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Genetic tests gauge breast-cancer recurrence risk

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Next step: confirm reproducibility among local labs

The Breast Cancer Index and the PAM50 and EndoPredict tests were all developed as prognostic assays. They were not designed to, nor have they been demonstrated to, predict patient sensitivity to an endocrine treatment or to help select a class of endocrine agent to use in therapy. Despite these limitations, the data presented on all three tests suggest that they perform well for discriminating recurrence risk among patients with hormone-receptor positive, lymph-node negative breast cancer. So far, there is not good evidence that they can predict outcomes in lymph-node positive patients.

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Dr. W. Fraser Symmans

The patients with the greatest potential for stopping treatment after 5 years are those who also have HER2-negative disease and grade 1 or 2 disease, similar to the women enrolled in the ABCSG 8 trial.

Another attractive feature of these tests is that they can be performed by local pathology laboratories, precluding the need to send specimens to distant testing sites. The pathology community has been waiting a long time to more fully participate in the genomic diagnostic/personalized medicine arena.

The next step is to confirm the reproducibility of these tests when used by a variety of labs, essentially guaranteeing quality control. You need a critical mass of labs working together and using these tests to be sure that everyone gets clinically valid and reproducible results. I expect this to happen during the next year.

Dr. W. Fraser Symmans is professor of pathology at the University of Texas M.D. Anderson Cancer Center in Houston. He said that he is a c-founder of, and has equity in, Nuvera Biosciences. He made these comments as an invited discussant for the reports at the meeting and in an interview.


 

AT IMPAKT 2013 BREAST CANCER CONFERENCE

BRUSSELS – A pair of genetic tests each showed the ability to aid long-term prognosis estimates in patients with estrogen receptor–positive breast cancer, based on results from two retrospective analyses reported at IMPAKT 2013 Breast Cancer Conference.

The new results mean that a total of three different genetic tests have now shown added prognostic utility in retrospective analyses, bringing the field closer to actually using these tests in routine practice. The tests would prove particularly useful for patients with estrogen receptor–positive, node-negative breast cancer by helping to find those who are at low risk for long-term metastatic disease and who could safely stop treatment after 5 years of hormonal therapy, said Dr. Michael Gnant, professor of surgery at the University of Vienna.

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Dr. Michael Gnant

But other experts stressed that it’s premature to start routinely using these tests.

"We’re getting to a point where we can offer to our patients genomic assays that are clinically validated and with demonstrated utility," Dr. W. Fraser Symmans said during the meeting. But, he added, while oncologists are "on the brink" of using the tests routinely, "we need to confirm reproducibility among labs, and that the test works in that setting," said Dr. Symmans, professor of pathology at the University of Texas M.D. Anderson Cancer Center in Houston.

None of the three genetic test panels were designed to predict late recurrences, noted Dr. Peter C. Dubsky, a surgeon at the University of Vienna and a collaborator with Dr. Gnant. "These data will need further validation before actually being incorporated into clinical decision-making concerning adjuvant endocrine therapy beyond 5 years," Dr. Dubsky said in a written statement.

The analysis reported by Dr. Gnant and Dr. Dubsky included formalin-fixed and paraffin-embedded tumor specimens from 1,478 patients who had been enrolled in the Austrian Breast and Colorectal Cancer Study Group (ABCSG) 8 trial, which had the primary goal of assessing two different 5-year treatment strategies in more than 3,700 postmenopausal women with estrogen receptor–positive breast cancer (J. Clin. Oncol. 2012;30:722-8).

Dr. Gnant, Dr. Dubsky, and their associates assessed the 1,478 specimens with the Prediction Analysis of Microarray test using a 58-gene classifier panel (PAM50), a test first reported in 2009 (J. Clin. Oncol. 2009;27:1160-7) that has since been commercialized as the Prosigna assay, available in Europe but not in the United States.

Using prespecified cutoffs on the PAM50 results for classifying patients as being at low, intermediate, and high risk for long term distant recurrences, the researchers tallied the rate of actual recurrences during a median follow-up of 11 years. The 15-year disease-free survival rate was 97.6% among low-risk patients, 90.9% in intermediate-risk patients, and 82.5% in high-risk patients, Dr. Gnant reported. The between-group differences were statistically significant.

The findings suggest that high-risk patients might be good candidates for extended adjuvant therapy, while low-risk patients, with a recurrence risk of less than 2% at 5-10 years and at 10-15 years following primary therapy "can be spared the side effects of extended adjuvant therapy," he said. The PAM50 risk of recurrence score "adds prognostic information beyond established clinicopathological factors."

The second analysis reported at the meeting retrospectively used medical records and specimens collected in the Arimidex, Tamoxifen Alone or in Combination (ATAC) study, which enrolled more than 6,000 postmenopausal women with localized invasive breast cancer (Lancet Oncology 2008;9:45-53). The researchers evaluated the prognostic efficacy of five different clinical, genetic, or histochemical test panels for predicting risk of distant recurrences during a median 10 years follow-up in 891 of the enrolled patients.

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Dr. Ivana Sestak

All five assessment panels yielded similar prognostic information during the first 5 years of follow-up. During the next 5 years, the strongest prognostic information came via the Clinical Treatment Score, which takes into account a patient’s nodal status, tumor grade and size, patient’s age, and treatment received, said Ivana Sestak, Ph.D., a statistician and epidemiologist at the University of London. The two most important prognostic features in this panel are tumor size and nodal status, she noted. Two other assessment panels – the PAM50 genetic panel and the Breast Cancer Index, a genetic test first described in 2011 – also provided statistically significant and clinically meaningful additional prediction of distant recurrences during 5-10 years of follow-up (Br. J. Cancer 2011;104:1762-9).

The other two tests Dr. Sestak and her associates evaluated did not add further prognostic information beyond what the Clinical Treatment Score provided. The uninformative tests were a set of four immunohistochemical markers (to estrogen, progesterone, HER2, and ki67), and the Oncotype Dx recurrence score – a 21-gene panel test marketed by Genomic Health.

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