The 21-gene assay is routinely used to provide information regarding prognosis for early estrogen receptor-positive HER2-negative breast cancer in female patients. However, no tumor samples from male patients with breast cancer were included in the development of the signature, and no studies to assess its validity in these patients are in the works.

Researchers conducted a systematic review and meta-analysis of studies to compare the genetic signature results from female patients with breast cancer with those from male patients with breast cancer. Their findings were published in The Breast.

The researchers analyzed 6 studies with a total of approximately 176,000 patients with breast cancer, 99% of whom were female. Male patients with breast cancer were more likely to have nodal involvement, grade 3 disease, and later tumor stage.

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Mean 21-gene expression assay score for male patients with breast cancer was only available from 1 of the 6 studies, and it was 18.8 compared with a mean score of 13.4 for the female patients. (A score of less than 18 is considered low risk, a score of 18 to 30 is classified as intermediate risk, and a score higher than 30 is high risk.)

The researchers reported that high-risk 21-gene assay scores were increased among male patients compared with female patients, nothing that scores higher than 30 occurred in 22.4% vs 18.3%, respectively.

Using data from just 3 of the studies, the researchers found the difference in 21-gene assay scores between female and male patients was nonsignificant. The scores from female patients fell into the risk categories along similar lines as the scores from male patients.

The results from this analysis suggest results are similar regardless of gender, despite the genetic signature being validated with breast cancer samples only from female patients, the researchers noted.

However, they cautioned against extrapolating from this, noting that breast cancer in male patients tends to be associated with more advance tumor staging and grade. Further validation of the assay is necessary before it can be used routinely in the multidisciplinary management of breast cancer in male patients.

The researchers pointed to the retrospective nature of the studies included in their analysis as one limitation. “In the absence of stage matching for male and female breast cancer, it proves difficult to provide relevant conclusion with respect to 21-gene assay scores,” they concluded. These results also are limited by potential biases regarding selection of patients to undergo 21-gene assay testing.


Davey MG, Davey CM, Bouz L, et al. Relevance of the 21-gene expression assay in male breast cancer: a systematic review and meta-analysis. Breast. 2022;64:41-46. doi:10.1016/j.breast.2022.04.009