Case Series

Paradox CA 15–3 increase in metastatic breast cancer patients treated with everolimus: a change of paradigm in a case series

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E-mail Address: armando.orlandi@unicatt.it

Unit of Clinical Oncology, Università Cattolica del Sacro Cuore, L.go F. Vito 1, 00168 Rome, Italy

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Carmela Di Dio

Unit of Clinical Oncology, Università Cattolica del Sacro Cuore, L.go F. Vito 1, 00168 Rome, Italy

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Maria Alessandra Calegari

Unit of Clinical Oncology, Università Cattolica del Sacro Cuore, L.go F. Vito 1, 00168 Rome, Italy

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Carlo Barone

Unit of Clinical Oncology, Università Cattolica del Sacro Cuore, L.go F. Vito 1, 00168 Rome, Italy

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Published Online:13 Oct 2016https://doi.org/10.2217/bmm-2016-0142

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Abstract

Everolimus and exemestane represent a standard treatment for metastatic hormone receptor-positive/HER2-negative advanced breast cancer resistant to aromatase inhibitors. CA 15–3 serum levels detect soluble forms of MUC-1, a transmembrane oncoprotein aberrantly overexpressed in breast cancers. In clinical practice, CA 15–3 may be used to indicate treatment failure in the absence of readily measurable disease during cytotoxic therapy. In the targeted therapy era, it is important to note that the C-terminal subunit of MUC-1 interacts with PI3K/AKT pathway, inducting cell growth. Vice versa, the block of this pathway may influence MUC-1 expression and CA 15–3 serum levels. In this report, we emphasize the equivocal role of CA 15–3 serum levels in monitoring treatment with everolimus, suggesting a potential and intriguing role of a CA 15–3 increase as paradox predictive biomarker of response to everolimus.

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Papers of special note have been highlighted as: • of interest; •• of considerable interest

