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Molecular tool identifies indolent breast cancers
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An ultralow-risk threshold of the MammaPrint 70-gene expression assay identified patients with breast cancer with an exceedingly low long-term risk for mortality, according to published findings.
“We have a threshold that truly identifies tumors that will hardly ever recur even without systemic therapy,” Laura Esserman, MD, MBA, professor of surgery and radiology and director of the Carol Franc Buck Breast Cancer Center at University of California, San Francisco, and co-leader of the breast oncology program at UCSF Helen Diller Family Comprehensive Cancer Center, told HemOnc Today. “That means that I can tell someone that they don’t need to worry — this will not kill them. So, let’s focus on avoiding overtreatment. A simple excision should suffice.”
The FDA–approved MammaPrint 70-gene assay (Agendia) is a prognostic tool initially developed for women with breast cancer who did not receive adjuvant systemic therapy. The low- vs. high-risk thresholds determined recurrence rates 5 years after diagnosis.
Esserman and colleagues used 25-year follow-up data form the NKI295 series to define an ultralow-risk threshold of the gene assay based on data from node-negative women with no breast cancer deaths at 15 years.
Researchers sought to validate this threshold via a secondary analysis of the randomized STO-3 clinical trial, in which 1,780 postmenopausal women with node-negative tumors 3 cm or smaller received 40 mg adjuvant tamoxifen daily or no adjuvant treatment. All women underwent mastectomy or lumpectomy and radiation between 1976 and 1990. After 2 years of tamoxifen or no systemic therapy, researchers randomly assigned patients without recurrence to 3 additional years of treatment or no therapy.
Researchers evaluated 727 immunohistochemical markers and Agilent microarrays for MammaPrint risk scoring from formalin-fixed paraffin-embedded primary tumor blocks from 652 women (median age, 62.8 years).
The score classified 58% (n = 377) of the women as low risk, 42% (n = 275) as high risk and 15% (n = 98) as ultralow risk.
After 20 years of follow-up, women with high-risk tumors (HR = 4.73; 95% CI, 1.38-16.22) and low-risk tumors (HR = 4.54; 95% CI, 1.4-14.8) had greater risk for disease-specific mortality than women with ultralow-risk tumors.
No patients with the ultralow-risk tumors treated with tamoxifen died at 15 years; 97% of these patients achieved 20-year disease-specific survival.
Researchers reported disease-specific survival rates of 97% at 10 years and 94% at 20 years among patients with ultralow-risk tumors who did not receive tamoxifen.
The ultralow risk threshold appeared to be the most significant predictor for good outcomes, according to recursive partitioning. Among nonultralow-risk tumors, size greater than 2 cm predicted outcomes.
The researchers noted that only 15% of patients were classified as ultralow-risk. Therefore, a large trial is needed to include more patients with ultralow-risk tumors.
“For over a decade, people have been writing about the problem of overdiagnosis and overtreatment — concerned that screening has led to the discovery of more low-risk tumors than might otherwise be found with screening,” Esserman said. “We used to think that early detection would really dramatically lower the death rate, but we did not understand that some tumors just are not high risk, that they exist and that more will be found when you screen. The problem is that, if you cannot tell which ones they are, you cannot act on it. The other problem is that breast cancer can come back after many years, so unless you have a study with long follow-up, then you cannot truly say that there is ultralow risk.
“We have cracked these problems,” Esserman added. – by Melinda Stevens
For more information:
Laura J. Esserman , MD, MBA, can be reached at Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, 1600 Divisadero St., Second Floor, PO Box 1710, San Francisco, CA 94115; email: laura.esserman@ucsf.edu.
Disclosure: Esserman reports no relevant financial disclosures. One researcher reports an inventor role for the MammaPrint 70-gene risk signature, and is a cofounder, stockholder and part-time employee of Agendia.
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