Molecular Biomarkers for Breast Cancer Prognosis

Oncotype DX Recurrence Score (RS) Test in Lymph Node–Negative Breast Cancer Patients

The prognostic significance of the RS test and its ability to predict benefit from adjuvant chemotherapy for the individual patient have been validated in ER/PR+, HER2-negative and axillary lymph node–negative breast cancer patients. In a retrospective analysis of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 trial, the RS test was performed in 668 breast cancer patients who were randomized to receive either tamoxifen or placebo. There were 51% (n = 338) in the low-risk (RS <18), 22% (n = 149) in the intermediate-risk (RS 18–30), and 27% (n = 181) in the high-risk (RS ≥31) groups ( Fig. 27.1 ). The 10-year rate of distant recurrence was significantly lower in the low-risk group (6.8%, 95% CI 4.0%–9.6%) than in the high-risk group (30.5%, 95% CI23.6%–37.4%) ( P < 0.001). When the distant recurrence-free intervals were stratified by RS, patients with a low- or intermediate-risk score had significant benefit from tamoxifen versus placebo, but the benefit of tamoxifen over placebo in the high-risk group was not significant. When distant recurrence-free intervals were compared according to quantitative ER expression (ER tertiles), quantitative ER expression in ER+, placebo-treated patients was not a prognostic factor ( P = 0.54). However, for patients treated with tamoxifen, those with ER expression in the lowest ER tertile had little benefit from tamoxifen, but there was a large benefit from tamoxifen in patients in the highest and mid-ER expression tertiles. These data established that RS was a prognostic factor for distant recurrence in node-negative ER+ patients. RS was also validated as being predictive of the magnitude of benefit for tamoxifen in individual patients.

The NSABP B-20 study was a multicenter trial to determine whether the addition of chemotherapy to tamoxifen for ER+, HER2-negative, node-negative breast cancer patients resulted in better survival compared with tamoxifen alone. The absolute benefit of chemotherapy at 10 years was 4.4%, which led to the widespread use of adjuvant cytotoxic therapy for this group of patients. In a retrospective study of a subgroup of the NSABP B-20 trial, the RS test was performed in 651 patients to determine the magnitude of benefit from chemotherapy as a function of the RS assay. Among these patients, 227 in the trial had received tamoxifen alone, while 424 had received tamoxifen plus chemotherapy. Patients with RS tests in the low (RS <18) or intermediate (RS 18–30) risk range derived no benefit from the addition of chemotherapy to tamoxifen. Only patients in the high-risk group (RS ≥31) significantly benefited from addition of chemotherapy to tamoxifen, with a relative risk of 10-year distant recurrence of 0.26 (95% CI 0.13–0.53, P < 0.001) compared with tamoxifen alone.

These retrospective analyses led to a prospective phase III noninferiority trial, Trial Assigning IndividuaLized Options for Treatment (TAILORx), randomizing patients between chemoendocrine therapy versus endocrine therapy alone in patients with ER+, HER2-negative, node-negative breast cancer and intermediate-risk RS test score. Women 18 to 75 years of age with T1–T2 cancers (or T1b and intermediate-high grade) were eligible, but they had to be willing to have chemotherapy assigned or randomized based on RS test results. There were 10,273 patients registered, divided into 1629 low-risk (RS 0–10), 6711 intermediate-risk (RS 11–25), and 1389 high-risk (RS 26–100) patients. Patients in the low-risk group received endocrine therapy alone, high-risk RS patients received endocrine therapy plus chemotherapy, and intermediate-risk patients were randomly assigned to endocrine therapy alone (3399 patients) or endocrine therapy plus chemotherapy (3312 patients). For the intent-to-treat population of patients with RS 11–25, there was not a significant difference in invasive disease-free survival (IDFS) between patients having chemoendocrine versus endocrine therapy (hazard ratio [HR] 1.08, 95% CI 0.94–1.24, P = 0.26). There was no benefit from chemotherapy for patients >50 years with RS result 11–25 or for patients ≤50 years with RS <16 ( Fig. 27.2 ). Patients who were ≤50 years with RS 16–20 had 1.6% greater freedom from distant recurrence at 9 years with chemoendocrine compared with endocrine therapy, whereas those with RS result 21–25 had 6.5% greater freedom from distant recurrence. Subsequent analysis of prespecified secondary objectives was done to determine whether clinical risk features added information for patients ≤50 years regarding prognosis for recurrence and prediction of chemotherapy benefit to that provided by the RS test. As defined by modified Adjuvant! Online criteria, low clinical risk features were: tumor size ≤3 cm and grade 1; tumor size ≤2 cm and grade 2; or tumor size ≤1 cm and grade 3. All other cases were defined as high clinical risk. For patients ≤50 years with RS results 16–20, there was no demonstrable benefit from chemotherapy for patients with low clinical risk, but there was 6.4% increase in freedom from distant recurrence at 9 years for patients with high clinical risk. For patients with RS results 21–25, there was 6.4% increase for patients with low clinical risk and 8.7% increase for patients with high clinical risk. Therefore the integration of clinical risk with genomic risk separated those with RS results 16–25 who had no demonstrable chemotherapy benefit from those who had absolute benefit ranging from 6.4% to 8.7%.

