A molecular test can pinpoint which patients will have a very low risk of death from breast cancer even 20 years after diagnosis and tumour removal, enabling ultra-low risk patients to be treated less aggressively and over-treatment to be avoided.
The clinical study was led by University of California-San Francisco (UCSF) in collaboration with colleagues in Sweden.
"This is an important step forward for personalising care for women with breast cancer," said lead author Dr Laura J Esserman a breast cancer specialist and surgeon with the Helen Diller Family Comprehensive Cancer Centre (HDFCCC), University of California–San Francisco. "We can now test small node-negative breast cancers, and if they are in the ultra-low risk category, we can tell women that they are highly unlikely to die of their cancers and do not need aggressive treatment, including radiation after lumpectomy.
"Oncologist have discussed the existence of ultra-low risk tumours and expressed concern that they might be exacerbated by screening. But, Esserman said, this is the first evidence that it is possible to run a diagnostic test at the time of diagnosis and identify them.
"This is an exciting advance because approximately 20%-25% of tumors diagnosed today may be ultra-low risk," said Esserman, a UCSF professor and director of the UCSF Carol Franc Buck Breast Care Centre who also co-leads the breast oncology program at the UCSF HDFCCC.
The medical community for many years has focused on identifying cancer early so that it can be cured or more easily treated. While this can benefit some patients, screening also can detect cancers that are extremely low risk and not life-threatening, which could lead to patients being over-treated. The issue is compounded because breast cancer can recur many years after diagnosis – for low-grade tumours, the majority of the risk occurs after five years. Until now, tools that could reliably identify ultra-low risk tumors at the time of diagnosis have not been available because physicians lacked the assurance that late recurrence could truly be avoided.
In the new study, researchers sought to determine whether a 70-gene test could accurately and reliably identify tumours with indolent, or slow-growing, behavior to assess the risk of cancer recurrence up to 20 years after diagnosis. The same test had shown last year that nearly half of early-stage breast cancer patients, who met traditional criteria for high risk, could safely skip chemotherapy based on the biological makeup of their tumors.
The authors disclosed that the test, called MammaPrint®, was devised by UCSF cancer researcher Laura van 't Veer, a co-author on the new study. Produced by Agendia, a company co-founded by van 't Veer, MammaPrint® tests for a 70-gene signature that can predict whether cancer will recur in early-stage breast cancer patients. It was approved by the US Food and Drug Administration in 2007.
In the new analysis, the investigators sought to assess breast cancer patients over 20 years, and to find cancers with no- or almost no-risk for metastatic progression. As such, they collaborated with the Stockholm breast cancer study group (STO), to evaluate patients who have been tracked for decades and were part of a randomised clinical trial of tamoxifen vs no systemic therapy.
The STO-3 low-risk trial included 1,780 lymph-node-negative patients with tumours less than or equal to 3cm in diameter, randomised to two years of adjuvant tamoxifen (40mg daily) versus no adjuvant treatment. Adjuvant therapy is a treatment provided after the initial surgery or treatment, with the intent to suppress recurrent tumor formation.
All the women had their tumours surgically removed. The researchers used these tissues to profile a total of 652 women, of whom 311 had received tamoxifen, and 339 had not received adjuvant systemic therapy. The majority of the women (79 percent) had received mastectomies and lymph node removal – the data did not include cases with less aggressive local therapy. All women had tumors detected in the era prior to the use of screening mammography, so none were detected via mammograph.
The multi-gene test classified 42% of the patients as high-risk, and 58% as low-risk. The investigators found that low-risk patients had a 95% survival rate at 5 years, but many later died from their disease.
The test classified 15% (98) of the cases as ultra-low risk, showing that such tumors are an inherent part of the spectrum of breast cancers, even in the era before screening. Not all low-risk tumors were ultra-low risk – in fact, only a quarter met the molecular definition. The women with ultra-low risk tumors had an excellent prognosis, whether or not they used tamoxifen for two years, said the authors.
"This emphasises the role that early detection can play, and how we can improve the impact of screening by focusing on those most likely to benefit," said Esserman.
The results suggest that the 70-gene test can be used to help physicians and patients determine their treatment course, and to inform choice of systemic therapy as well as local therapy. In an un-screened population, 15% of women will have ultra-low risk tumors, said the authors. With widespread screening, approximately 25% of post-menopausal women could have ultra-low risk breast cancer that would rarely be associated with recurrence or death, they wrote. For ultra-low risk elderly women over age 75 who have other conditions and face a life expectancy of less than a decade, simple excision may be sufficient, they said.
"There are breast cancers that pose little or no systemic risk," said Esserman. "Women who have a tumour that is classified as ultra-low risk by 70-gene signature can be reassured that their long-term outcome is expected to be excellent, with or without endocrine therapy. Having a test that accurately identifies a population of women, who have very little risk to begin with, should be welcomed by patients and clinicians alike. These tools will enable doctors to better personalise therapy to safely minimise treatment and reassure women if a cancer is ultralow risk."
Abstract
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.
Authors
Laura J Esserman; Christina Yau; Carlie K Thompson; Laura J van 't Veer; Alexander D Borowsky; Katherine A Hoadley; Nicholas P Tobin; Bo Nordenskjöld; Tommy Fornander; Olle Stål; Christopher C Benz; Linda S Lindström
[link url="https://www.ucsf.edu/news/2017/06/407546/molecular-test-identifies-breast-cancer-patients-lowest-risk-death"]University of California – San Francisco material[/link]
[link url="http://jamanetwork.com/journals/jamaoncology/article-abstract/2634502"]JAMA Oncology abstract[/link]