Study Identifies Novel Breast Cancer Prognostic Markers


ATLANTA — New data suggest that the Notch signaling genes—Notch1 and Jagged1—are potential novel prognostic markers for breast cancer, Michael Reedijk, M.D., FACS, reported at a symposium sponsored by the Society of Surgical Oncology.

“Patients expressing high levels of Jagged1 or Notch1 demonstrated significantly poorer overall survival than patients expressing low levels,” said Dr. Reedijk of University Health Network, Princess Margaret Hospital in Toronto.

Abnormal Notch signaling has been observed in a number of malignancies, but this is the first report of direct evidence linking high-level Notch1 and Jagged1 expression with poorer outcomes in women with breast cancer.

The data also suggest a mechanism by which Notch is activated in aggressive breast cancer that may be targeted with drugs currently under development for Alzheimer's disease, Dr. Reedijk said.

Dr. Reedijk and colleagues at Toronto's Hospital for Sick Children and the University Health Network analyzed tumor samples from 184 breast cancers using in situ hybridization. One-third of the cancers were node-positive, one-third were node-negative, and one-third had metastasized at presentation. Notch2 was expressed at high levels in most tumors.

In contrast, high levels of Notch1,Jagged1, and Notch3 were found in the tumors of a subset of patients with poor prognostic pathological features.

Patients with tumors expressing high levels of these genes showed lower overall survival than those expressing low levels of these genes, although the association was not statistically significant for Notch3.

The 5-year survival rate for women expressing high levels of Jagged1 was 42%, with a median survival of 50 months, compared with 65% and 83 months for patients with low levels of Jagged1.

The 5-year survival rate was 49% for women expressing high levels of Notch1, with a median survival of 53 months, compared with 64% and 91 months for patients with low levels of Notch1, he said at the meeting.

For patients coexpressing high levels of both Jagged1 and Notch1, the 5-year survival rate and median survival time were approximately half of those seen for tumors without Jagged1 and/or Notch1 expression. The 5-year survival rate was just 34%, with a median survival of 43 months.

“This suggests that there is a ligand and receptor circuit that is functioning in these tumors and may identify a signaling pathway that can be therapeutically targeted using newly developed γ-secretase inhibitors, which block Notch signaling,” Dr. Reedijk said.

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