The use of the RS test for ER+, HER2-negative, node-negative breast cancer has also been supported by other clinical trials, including the Clalit Health Services (CHS) registry study and that using Surveillance, Epidemiology, and End Results (SEER) data.

Oncotype DX Recurrence Score (RS) Test in Lymph Node–Positive Breast Cancer Patients

For patients with ER/PR+, HER2-negative, and node-positive breast cancer, the prognostic utility of the RS test has been established by clinical trials and a retrospective study, including West German Study Group (WSG) Plan B (n = 3198, pN0-1), NSABP B-28 (n = 1065, pN+), PACS-01 (n = 530, pN+), and SEER (n = 6768, pN+). Southwest Oncology Group (SWOG) 8814 was a prospective randomized trial that demonstrated superior disease-free survival and overall survival (OS) at 10 years for postmenopausal patients receiving sequential Cytoxan, Adriamycin, 5-Fluorouracil (CAF) plus tamoxifen versus tamoxifen alone. A subanalysis of the RS test done on 367 patients from that trial demonstrated that the RS result was able to stratify the 10-year risk of disease-free and OS in patients receiving tamoxifen alone. These results confirmed that the RS test was a prognostic factor in node-positive patients. When disease-free survival was analyzed according to low risk (RS <18), intermediate risk (RS 18–30), or high risk (RS ≥31), only patients with high-risk RS results had survival benefit for the addition of chemotherapy to tamoxifen, suggesting a predictive role of the RS test for chemotherapy benefit in postmenopausal women with node-positive breast cancer.

The RxPONDER trials was a prospective phase III randomized clinical trial for patients with one to three positive axillary lymph nodes and hormone receptor–positive (HR+), HER2-negative breast cancer with RS ≤25, comparing IDFS for patients receiving adjuvant chemotherapy followed by endocrine therapy (2547 patients) to endocrine therapy alone (2536 patients). A prespecified interim analysis for IDFS was done after the disease site monitoring committee and the National Cancer Institute requested that the data be reported when 58% of expected events had occurred. At a median follow-up of 5.3 years there was 1.2% advantage in IDFS for patients receiving chemoendocrine therapy (92.2%) over endocrine therapy alone (91.0%) (HR 0.86, 95% CI 0.72–1.03, P = 0.10). There was no significant difference in IDFS for postmenopausal patients receiving chemoendocrine therapy (91.3%) versus endocrine therapy alone (91.9%), but there was a significant difference in IDFS for premenopausal patients receiving chemoendocrine therapy (93.9%) versus endocrine therapy alone (89.0%) (HR 0.60, 95% CI 0.43–0.83, P = 0.002). The significant differences in IDFS for premenopausal patients persisted regardless of whether RS was 0–13 versus 14–25 or whether patients had one versus two to three positive lymph nodes. From this interim analysis, it was concluded that postmenopausal patients with one to three positive lymph nodes and RS 0–25 can likely forego adjuvant chemotherapy without compromising IDFS, but premenopausal patients with one to three positive lymph nodes are likely to significantly benefit from adjuvant chemotherapy, even with a very low RS.

Other studies supporting the use of the RS test for lymph node–positive patients are the National Cancer Database study (NCDB; n = 13,163, pN1-2) and CHS trial (n = 709, pN1mi-1).