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
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.