Prediction Of Prognosis In Nodenegative Breast Cancer

Prognostic models for node-negative breast cancer that rely on tumor size and histological grade are useful but imperfect. At least two distinct gene-expression profiling-based tests were recently developed which may improve prognostic prediction for these patients. One of these - Mammaprint™ (Agendia Inc, Amsterdam, the Netherlands) - was recently cleared by the US Food and Drug Administration (FDA) to aid prognostic prediction in node-negative breast cancer, and it may become available commercially shortly. This assay measures the expression of 70 genes and calculates a prognostic score which can be used to categorize patients into good or poor prognostic risk groups. This test was evaluated on two separate cohorts of patients that received no systemic adjuvant therapy. The first cohort included 295 patients and showed that those with the good prognosis gene signature had 95% (±2 % standard error (SE)) and 85% (±4% SE) distant metastasis-free survival at 5 and 10 years, respectively, compared to 60% (±4% SE) and 50% (±4.5% SE) in the poor prognostic group.5 A second validation study (n = 307) confirmed these findings, and showed that patients with the good prognosis signature had 90% (85-96% confidence interval (CI) 95%) distant metastasis-free survival at 10 years compared to 71% (65-78%) in the poor prognosis group.6 Importantly, the gene signature could restrat-ify patients within clinical risk categories defined by the Adjuvant Online program. In other words, some of the clinically low-risk patients were correctly recategorized as high risk based on their gene signatures, and some clinically high-risk patients were correctly predicted to be low risk by the genomic test.

Other investigators also identified genes which were associated with relapse in node-negative breast cancer; markers were selected separately from ER-negative and ER-positive tumors, and were combined into a single 76-gene prognostic signature (VDX2, Veridex LLC, Warren, NJ, USA). This test was also evaluated on two separate cohorts of patients that received no systemic adjuvant therapy and were not included in the development of the test. The first cohort included 180 patients, and showed 5- and 10-year distant metastasis-free survival rates of 96% (89-99%) and 94% (83-98%), respectively, for the good prognosis group. The 5- and 10-year distant metastasis-free survival rates were 74% (64-81%) and 65% (53-74%) for the poor prognosis group.7 A second independent validation of this 76-gene signature included 198 node-negative cases, and demonstrated again that the 5- and 10-year distant metastasis-free survival rates were 98% (88-100%) and 94% (83-89%), respectively, for the good prognosis group, and 76% (68-82%) and 73% (65-79%) for the poor prognosis group.8 In this instance too, the gene signature could restratify patients within clinical risk categories defined by the Adjuvant Online program, and recurrence hazard ratios remained similar after adjusting for tumor grade, size and ER status.8

Both of these microarray-based assays provide prognostic prediction with moderately high precision (see CI around outcome estimates), and seem to have at least complementary value to tumor size- and grade-based predictions. However, what constitutes low enough risk to forgo systemic adjuvant chemotherapy is influenced not only by the absolute risk of relapse but also by the risk of adverse events, the probability of benefit from therapy, and also by personal preferences. Many patients seem to be willing to accept adjuvant chemotherapy for rather small gains in survival.2 Molecular prognostic markers may provide little clinical value for these individuals because no predictive test is accurate enough to completely rule out the risk of relapse and some potential benefit from adjuvant therapy. However, many other patients are reluctant to accept the toxi-cities, inconvenience and costs of chemotherapy for small and uncertain benefit. For these individuals, more precise prediction of risk of recurrence and sensitivity to adjuvant therapy with genomic tests can assist in making a more informed decision.


One of the most pressing questions for patients with stage I-II ER-positive breast cancer is whether to take adjuvant endocrine therapy alone or to also receive adjuvant chemotherapy in addition to the endocrine treatment. Recently, a novel multigene diagnostic assay, Oncotype Dx (Genomic Health Inc, Redwood City, CA, USA), became commercially available to assist decision-making in this situation. This RT-PCR-based assay represents an important conceptual advance in the diagnosis of ER-positive breast cancers. Oncotype Dx measures the expression of 21 genes at the mRNA level from formalin-fixed paraffin-embedded specimens. In addition to ER mRNA, several downstream ER-regulated genes are also measured which may contain information on ER functionality. The assay also quantifies HER2 expression and several proliferation related genes, and combines these into a genomic recurrence score. A seminal study examined the correlation between the Oncotype Dx recurrence score and distant relapse in 668 ER-positive, node-negative, tamoxifen-treated patients who were enrolled in the National Surgical Adjuvant Breast and Bowel Project (NSABP) clinical trial B14.9 The 10-year distant recurrence rates were 6.8% (4-10%), 14.3% (8-20%) and 30.5% (24-37%) for the low-, intermediate- and high-risk categories, respectively, based on the recurrence score (p <0.001). These results suggest that ER-positive patients with a high recurrence score may not be treated optimally with 5 years of tamoxifen. Similar results were observed in a community-based patient popu-lation.10 In multivariate analysis, the genomic test predicted relapse and overall survival independently of age and tumor size, indicating an at least complementary value.

The value of the recurrence score for predicting benefit from adjuvant cyclophosphamide methotrexate, 5-fluorouracil (CMF) chemotherapy in ER-positive, node-negative breast cancers was also examined. A study that included 651 patients who were enrolled in the NSABP B20 randomized study showed that a higher recurrence score was associated with greater benefit from adjuvant CMF chemotherapy when used in combination with tamoxifen therapy.11 The absolute improvement in 10-year distant recurrence-free survival was 28% (60% vs 88%) in patients with a recurrence score >31, while there was no benefit in patients with a recurrence score <18 (test for interaction p = 0.038). The hazard ratio for distant recurrence after CMF chemotherapy was 1.31 (0.46-3.78 CI 95%) for patients with recurrence scores <18 and it was 0.26 (0.13-0.53) for patients with scores >31. These data indicate that a high recurrence score identifies a subset of women with ER-positive and node-negative breast cancer at high risk of recurrence despite 5 years of tamoxifen therapy, and this risk can be reduced with the administration of adjuvant chemotherapy.

Oncotype Dx can be useful when the decision regarding adjuvant chemotherapy is not straightforward based on routine clinical variables. However, some important caveats must also be noted. Oncotype Dx is not appropriate to risk stratify ER-negative patients because all patients are categorized as high risk.12

The predictive performance of this test in patients who receive aromatase inhibitor therapy or more modern anthracycline- or taxane-containing chemotherapy regimens remains to be studied.12 In particular, the magnitude of benefit that patients with a low or medium recurrence score experience when treated with third-generation adjuvant chemotherapy regimens is unknown.

Other gene signatures are also emerging in the literature which may in the future assist selection of endocrine therapy or chemotherapy for ER-positive breast cancers. A 200-gene endocrine sensitivity index was recently reported which could identify patients with excellent survival after 5 years of tamoxifen therapy. The same index had limited prognostic value in the absence of endocrine therapy, indicating a true predictive marker.13 An antibody-based prognostic panel (MammostratTM, Applied Genomics Inc, Burlingame, CA, USA) is also currently being developed using samples from the NSABP B14 and B20 studies to risk stratify ER-positive patients, somewhat similar to what can be accomplished by Oncotype Dx.14

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