The first ever comparison of tests used in the management of early-stage breast cancer has shown a large variation in the tests' prognostic performance. These tests are used to predict disease recurrence and to provide guidance on treatment decisions, such as when to use adjuvant chemotherapy and how long endocrine therapy should be administered.
"This is the first time that anyone has directly compared the prognostic performance of these four common commercially available tests. This gives clinicians and oncologists the opportunity to review all the results and decide upon the test they want to use for their breast cancer patients," lead author Ivana Sestak, PhD, from Queen Mary University of London, United Kingdom, said in a statement.
The study was published online February 15 in JAMA Oncology.
It compared the prognostic performance of six tests, of which the first two are not commercially available but are used in research:
The Clinical Treatment Score (CTS)
The four-marker immunohistochemical score (IHC4)
The Oncotype Dx Breast Recurrence Score (RS), from Genomic Health
The PAM50-based Prosigna Risk of Recurrence (ROR), from NanoString
The Breast Cancer Index (BCI), from bioTheranostics
The EndoPredict (EPclin), from Myriad Genetics
The team conducted a retrospective biomarker analysis, performed as a preplanned secondary study of data from the Anastrozole, Tamoxifen Alone or in Combination (TransATAC) randomized clinical trial. That trial compared anastrozole with tamoxifen; the treatment period was 5 years for both drugs, and 10 years of follow-up data were available.
The trial included 774 postmenopausal women with estrogen receptor (ER)–positive HER2-negative early-stage breast cancer.
Of these 774 women, 591 had node-negative disease, and 183 women had breast cancer with one to three positive lymph nodes.
Women with node-negative disease were on average 63.4 years old. The average tumor size was 17.6 mm. In this group of women, 58 distant recurrences were recorded from 0 to 10 years after diagnosis, of which 34 recurrences occurred in the late follow-up period (5 to 10 years after diagnosis).
Women with node-positive disease were significantly older (average age: 66.4 years) and had significantly larger tumors (24.2 mm) compared with those with node-negative disease. Of the 40 distant recurrences observed in this group from 0 to 10 years after diagnosis, 21 occurred 5 years or more after diagnosis.
The primary objective of the study was to compare the prognostic value of the tests for distant recurrences occurring 0 to 10 years and 5 to 10 years after diagnosis. The team reported the results for node-negative breast cancer separately from the results for node-positive disease.
In women with node-negative disease, results for all six signatures were of statistically significant prognostic value for distant recurrence from years 0 to 10.
The BCI and the ROR tests had the highest prognostic value. On the basis of hazard ratio (HR), the researchers found that the ROR (HR: 2.56), the BCI (HR: 2.46), and the EPclin (HR: 2.14) tests were statistically more prognostic than the CTS (HR: 1.99), the IHC4 (HR: 1.95), and the RS (HR: 1.69).
All four commercial signatures identified a large proportion of women at low risk of experiencing 10-year distant recurrence (<10%).
However, the EPclin, the BCI, and the ROR identified a larger proportion of women at high risk for 10-year distant recurrence (22.1%, 27.3%, and 32.4%, respectively).
For the 535 women who were alive without distant recurrence after 5 years, results of the ROR, the BCI, and the EPclin tests were again of significant prognostic value for late distant recurrence.
With all four commercial tests, most women were classified as having a low mean risk for distant recurrence in years 5 to 10 (<5% risk). The EPclin categorized 26.5% of women as being at high risk; these women had the lowest 10-year distant recurrence risk, at 14.6%. For the ROR, 14.6% of women were classified as being at high risk; these patients had the highest 10-year risk for distant recurrence, at 23.2%.
For women with node-positive disease, the prognostic significance for distance recurrence from 0 to 10 years after diagnosis was weaker for all tests compared with the tests' performance for node-negative disease, but the pattern of prognostic significance was similar with node-negative disease.
The RS categorized 57.4% women as being at low risk; 10-year risk for distant recurrence was 19.4%. The ROR categorized 8.2% of women as being at low risk; for these women, the 10-year distant recurrence risk was 0%.
Of 154 women who were alive without distant recurrence after the first 5 years, the EPclin provided the most prognostic value (HR: 1.87), followed by the ROR (HR: 1.65) and the BCI (HR: 1.60). The researchers reported good risk stratification with the BCI, the ROR, and the EPclin tests; no clear risk stratification was observed for RS.
Does This Make a Difference to Clinical Practice?
In an earlier report by the researchers, the four commercial signatures all provided significant and similar prognostic information during the first 5 years following diagnosis.
However, the current study, which had a 10-year follow-up period, shows that the tests vary with regard to prognostic performance.
The researchers found that all four commercially available tests provide substantial prognostic value for women with node-negative disease, in that they are able to predict the recurrence of breast cancer up to 10 years after the start of treatment.
However, the researchers comment that the critical time for late recurrence is 5 to 10 years after the start of treatment, during which period more than 50% of recurrences occur in women with ER+ early-stage breast cancer. For women with node-negative disease, it is during this period that the BCI, the ROR, and the EPclin were most accurate for stratifying women as having low or high risk for recurrence.
The authors suggest that the better performance of the BCI, the ROR, and the EPclin compared to the Oncotype Dx may be attributed to molecular components in the signatures that were more specific for late recurrences.
What Test Should Clinicians Use?
For patients with node-positive disease, the researchers suggest that the BCI, the ROR, or the EPclin be used. "Of importance, combined genomic and clinical models showed enhanced prognostic performance particularly for patients with 1 to 3 lymph nodes and thus may be the preferred approach for the decision-making process for this group of patients," they write. With a mean 10-year risk for distance recurrence of <6%, chemotherapy is of limited benefit to these women, the researchers note.
The team points out that, in addition to gene expression levels associated with their respective panels, the ROR and the EPclin also include clinical information, such as tumor size and the number of positive lymph nodes.
"The combination of clinical and molecular information enhanced prognostic performance, particularly for women with node-positive disease," the researchers write.
Sestak pointed out that in an era in which women are being prescribed preventive endocrine therapy, being able to accurately predict the risk for breast cancer recurrence is more important now than ever before. "If we were better able to accurately assess a woman's long-term risk, then some women may be able to end their endocrine therapy after 5 years. But for those deemed high risk of a late recurrence, continuing their endocrine therapy would be a valuable option," she said.
The recommendations from the researchers, based on their latest study, are not much different from the information for patients that is provided on Breastcancer.org, which includes the following:
The Oncotype Dx should be considered for patients with stage I or II invasive ER+, lymph-node negative breast cancer to make decisions about chemotherapy.
The Prosigna ROR is recommended for postmenopausal women with HR+ stage I or II lymph node–negative disease and for women with stage II disease with one to three positive lymph nodes who have been treated with surgery and hormonal therapy.
The BCI test is recommended for women with HER2-negative, HR+, lymph node–negative stage I to III breast cancer who have been receiving hormonal therapy for 4 to 5 years to determine whether further hormonal therapy may be beneficial.
The EndoPredict test is recommended for women with stage I to II ER+, HER2-negative breast cancer with or without one to three positive lymph nodes to determine whether they are candidates for chemotherapy.
Several authors have received speaker's fees from several pharmaceutical companies, some of which market the commercially available tests, and some authors are employees of some of these companies. A detailed list can be found at the end of the publication.
Lancet Oncol. Published online February 15, 2018. Full text
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Cite this: First Comparison of Breast Cancer Tests Finds Variability - Medscape - Feb 27, 2018.