References

1 Baselga J, Campone M, Piccart M et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N. Engl. J. Med. 366(6), 520–529 (2012). •• This is the pivotal trial of everolimus plus exemestane in metastatic breast cancer patients.
Medline CASGoogle Scholar
2 Hortobagyi GN, Chen D, Piccart M et al. Correlative analysis of genetic alterations and everolimus benefit in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: results from BOLERO-2. J. Clin. Oncol. 34(5), 419–426 (2016).
Medline CASGoogle Scholar
3 Harris L, Fritsche H, Mennel R et al. American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J. Clin. Oncol. 25, 5287–5312 (2007).
Medline CASGoogle Scholar
4 Van Poznak C, Somerfield MR, Bast RC et al. Use of biomarkers to guide decisions on systemic therapy for women with metastatic breast cancer: American Society of Clinical Oncology Clinical Practice Guideline. J. Clin. Oncol. 33(24), 2695–2704 (2015). • This is the last update of American Society of Clinical Oncology practice guideline about the use of biomarkers in metastatic breast cancer treatment.
Medline CASGoogle Scholar
5 Willemsen AE, Grutters JC, Gerritsen WR, Tol J, van Herpen CM. Caution for interstitial lung disease as a cause of CA 15–3 rise in advanced breast cancer patients treated with everolimus. Int. J. Cancer 135(4), 1007 (2014). •• Reports a confounding cancer antigen 15–3 increase during treatment with everolimus due to interstitial lung adverse event.
Medline CASGoogle Scholar
6 Duffy MJ, Duggan C, Keane R et al. High preoperative CA 15–3 concentrations predict adverse outcome in node-negative and node-positive breast cancer: study of 600 patients with histologically confirmed breast cancer. Clin. Chem. 50(3), 559–563 (2004).
Medline CASGoogle Scholar
7 Kurebayashi J, Nishimura R, Tanaka K et al. Significance of serum tumour markers in monitoring advanced breast cancer patients treated with systemic therapy: a prospective study. Breast Cancer 11(4), 389–395 (2004).
MedlineGoogle Scholar
8 Duffy MJ. Serum tumour markers in breast cancer: are they of clinical value? Clin. Chem. 52(3), 345–351 (2006).
Medline CASGoogle Scholar
9 Yonemori K, Katsumata N, Noda A et al. Development and verification of a prediction model using serum tumor markers to predict the response to chemotherapy of patients with metastatic or recurrent breast cancer. J. Cancer Res. Clin. Oncol. 134(11), 1199–1206 (2008).
Medline CASGoogle Scholar
10 Duffy MJ, Walsh S, McDermott EW, Crown J. Biomarkers in breast cancer: where are we and where are we going? Adv. Clin. Chem. 71, 1–23 (2008).
Google Scholar
11 Wu SC, Chou FF, Rau KM. Clinical significance of a serum CA 15–3 surge and the usefulness of CA 15–3 kinetics in monitoring chemotherapy response in patients with metastatic breast cancer. Breast Cancer Res. Treat. 124(3), 879–882 (2010).
MedlineGoogle Scholar
12 Duffy MJ, Evoy D, McDermott EW. CA 15–3: uses and limitation as a biomarker for breast cancer. Clin. Chim. Acta 411(23–24), 1869–1874 (2010).
Medline CASGoogle Scholar
13 Di Gioia D, Heinemann V, Nagel D et al. Kinetics of CEA and CA15–3 correlate with treatment response in patients undergoing chemotherapy for metastatic breast cancer (MBC). Tumor Biol. 32(4), 777–785 (2011).
Medline CASGoogle Scholar
14 Duffy MJ. Tumor markers in clinical practice: a review focusing on common solid cancers. Med. Princ. Pract. 22, 4–11 (2013).
MedlineGoogle Scholar
15 Eisenhauer EA, Therasse P, Bogaerts J et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur. J. Cancer 45(2), 228–247 (2009).
Medline CASGoogle Scholar
16 Kim JH. Comparison of the RECIST 1.0 and RECIST 1.1 in patients treated with targeted agents: a pooled analysis and review. Oncotarget 7(12), 13680–13687 (2016).
MedlineGoogle Scholar
17 Gendler SJ, Spicer AP, Lalani EN et al. Structure and biology of a carcinoma-associated mucin, MUC1. Am. Rev. Respir. Dis. 144, S42–S44 (1991).
Medline CASGoogle Scholar
18 Duffy MJ. Biochemical markers in breast cancer: which ones are clinically useful? Clin. Biochem. 34, 347–352 (2001).
Medline CASGoogle Scholar
19 Li Y, Liu D, Chen D, Kharbanda S, Kufe D. Human DF3/MUC1 carcinoma-associated protein functions as an oncogene. Oncogene 22, 6107–6110 (2003).
Medline CASGoogle Scholar
20 Ramasamy S, Duraisamy S, Barbashov S, Kawano T, Kharbanda S, Kufe D. The MUC1 and galectin-3 oncoproteins function in a microRNA-dependent regulatory loop. Mol. Cell 27, 992–1004 (2007).
Medline CASGoogle Scholar
21 Hattrup CL, Gendler SJ. Structure and function of the cell surface (tethered) mucins. Annu. Rev. Physiol. 70, 431–457 (2008).
Medline CASGoogle Scholar
22 Kufe D. Targeting the MUC1 oncoprotein: a tale of two proteins. Cancer Biol Ther. 7, 81–84 (2008).
Medline CASGoogle Scholar
23 Hattrup CL, Gendler SJ. Structure and function of the cell surface (tethered) mucins. Annu. Rev. Physiol. 70, 431–457 (2008).
Medline CASGoogle Scholar
24 Kufe D. Functional targeting of the MUC1 oncogen in human cancers. Cancer Biol. Ther. 8, 1199–1205 (2009).
Google Scholar
25 Schroeder JA, Masri AA, Adriance MC et al. MUC1 overexpression results in mammary gland tumorigenesis and prolonged alveolar differentiation. Oncogene 23, 5739–5747 (2004).
Medline CASGoogle Scholar
26 Kufe DW. Mucins in cancer: function, prognosis and therapy. Nat. Rev. Cancer 9, 874–885 (2009).
Medline CASGoogle Scholar
27 Schroeder J, Thompson M, Gardner M, Gendler S. Transgenic MUC1 interacts with epidermal growth factor receptor and correlates with mitogen-activated protein kinase activation in the mouse mammary gland. J. Biol. Chem. 276, 13057–13064 (2001).
Medline CASGoogle Scholar
28 Raina D, Kharbanda S, Kufe D. The MUC1 oncoprotein activates the anti-apoptotic PI3K/Akt and Bcl-xL pathways in rat 3Y1 fibroblasts. J. Biol. Chem. 279, 20607–20612 (2004).
Medline CASGoogle Scholar
29 Pochampalli MR, el Bejjani RM, Schroeder JA. MUC1 is a novel regulator of ErbB1 receptor trafficking. Oncogene 26, 1693–1701 (2007).
Medline CASGoogle Scholar
30 Agata N, Ahmad R, Kawano T, Raina D, Kharbanda S, Kufe D. MUC1 oncoprotein blocks death receptor-mediated apoptosis by inhibiting recruitment of caspase-8. Cancer Res. 68, 6136–6144 (2008).
Medline CASGoogle Scholar
31 Raina D, Kosugi M, Ahmad R et al. Dependence on the MUC1-C oncoprotein in non-small cell lung cancer cells. Mol. Cancer Therap. 10, 806–816 (2011).
Medline CASGoogle Scholar
32 Efeyan A, Sabatini DM. mTOR and cancer: many loops in one pathway. Curr. Opin. Cell Biol. 22, 169–176 (2010).
Medline CASGoogle Scholar
33 Jin C, Rajabi H, Rodrigo CM, Porco JA Jr, Kufe D. Targeting the eIF4A RNA helicase blocks translation of the MUC1-C oncoprotein. Oncogene 32, 2179–2188 (2013). •• Shows the relationship between C-terminal mucin 1 and the PI3K/AKT/mTOR pathway.
Medline CASGoogle Scholar
34 Burgio SL, Conteduca V, Rudnas B et al. PSA flare with abiraterone in patients with metastatic castration-resistant prostate cancer. Clin. Genitourin. Cancer 13, 39–43 (2015).
MedlineGoogle Scholar
35 Mundle SD, Marathe AS, Chelladurai M. Transient therapy-related surge in serum tumor biomarkers: characterizing behavior and postulating its biologic role. Crit. Rev. Oncol. Hematol. 86, 15–22 (2013).
MedlineGoogle Scholar

Vol. 10, No. 11

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Published online 13 October 2016

Published in print November 2016

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Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

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