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Original Investigation
November 2017

Use of Molecular Tools to Identify Patients With Indolent Breast Cancers With Ultralow Risk Over 2 Decades

Author Affiliations
  • 1Helen Diller Family Comprehensive Cancer Center, University of California–San Francisco, San Francisco
  • 2Buck Institute for Research on Aging, Novato, California
  • 3Center for Comparative Medicine, University of California–Davis, Davis
  • 4Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill
  • 5Department of Oncology-Pathology, Karolinska Institutet and University Hospital, Stockholm, Sweden
  • 6Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
  • 7Department of Oncology, Linköping University, Linköping, Sweden
  • 8Department of Biosciences and Nutrition, Karolinska Institutet and University Hospital, Stockholm, Sweden
JAMA Oncol. 2017;3(11):1503-1510. doi:10.1001/jamaoncol.2017.1261
Key Points

Question  Can a molecular signature—an ultralow-risk threshold of the US Food and Drug Administration–cleared MammaPrint 70-gene expression score—be used to identify tumors with indolent behavior?

Findings  In this secondary analysis of a trial of node-negative postmenopausal women randomized to tamoxifen vs no systemic therapy that included 652 patients with MammaPrint risk scoring, 15% met the ultralow-risk threshold. Ultralow-risk patients have a 20-year disease-specific survival rates of 97% and 94% in the tamoxifen arm and control arm, respectively.

Meaning  The ultralow-risk threshold can identify patients whose long-term risk of dying from breast cancer is exceedingly low.


Importance  The frequency of cancers with indolent behavior has increased with screening. Better tools to identify indolent tumors are needed to avoid overtreatment.

Objective  To determine if a multigene classifier is associated with indolent behavior of invasive breast cancers in women followed for 2 decades.

Design, Setting, and Participants  This is a secondary analysis of a randomized clinical trial of tamoxifen vs no systemic therapy, with more than 20-year follow-up. An indolent threshold (ultralow risk) of the US Food and Drug Administration–cleared MammaPrint 70-gene expression score was established above which no breast cancer deaths occurred after 15 years in the absence of systemic therapy. Immunohistochemical markers (n = 727 women) and Agilent microarrays, for MammaPrint risk scoring (n = 652 women), were performed from formalin-fixed paraffin-embedded primary tumor blocks. Participants were postmenopausal women with clinically detected node-negative breast cancers treated with mastectomy or lumpectomy and radiation enrolled in the Stockholm tamoxifen (STO-3) trial, 1976 to 1990.

Exposures  After 2 years of tamoxifen vs no systemic therapy, regardless of hormone receptor status, patients without relapse who reconsented were further randomized to 3 additional years or none.

Main Outcomes and Measures  Breast cancer–specific survival assessed by Kaplan-Meier analyses and multivariate Cox proportional hazard modeling, adjusted for treatment, patient age, year of diagnosis, tumor size, grade, hormone receptors, and ERBB2/HER2 and Ki67 status.

Results  In this secondary analysis of node-negative postmenopausal women, conducted in the era before mammography screening, among the 652 women with MammaPrint scoring available (median age, 62.8 years of age), 377 (58%) and 275 (42%) were MammaPrint low and high risk, respectively, while 98 (15%) were ultralow risk. At 20 years, women with 70-gene high and low tumors but not ultralow tumors had a significantly higher risk of disease-specific death compared with ultralow-risk patients by Cox analysis (hazard ratios, 4.73 [95% CI, 1.38-16.22] and 4.54 [95% CI, 1.40-14.80], respectively). There were no deaths in the ultralow-risk tamoxifen-treated arm at 15 years, and these patients had a 20-year disease-specific survival rate of 97%, whereas for untreated patients the survival rate was 94%. Recursive partitioning identified ultralow risk as the most significant predictor of good outcome. In tumors “not ultralow risk,” tumor size greater than 2 cm was the most predictive of outcome.

Conclusions and Relevance  The ultralow-risk threshold of the 70-gene MammaPrint assay can identify patients whose long-term systemic risk of death from breast cancer after surgery alone is exceedingly low.