Researchers are currently investigating tissue inhibitor of metalloproteinases (TIMP) as potential biomarkers in a number of different diseases including cancer, cardiovascular disease, chronic lung disease and diabetes. TIMPs may be especially relevant as cancer biomarkers because they inhibit the activity of matrix metalloproteinases (MMPs), which play a role in tumor invasion and metastasis. Many studies have shown that serum levels of TIMP proteins are elevated in cancers, including breast and colorectal cancer.

A research group led by Hsiu-Pei Tsai1 investigated the relationship between TIMP-1 serum levels, the HER2 extracellular domain (HER2 ECD) and clinical outcomes in Taiwanese breast cancer patients. Tissue-based HER2 testing is a well-validated diagnostic and prognostic biomarker in breast cancer. HER2 ECD is produced when the extracellular domain of HER2 is shed into serum. Broad-spectrum metalloproteases such as TIMP-1 inhibit extracellular domain shedding.

Tsai and the research team selected 185 breast cancer patients who had received a curative mastectomy without prior chemotherapy. This group also had high levels of HER2 overexpression. A group of 23 women without breast cancer were recruited as normal controls. The team retrospectively collected clinical and pathological information for all subjects.

Researchers analysed the levels of HER ECD and TIMP-1 in pre-operative blood samples, as well as levels of TIMP-2, MMP-2 and MMP-9.

  • Of the 185 patients in the breast cancer cohort, 23 (12.4%) were HER2 ECD-positive.
  • Patients who were HER2 ECD-positive had a shorter disease-free survival and overall survival when compared to patients who were HER2 ECD-negative.
  • Serum levels of TIMP-1 were significantly higher in HER2 ECD-positive patients compared to HER2 ECD-negative patients after correcting for various factors such as age, stage, ER and HER2/neu status.
  • There were no differences in MMP-1, MMP-9 and TIMP-2 serum levels between HER2 ECD-positive and -negative patients.
  • Low TIMP-1 serum levels were related to a better disease-free survival. The effect of serum TIMP-1 on overall survival was not significant, but the combined effect of serum TIMP-1 levels with HER2 ECD was significant.
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The study concludes that TIMP-1 serum levels are significantly associated with HER2 ECD-positivity and poorer disease-free survival among Taiwanese primary breast cancer patients with HER2 overexpression. Combined analysis of both serum TIMP-1 and HER2 ECD may have value for clinical management of breast cancer patients with HER2 overexpression. While these results are promising, more work is required to determine if TIMP-1 and HER2 ECD will be useful prognostic biomarkers in the long run.

While TIMP-1 may not be a strong biomarker alone, it may have greater utility when combined with other biomarkers. This was demonstrated in a recent prospective validation study of TIMP-1 and CEA as biomarkers to detect primary colorectal cancer.2 The researchers concluded that the sensitivities and specificities in this study were not sufficient to warrant the use of plasma TIMP-1 and CEA as a screening test for colorectal cancer. However, like TIMP-1 and HER2 ECD in breast cancer, plasma TIMP-1 and CEA in colorectal cancer are easy to measure and may provide supplemental information when combined with other biomarkers.

References

  1. Tsai HP, Chen SC, Chien HT, et al. Relationships between serum HER2 ECD, TIMP-1 and clinical outcomes in Taiwanese breast cancer. World J Surg Oncol. 2012 Feb 17;10:42. doi: 10.1186/1477-7819-10-42.
  2. Christensen IJ, Brünner N, Dowell B, et al. Plasma TIMP-1 and CEA as Markers for Detection of Primary Colorectal Cancer: A Prospective Validation Study Including Symptomatic and Non-symptomatic Individuals. Anticancer Res. 2015 Sep;35(9):4935-41.