St Gallen molecular subtypes in feline mammary carcinoma and paired metastases—disease progression and clinical implications from a 3-year follow-up study
- 253 Downloads
Considering that scarce data are available on disease progression of feline mammary carcinoma (FMC), this study aimed to analyze the clinical, pathological, and immunophenotypic features collected from 61 queens with FMC and to compare the concordance ratios of the expression levels of five molecular markers (ER, PR, fHER2, CK5/6, and Ki-67) between primary tumors (PT) and metastatic lesions. The results showed that cats with luminal A mammary carcinomas (MC) had higher overall survival (924.6 days, p = 0.001) and longer disease-free period (385.4 days, p = 0.005) compared to the ones with other MC subtypes. In fact, queens with triple negative/basal-like MC showed the lowest survival (mean 156.2 days) and the shortest disease-free survival (mean 28 days) among the molecular subtypes of MC. The lung was the organ most frequently affected by metastases, and animals with lung and/or pleural metastases were more likely to display metastases at three or more locations (p = 0.039). A large heterogeneity in protein expression levels was found between PT and paired metastases, with both estrogen and progesterone receptors more likely to be downregulated in metastases. Paired metastases frequently had higher Ki-67 index than PT, whereas fHER2 overexpression was seen in 46 samples (30 %) and CK5/6 expression was found in 50.7 % of metastases (36/71). Results also revealed that disease progression leads to a high percentage of triple negative/basal-like metastases (9/23; 39.1 %) associated with the absence of luminal A subtype in distant metastases (0/23). This study highlights the prognostic importance of immunophenotyping of MC in cats, although the modified protein expression identified in metastases contributes to justify why possible targeted therapies may fail in some animals with metastatic disease. Altogether, the results obtained also demonstrate that FMC can be used as a model to study human breast cancer.
KeywordsFeline mammary carcinoma Metastatic disease Molecular classification Prognostic biomarkers
This study was supported by “Fundação para a Ciência e Tecnologia” (FCT) through the project CIISA/UID/CVT/00276/2013 and the PhD fellowship (SFRH/BD/70720/2010). The authors would like to thank João Matos and José Cabeçadas (MD) from Instituto Português de Oncologia de Lisboa (IPO); Manuel Mestre (DVM), Ana Mota (DVM, MSc) and Tiago Rafael (DVM, MSc) from the Clínica Veterinária Zoomédica; Mafalda Lage (DVM, MSc) from the Clínica Veterinária Villa Animal; Rafaela Lalanda (DVM, MSc) and Miguel Caninhas (DVM) from the Clínica Veterinária Mvet; Verónica Azevedo (DVM, MSc) from the Hospital Sul do Tejo; and António Ferreira (DVM, PhD), Ana Murta (DVM, MSc) and Rodrigo Bom (DVM) from the Small Animal Hospital from the Faculty of Veterinary Medicine at the University of Lisbon, for the clinical follow-up. We would also like to thank Margarida Simões (DVM, MSc) and Shabir Najmudin (DSc, PhD) from the Faculty of Veterinary Medicine at the University of Lisbon for English language editing.
Compliance with ethical standards
Tumor samples were collected in accordance with the EU Directive 2010/63/EU, and research was approved by the ethics committee of the Faculty of Veterinary Medicine (FVM), University of Lisbon (ULisboa).
Conflicts of interest
- 9.Aurilio G, Disalvatore D, Pruneri G, Bagnardi V, Viale G, Curigliano G, et al. A meta-analysis of oestrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 discordance between primary breast cancer and metastases. Eur J Cancer. 2014;50:277–89.CrossRefPubMedGoogle Scholar
- 12.Falck AK, Fernö M, Bendahl PO, Rydén L. St Gallen molecular subtypes in primary breast cancer and matched lymph node metastases—aspects on distribution and prognosis for patients with luminal A tumours : results from a prospective randomised trial. BMC Cancer. 2013;13:558.CrossRefPubMedPubMedCentralGoogle Scholar
- 20.Soares M, Correia J, Rodrigues P, Simões M, de Matos A, Ferreira F. Feline HER2 protein expression levels and gene status in feline mammary carcinoma: optimization of immunohistochemistry (IHC) and in situ hybridization (ISH) techniques. Microscopy Microanalysis. 2013;19:1–7.Google Scholar
- 25.Elston CW, Ellis IO. Assessment of histological grade. In: Rosen’s breast pathology. Philadelphia: Lippincott-Raven; 1998. p. 365–82.Google Scholar
- 26.Misdorp W. Tumors of the mammary gland. In: Tumors in Domestic Animals. Fourth Ed. Meuten DJ editor, Iowa: 2002. pp. 575–606.Google Scholar
- 27.Mills SW, Musil KM, Davies JL, Hendrick S, Duncan C, Jackson ML, Kidney B, Philibert H, Wobeser BK, Simko E. Prognostic value of histologic grading for feline mammary carcinoma: a retrospective survival analysis. Vet Pathol. 2014; 1–12.Google Scholar
- 30.Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol. 2013;31:3997–4014.CrossRefPubMedGoogle Scholar
- 34.Soares M, Ribeiro R, Carvalho S, Peleteiro M, Correia J, Ferreira F. Ki-67 as a Prognostic Factor in Feline Mammary carcinoma: what is the optimal cutoff value? Veterinary Pathology. 2015.Google Scholar
- 35.Goldhirsch A, Winer EP, Coates AS, Gelber RD, Piccart-Gebnart M, Thürlimann B, et al. Panel members. Personalizing the treatment of women with early breast cancer: highlights of the St Gallen international expert consensus on the primary therapy of early breast cancer. Ann Oncol. 2013;24:2206–23.CrossRefPubMedPubMedCentralGoogle Scholar
- 39.Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer (unabridged version). Arch Pathol Lab Med. 2010;134:48–72.Google Scholar
- 46.Joensuu K, Leidenius M, Kero M, Andersson LC, Horwitz KB, Heikkilä P. ER, PR, HER2, Ki-67 and Ck5 in early and late relapsing breast cancer—reduced CK 5 expression in metastases. Breast Cancer: Basic Clin Res. 2013;7:23–34.Google Scholar