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Ellegård, S., Veenstra, C., Pérez-Tenorio, G., Fagerström, V., Garsjo, J., Gert, K., . . . Stål, O. (2019). ERBB2 and PTPN2 gene copy numbers as prognostic factors in HER2-positive metastatic breast cancer treated with trastuzumab. Oncology Letters, 17(3), 3371-3381
Open this publication in new window or tab >>ERBB2 and PTPN2 gene copy numbers as prognostic factors in HER2-positive metastatic breast cancer treated with trastuzumab
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2019 (English)In: Oncology Letters, ISSN 1792-1074, E-ISSN 1792-1082, Vol. 17, no 3, p. 3371-3381Article in journal (Refereed) Published
Abstract [en]

Trastuzumab has markedly improved the treatment and long-term prognosis of patients with HER2-positive breast cancer. A frequent clinical challenge in patients with relapsing and/or metastatic disease is de novo or acquired trastuzumab resistance, and to date no predictive biomarkers for palliative trastuzumab have been established. In the present study, the prognostic values of factors involved in the HER2-associated PI3K/Akt signalling pathway were explored. The first 46 consecutive patients treated at the Department of Oncology, Linkoping University Hospital between 2000 and 2007 with trastuzumab for HER2-positive metastatic breast cancer were retrospectively included. The gene copy number variation and protein expression of several components of the PI3K/Akt pathway were assessed in the tumour tissue and biopsy samples using droplet digital polymerase chain reaction and immunohistochemistry. Patients with tumours displaying a high-grade ERBB2 (HER2) amplification level of amp;gt;= 6 copies had a significantly improved overall survival hazard ratio [(HR)=0.4; 95%, confidence interval (CI): 0.2-0.9] and progression-free survival (HR=0.3; 95% CI: 0.1-0.7) compared with patients with tumours harbouring fewer ERBB2 copies. High-grade ERBB2 amplification was significantly associated with the development of central nervous system metastases during palliative treatment. Copy gain (amp;gt;= 3 copies) of the gene encoding the tyrosine phosphatase PTPN2 was associated with a shorter overall survival (HR=2.0; 95% CI: 1.0-4.0) and shorter progression-free survival (HR=2.1; 95% CI: 1.0-4.1). In conclusion, high ERBB2 amplification level is a potential positive prognostic factor in trastuzumab-treated HER2-positive metastatic breast cancer, whereas PTPN2 gain is a potential negative prognostic factor. Further studies are warranted on the role of PTPN2 in HER2 signalling.

Place, publisher, year, edition, pages
Athens, Greece: Spandidos Publications, 2019
Keywords
HER2; brain metastasis; protein tyrosine phosphatase non-receptor type 2; ribosomal protein S6 kinase B1; PI3K; phosphatase and tensin homolog
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-155540 (URN)10.3892/ol.2019.9998 (DOI)000460555900098 ()30867772 (PubMedID)2-s2.0-85062153648 (Scopus ID)
Note

Funding Agencies|Swedish Cancer Society [17-0479]; Medical Research Council of Southeast Sweden [FORSS-757671]; ALF Grants Region Ostergotland [LIO-795201]; Stiftelsen Onkologiska Klinikernas Forskningsfond i Linkoping [2016-06-21]

Available from: 2019-03-20 Created: 2019-03-20 Last updated: 2019-08-27Bibliographically approved
Veenstra, C., Perez-Tenorio, G., Stelling, A., Karlsson, E., Mirwani Mirwani, S., Nordenskjöld, B., . . . Stål, O. (2016). Met and its ligand HGF are associated with clinical outcome in breast cancer. OncoTarget, 7(24), 37145-37159
Open this publication in new window or tab >>Met and its ligand HGF are associated with clinical outcome in breast cancer
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2016 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 24, p. 37145-37159Article in journal (Refereed) Published
Abstract [en]

