Anatomic Pathology: Breast Pathology

• Oncotype DX and MammaPrint are prognostic and predictive tests for invasive breast carcinoma. These tests provide risk assessment of distant recurrence that is independent of the classic clinicopathologic parameters used to evaluate breast cancer (size, lymph node status, and grade); however, the classic clinicopathologic parameters still contain prognostic information.

• Oncotype DX is based on a 21-gene signature (16 cancer-related genes and 5 reference/controls). It is a quantitative reverse transcriptase polymerase chain reaction–based test performed on formalin-fixed paraffin-embedded tissue. It typically is performed on node-negative, estrogen receptor–positive invasive carcinoma. A recurrence score is generated that predicts the risk for distant relapse in 10 years for patients on tamoxifen therapy. The recurrence score may range from 0 to 100. A low recurrence score (<18) is associated with an estimated 7% risk of distant relapse in 10 years. An intermediate recurrence score (18 to 31) is associated with an average 14% risk of distant relapse in 10 years. A high recurrence score (≥31) is associated with a 30% risk of distant relapse rate in 10 years.

• MammaPrint is based on a 70-gene signature providing a dichotomous output: high risk and low risk. The high-risk category is associated with a 22% risk of distant metastasis in 5 years (30% in 10 years), and the low-risk category is associated with a 7% risk of distant metastasis in 5 years (10% in 10 years). MammaPrint was originally approved by the U.S. Food and Drug Administration as a test on frozen tissue only, but it has become available more recently on formalin-fixed paraffin-embedded tissue. MammaPrint is offered on node-negative invasive tumors less than 5 cm that are either estrogen receptor positive or negative; however, it has limited discriminatory capacity in estrogen receptor–negative cancers because greater than 95% of estrogen receptor–negative cases are classified as high risk.

• Both Oncotype DX and MammaPrint are predictive tests. The test results suggest that the high-risk group benefits from chemotherapy and that the low-risk group does not (if they are both treated with adjuvant tamoxifen). This suggestion is in keeping with the observation that the high-risk group is highly proliferating, and it is this group that benefits from chemotherapy.

• In the case of Oncotype DX, an ongoing trial (TAILORx) is evaluating the role of chemotherapy in the intermediate-risk group. For MammaPrint, the MINDACT trial is comparing the outcome of patients treated with or without chemotherapy in cases of discordance of risk categorization between MammaPrint and traditional clinicopathologic criteria.

• Oncotype DX has been primarily applied to lymph node–negative cancers, but it is also prognostic in lymph node–positive disease. However, in disease with greater than three positive lymph nodes, the low-risk category absolute risk of distant recurrence is too high to avoid chemotherapy. Oncotype DX has limited utility in chemotherapy predictiveness in this setting (it has been suggested that Oncotype DX and MammaPrint have utility in predictive testing for chemotherapy in cancers with one to three positive lymph nodes).

• Some data suggest that the prognostic information offered by these tests may be limited if one integrates clinicopathologic parameters with immunohistochemistry-based determination of estrogen receptor, progesterone receptor, Ki-67, and HER2.