lower five-year recurrence rates than patients with high scores (node-negative 4% vs 13%; node-positive 5% vs 25%). This finding was consistent among the node-negative and node-positive patient subsets. At ten -year follow up, the Breast Recurrence Score continued to be a highly significant predictor of distant recurrence (p<0.0001). The authors concluded that the Breast Recurrence Score result may potentially be used to distinguish between patients who do well with standard chemotherapy regimens and those who may be suitable candidates for clinical trials evaluating alternative chemotherapy regimens or other strategies.

An evaluation of post-menopausal, node-positive, hormone receptor-positive, early stage breast cancer patients from the SWOG-8814 trial showed the Breast Recurrence Score result to be prognostic for disease-free survival and overall survival in node-positive patients treated with tamoxifen alone; patients with a low Breast Recurrence Score result had a better prognosis than patients with a high Breast Recurrence Score result.2 The Breast Recurrence Score was also shown to be predictive of CAF therapy benefit. Patients with lower Breast Recurrence Score results had little if any benefit from sequential CAFàtamoxifen (CAF-T) therapy compared to tamoxifen alone in terms of disease-free survival , with a treatment hazard ratio of 1.02 (stratified log rank p=0.97). In contrast, patients with higher Breast Recurrence Score results had a statistically significant benefit with sequential CAF-T therapy compared to tamoxifen alone, with a treatment hazard ratio of 0.59 (stratified log rank p=0.033). An exploratory subgroup analysis of breast cancer-specific survival (BCSS) as a function of Breast Recurrence Score group and treatment is summarized in the Table 3 below. There was no statistically significant benefit of CAF-T therapy compared to tamoxifen alone for patients with low and intermediate Breast Recurrence Score results and a significant benefit from anthracycline-based chemotherapy for patients with high Breast Recurrence Score results. The test for interaction was significant (p=0.021).

Table 3. Ten-Year BCCS Estimates for Node-Positive Patients3
Breast Recurrence Score Group Tamoxifen (95% Cl) CAF-T (95% Cl)
Low(<18) 92% (79%-97%) 87% (76%-93%)
Intermediate (18-30) 70% (50%-83%) 81% (67%-89%)
High (=31) 54% (38%-68%) 73% (60%-82%)

A validation study was conducted in hormone receptor-positive, post-menopausal patients enrolled in the ATAC trial.4 In this study, 1,231 tumor samples from the two monotherapy arms were used to determine whether the Breast Recurrence Score result was prognostic. Of these, 306 samples were from patients with node-positive disease. The Breast Recurrence Score result was shown to predict distant recurrence in node-positive patients treated with either tamoxifen or anastrozole. Node-positive patients with low, intermediate, and high Breast Recurrence Scores had an average nine-year risk of distant recurrence of 17%, 28%, and 49%, respectively. Further, the risk of distant recurrence was shown to increase with the number of positive nodes; patients with 1-3 positive nodes experienced a lower risk of distant recurrence compared to patients with ≥4 positive nodes.5

A fourth study was conducted in a cohort of patients who participated in the NSABP B-28 trial, a study that compared four cycles of AC vs AC followed by paclitaxel in 3,060 node-positive patients.6 Analyses of a subset of 1,065 ER-positive patients from this trial who were tested using the Oncotype DX assay showed that the Breast Recurrence Score result was a significant predictor of outcome (p<0.001 for disease free survival and overall survival, distance recurrence free interval, and BCSS). The analysis of distant recurrence free interval showed that for patients with low, intermediate, and high Breast Recurrence Score results, 80.9%, 64.9%, and 55.8% of patients were distant recurrence free at 10 years, respectively. A multivariable model showed that the Breast Recurrence Score result was independent of other prognostic indicators including number of nodes, tumor size, tumor grade, treatment, and whether or not the patient had a mastectomy. This large study demonstrated that the Breast Recurrence Score result is strongly predictive of the 10-year risk of distant recurrence, overall survival, and BCSS in women with node-positive breast cancer treated with chemotherapy.

Finally, Penault-Llorca and colleagues evaluated the association between the Oncotype DX Breast Recurrence Score result and the risk of distant recurrence in HR-positive, node-positive breast cancer patients treated with endocrine therapy plus adjuvant fluorouracil, epirubicin, and cyclophosphamide (FEC) with or without docetaxel (FEC-D).7 Analyses were conducted in a cohort of 530 patients enrolled in the PACS 01 parent trial. In the primary analysis, the Breast Recurrence Score result was a significant predictor of distant recurrence free interval (HR=4.1 for a 50 point difference, p<0.001), disease free survival (HR=3.3, p<0.001) and OS (HR=5.0, p<0.001). In multivariate analyses, the recurrence score result provided independent prognostic information beyond clinicopathologic factors including treatment, age, tumor size and grade, number of positive nodes, surgery type and Ki-67 status (p<0.001). These data further confirm the prognostic significance of the Breast Recurrence Score results previously reported from multiple studies in hormone receptor-positive, node-positive breast cancer patients treated with adjuvant endocrine and chemotherapy.

 

REFERENCES

1. Goldstein L, Gray R, et al. Prognostic utility of the 21-gene assay in hormone receptor–positive operable breast cancer compared with classical clinicopathologic features. J Clin Oncol. 2008; 26(25):4063-71.
2. Albain KS, Barlow WE, Shak S, et al. Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial. Lancet Oncol. 2010;11(1):55-65.
3. Albain K, Barlow WE, Shak S, et al. Prediction of 10-year chemotherapy benefit and breast cancer-specific survival by the 21-gene Recurrence Score (RS) assay in node-positive, ER-positive breast cancer – an update of SWOG-8814 (TBCI 0100). Poster presented at : San Antonio Breast Cancer Symposium; December 2009; San Antonio, TX.
4. Dowsett M, Cuzick J, et al. Prediction of risk of distant recurrence using the 21-gene recurrence score in node-negative and node-positive postmenopausal patients with breast cancer treated with anastrozole or tamoxifen: a TransATAC study. J Clin Oncol. 2010; 28(11):1829-1834.
5. Paik S, Shak S, Tang G, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med. 2004; 351 (27): 2817-26.
6. Mamounas EP, Tang G, Paik S, et al. Prognostic impact of the 21-gene Recurrence Score result on disease-free and overall survival of node-positive, ER-positive breast cancer patients treated with adjuvant chemotherapy: results from NSABP B-28. Poster presented: American Society Clinical Oncology Breast Cancer Symposium; September 2012; San Francisco, CA.
7. Penault-Llorca F, Filleron T, Asselain B, Et al. Prediction of Recurrence with the Oncotype DX Recurrence Score in Node-Positive, HR-Positive, Breast Cancer Patients Treated with Adjuvant FEC-D or FEC Chemotherapy. Poster presented: American Society of Clinical Oncology Annual Meeting; May 2014; Chicago, IL.

 

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