The PAM50 test, designed to determine a risk of recurrence score for patients with breast cancer, adds significant prognostic information to clinical decision making and might be superior to other risk assays.
Mitch Dowsett, PhD
Head, Academic Department of Biochemistry
Professor, Biochemical Endocrinology and Translational Research Breakthrough Research
Centre Royal Marsden Hospital London, England
The PAM50 test, designed to determine a risk of recurrence (ROR) score for patients with breast cancer, adds significant prognostic information to clinical decision making and might be superior to other risk assays, findings from two recent studies indicate.
On the heels of those analyses, the FDA cleared the Prosigna Breast Cancer Prognostic Gene Signature Assay, which incorporates the PAM50 test, for marketing in the United States under its 510(k) program, according to a September 9 announcement from the manufacturer, NanoString Technologies.
The assay is indicated for postmenopausal women with breast cancer whose tumors are stage I/II node-negative or stage II node-positive (1 to 3 positive nodes) and hormone receptor-positive. The test would be administered after patients have undergone surgery as part of locoregional standard-of-care.
The Prosigna assay will be available in the United States starting later this year through an in vitro diagnostic kit that can be operated by qualified laboratories. It has been sold in Europe and Israel since early this year.
The assay is based on the PAM50 gene signature, which measures expression profiles for 50 genes and classifies tumors into four intrinsic subtypes (luminal A, luminal B, HER2-enriched, and basal-like). An algorithm is then used to combine the gene signature, intrinsic subtype, tumor size, and proliferation score.
In the Journal of Clinical Oncology study, researchers reported that the ROR score obtained via the 50- gene assay provided more prognostic information than the recurrence score (RS) obtained by the Oncotype DX 21-gene assay and an immunohistochemical 4 (IHC4) assessment in patients with estrogen receptor (ER)-positive, node-negative early breast cancer. Dowsett et al also concluded that the PAM50 test was better able to distinguish between intermediate and higher-risk groups of patients.1
More than 20% of patients treated for ER-positive disease will experience recurrence within the first 10 years and, while chemotherapy is effective in managing these recurrences, it may be completely unnecessary in patients with a low-risk of recurrence.
Currently, the Oncotype DX 21-gene RS is widely used to determine the risk of recurrence in these patients. A similar score, IHC4, is derived from four immunohistochemically measured markers: ER, progesterone receptor, Ki67, and human epidermal growth factor receptor 2 (HER2). This study compared Oncotype DX and IHC4 with the PAM50 test.
Dowsett et al used mRNA from 1017 postmenopausal women with hormone receptor-positive primary breast cancer treated with either anastrozole or tamoxifen in the TransATAC trial and assessed these samples for the PAM50 ROR score.
The ROR score was compared with a clinical treatment score (CTS), consisting of prognostic information from nodal status, tumor size, histopathologic grade, age, and type of hormone therapy, as well as with the RS and IHC4 scores.
Comparisons were made for all patients and by four subgroups categorized as node-negative, node-positive, HER2-negative, and HER2-negative/ node negative. Findings were expressed as a likelihood ratio of added value, with any score over a likelihood ratio of 4 considered statistically significant.
The researchers found that the ROR used in conjunction with the CTS provides significantly more prognostic information than the CTS alone, expressed as a likelihood ratio of 33.9 (P <.001) for all patients. By comparison, the likelihood that RS plus CTS would add prognostic value versus CTS alone was 22.7 (P <.001).
For the IHC4 comparison, the sample size had to be split because of the algorithm used to compute IHC4 in the original sample set, leading to lower likelihood ratios for both the ROR and the RS for this part of the study. Nevertheless, the ROR had a comparable likelihood ratio of adding information to the CTS as did the IHC4 (27.6 vs 28.7), and a significantly higher ratio than IHC4 among patients whose tumors were HER2-negative/node-negative (22.4 vs 13.6). By contrast, the RS ratio across all patients was 17.6.
In addition, investigators felt the ROR shed more light on how to treat patients whose risk of recurrence scores were in the intermediate range.
“Our work indicates that the PAM50 ROR gives better separation of the high and intermediate risk patients than RS such that there are fewer in the group in which further management is uncertain,”said lead author Mitch Dowsett, PhD, head of the Academic Department of Biochemistry, professor of Biochemical Endocrinology, and professor of Translational Research at the Breakthrough Research Centre at Royal Marsden Hospital in London, England.
The researchers determined that the ROR score categorized fewer patients as intermediate risk and more as high risk when using cutoffs of <10%, 10% to 20%, and >20% to distinguish between low-, intermediate-, and high-risk patients, respectively.
Michael Gnant, MD
Department of Surgery
Medical University of Vienna
In another study, presented at the 2013 Annual Meeting of the American Society of Clinical Oncology, researchers found that patients with ER-positive disease with one or two positive nodes have a very limited long-term risk of developing recurrence and patients appropriately identified with PAM50 may be spared from unnecessary chemotherapy.2
A total of 2485 tissue samples and long-term follow-up data from postmenopausal, hormone receptor- positive patients from the ABCSG-8 (n = 1478) and TransATAC (n = 1007) trials were used, and the PAM50 test was conducted on RNA extracted from paraffin blocks with these samples.
The researchers found that ROR added statistically significant prognostic information about recurrence beyond the CTS. Using this information, they were able to determine that the median 10-year risk of distant recurrence in patients with one to three positive nodes was 7.9% (95% CI, 4.3%-14.1%) in patients who were identified as low risk by PAM50; 13.8% (95% CI, 9.2%-20.3%) in the intermediate group; and 29.9% (95% CI, 23.9%-37.1%) in the high-risk group.
“For most patients and clinicians, that is considered a reasonably low risk of metastases, so you could consider avoiding chemotherapy for them,” said Michael Gnant, MD, a professor in the Department of Surgery at the Medical University of Vienna in Austria and lead author of the study.
Gnant said that the study is important because patients with ER-positive disease represent the majority of breast cancer patients, and that this study represents the average patient and her recurrence risk.