Circulating Protein Biomarkers a Boon to Breast Cancer Management

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HER-2 is an oncogene and a member of the human epidermal growth factor receptor (HER/EGFR/ERBB) family. Amplification or overexpression of HER-2 plays an important role in the development and progression of certain aggressive types of breast cancer.

Mary F. Lopez, Ph.D.

Immunoassays Are the Gold Standard for Measuring Soluble Breast-Cancer-Related Proteins

Breast cancer patients often display elevated levels of proteins in plasma or serum, and many of these proteins correlate to active or recurrent disease, metastasis, prognosis, and therapeutic response. Several of these markers have demonstrated clinical utility, particularly in the area of monitoring disease recurrence after or during therapeutic treatment in advanced disease.

The application of immunoassays to monitor levels of breast-cancer-related proteins in blood or serum is complementary to other diagnostics such as imaging and can be a valuable part of the routine management of disease. The availability of a group of easily applied blood tests is a convenient and powerful addition to the arsenal of technologies available to physicians for patient management. Immunoassays are available for serum-borne breast-cancer-related markers such as cancer antigen 15-3 (CA 15-3), carcinoembryonic antigen (CEA), tissue inhibitor of metalloproteinases-1 (TIMP-1), and human epidermal growth factor receptor 2 (HER2)—all of which are discussed in this article.


Clinical Utility Considered by Multiple Studies

While essential for diagnosis and typing, tissue testing during long-term breast cancer management is impractical, costly, and painful for patients. A growing number of studies support serum-based immunoassay testing to monitor drug response, disease progression, and potential for metastases.

In 2012, Tsai et al.1 studied serum levels of HER2 and TIMP-1 in 185 breast cancer patients in Taiwan. They concluded that TIMP-1 was significantly associated with serum HER2-positive status in circulation, as well as poorer disease-free survival—suggesting that monitoring both of these biomarkers may be beneficial.

In the same year, Kontani et al.2 reported that serum HER2 is a useful biomarker not only for detecting breast cancer recurrence but also for predicting tumor responses to trastuzumab. In 2014, Shao et al.3 found that elevated serum HER2 levels were significantly associated with short-term response to trastuzumab treatment. The median progression-free survival was significantly longer in patients with low levels of serum HER2. Furthermore, they found that over time patients with remaining low serum HER2 levels or those who achieved low serum HER2 levels after treatment had significantly longer progression-free survival than those whose levels remained high or converted from low to high.

In 2015, Di Gioia et al.4 reported that they had investigated the combination of CEA, CA 15-3, and serum HER2 in the pretherapeutic serum of 241 patients as biomarkers for prognosis in early breast cancer. Their retrospective analysis confirmed that serum HER-2 and CA15-3 (but not CEA) were independent and better prognostic tools than HER-2 in tissue. However, they concluded that prospective validation is necessary to confirm usefulness in routine clinical practice.

In a review published in 2015, Ravelli et al.5 discussed the advantages, drawbacks, and new insights with respect to measuring circulating breast-cancer-related biomarkers with immunoassays as compared to standard tissue-based biopsies. They suggested that a reliable panel of circulating cancer biomarkers would be helpful for the following tasks:

  1. Screening and diagnostic procedures
  2. Predicting prognosis
  3. Selecting therapeutic options, including experimental ones
  4. Detecting a lack of efficacy of an ongoing therapy and predicting side-effects
  5. Identifying recurrence

In this review, the authors emphasized “classic” markers such as CA 15-3, CEA, and serum HER2. With respect to CA 15-3 and CEA, the authors noted that they might be most useful in combination. “[More] reliable prediction power have been obtained with the combination of the two biomarkers, whereas when measured singularly, both sensitivity and specificity values were drastically decreased,” the authors wrote. “As a result, the association of the two markers may be a useful independent tool in the follow-up of [breast cancer] patients.”

In their discussion of HER2, the researchers pointed out that increased serum HER2 levels have been clearly associated with the tissue HER2 status, the presence and number of metastases, and the levels of CA 15-3 and CEA.


Utility Strongly Suggested by a Large Study

The review cited a 2014 study that reported how 2,862 primary breast cancer patients had been monitored to demonstrate the correlation between serum HER2 and tissue HER2 overexpression.6 This study showed that 15% of tissue-HER2-positive patients also had increased serum HER2 levels and that there was a linear correlation with the increased aggressiveness of tumors. Multivariate analysis confirmed that increased serum HER2 is an independent prognostic factor that can be clinically useful, particularly in patients with tissue-HER2-positive tumors.

The authors of the study concluded that measuring serum HER2 could help oncologists monitor patient response to trastuzumab in the absence of tissue HER2. They added that further clinical validation would be worthwhile.


Summary

Basic immunoassay technology has been in place since the 1950s and has become the gold standard for clinical protein measurement due to high sensitivity and selectivity.7 Growing evidence suggests that these reliable, robust tests can provide valuable insights for physicians managing breast cancer treatment.







































Mary F. Lopez, Ph.D., is chief operating officer and vice president of proteomics discovery at Nuclea Biotechnologies.

1 Tsai HP, Chen SC, Chien HT, Jan YY, Chao TC, Chen MF, Hsieh LL. Relationships between serum HER2 ECD, TIMP-1 and clinical outcomes in Taiwanese breast cancer. World J Surg Oncol. 2012;10:42-49.
2 Kontani K, Kuroda N, Hashimoto S, Murazawa C, Norimura S, tanaka H, Ohtani M, Fujiwara-Honjo N, Kushida Y, Date M, haba R, Houchi H, Yamauchi A, Yokomise H.  Clinical usefulness of human epidermal growth factor receptor-2 extracellular domain as a biomarker for monitoring cancer status and predicting the therapeutic efficacy in breast cancer. Cancer Biol Ther. 2013;14(1):20–28.
3 Shao X, Wang X, Xu X, Feng J, Han M, Zhang H, Chen ZH, Wang S, Zang YM, Huang P, Jin H, Wang X. Outcome prediction values of soluble human epidermal growth factor receptor-2 extracellular domain in metastatic breast cancer. Int J Clin Exp Pathol. 2014;7(3):1108-1113.
4 Di Gioia DD, Dresse M, Mayr D, Nagel D, Heinemann V, Stieber P. Serum HER2 in combination with CA15-3 as a parameter for prognosis in patients with early breast cancer. Clin Chim Acta. 2015;440:16-22.
5 Ravelli A, Reuben JM, Lanza F, Anfossi S, Capellati MR, Zanotti L, Gobbi A, Senti C, Brambilla P, Milani M, Spada D, Pedrazzoli P., martino M, Bottini A, Generali D. Breast cancer circulating biomarkers: advantages, drawbacks, and new insights. Tumour Biol. 2015. [Epub ahead of print]
6 Lee SB, Lee JW, Yu JH, Ko BS, Kim HJ, Son BH, Gong G, Lee HJ, Kim SB, Jung KH, Ahn JH, Lee W, Sung J, Ahn SH. Preoperative serum HER2 extracellular domain levels in primary invasive breast cancer. BMC Cancer. 2014;14:929-944.
7 en.wikipedia.org/wiki/Immunoassay

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