Few biomarkers exist to predict radiotherapy response in breast cancer. In vitro studies suggest a role for Met and its ligand HGF. To study this suggested role, MET and HGF gene copy numbers were determined by droplet digital PCR in tumours from 205 pre-menopausal and 184 post-menopausal patients, both cohorts randomised to receive either chemo-or radiotherapy. MET amplification was found in 8% of the patients in both cohorts and HGF amplification in 7% and 6% of the patients in the pre-and post-menopausal cohort, respectively. Met, phosphorylated Met (pMet), and HGF protein expression was determined by immunohistochemistry in the premenopausal cohort. Met, pMet, and HGF was expressed in 33%, 53%, and 49% of the tumours, respectively. MET amplification was associated with increased risk of distant recurrence for patients receiving chemotherapy. For the pre-menopausal patients, expression of cytoplasmic pMet and HGF significantly predicted benefit from radiotherapy in terms of loco-regional recurrence. Similar trends were seen for MET and HGF copy gain. In the post-menopausal cohort, no significant association of benefit from radiotherapy with neither genes nor proteins was found. The present results do not support that inhibition of Met prior to radiotherapy would be favourable for pre-menopausal breast cancer, as previously suggested.

Place, publisher, year, edition, pages
IMPACT JOURNALS LLC, 2016
Keywords
radiation; copy number variation; droplet digital PCR; triple-negative breast cancer; radiotherapy
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-130130 (URN)10.18632/oncotarget.9268 (DOI)000377756800127 ()27175600 (PubMedID)
Note

Funding Agencies|Swedish Cancer Society; Swedish Research Council; LiU Cancer Foundation

Available from: 2016-07-12 Created: 2016-07-11 Last updated: 2019-06-28
Karlsson, E., Veenstra, C., Emin, S., Dutta, C., Perez-Tenorio, G., Nordenskjöld, B., . . . Stål, O. (2015). Loss of protein tyrosine phosphatase, non-receptor type 2 is associated with activation of AKT and tamoxifen resistance in breast cancer. Breast Cancer Research and Treatment, 153(1), 31-40
Open this publication in new window or tab >>Loss of protein tyrosine phosphatase, non-receptor type 2 is associated with activation of AKT and tamoxifen resistance in breast cancer
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2015 (English)In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 153, no 1, p. 31-40Article in journal (Refereed) Published
Abstract [en]

Breast cancer is a heterogeneous disease and new clinical markers are needed to individualise disease management and therapy further. Alterations in the PI3K/AKT pathway, mainly PIK3CA mutations, have been shown frequently especially in the luminal breast cancer subtypes, suggesting a cross-talk between ER and PI3K/AKT. Aberrant PI3K/AKT signalling has been connected to poor response to anti-oestrogen therapies. In vitro studies have shown protein tyrosine phosphatase, non-receptor type 2 (PTPN2) as a previously unknown negative regulator of the PI3K/AKT pathway. Here, we evaluate possible genomic alterations in the PTPN2 gene and its potential as a new prognostic and treatment predictive marker for endocrine therapy benefit in breast cancer. PTPN2 gene copy number was assessed by real-time PCR in 215 tumour samples from a treatment randomised study consisting of postmenopausal patients diagnosed with stage II breast cancer 1976-1990. Corresponding mRNA expression levels of PTPN2 were evaluated in 86 available samples by the same methodology. Gene copy loss of PTPN2 was detected in 16 % (34/215) of the tumours and this was significantly correlated with lower levels of PTPN2 mRNA. PTPN2 gene loss and lower mRNA levels were associated with activation of AKT and a poor prognosis. Furthermore, PTPN2 gene loss was a significant predictive marker of poor benefit from tamoxifen treatment. In conclusion, genomic loss of PTPN2 may be a previously unknown mechanism of PI3K/AKT upregulation in breast cancer. PTPN2 status is a potential new clinical marker of endocrine treatment benefit which could guide further individualised therapies in breast cancer.

Place, publisher, year, edition, pages
Springer Verlag (Germany), 2015
Keywords
18p; AKT; Breast cancer; Endocrine resistance; Phosphatases; PTPN2
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-121133 (URN)10.1007/s10549-015-3516-y (DOI)000359775100005 ()26208487 (PubMedID)
Note

Funding Agencies|Swedish Cancer Society [13 0435]; Swedish Research Council [A0346701]

Available from: 2015-09-08 Created: 2015-09-08 Last updated: 2019-06-28
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-3084-7881

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