Development of resistance to the antioestrogen tamoxifen occurs in a large proportion of patients with oestrogen receptor-positive (ER+) breast cancer and is an important clinical challenge. While loss of ER occurs in c.20\% of tamoxifen-resistant tumours, this cannot be the sole explanation for tamoxifen treatment failure. PI3K pathway activation, including by insulin-like growth factor receptor 1 (IGF1R), has been implicated in some resistance models. The primary aim was to determine whether evidence exists in clinical breast cancer for a role of IGF1R and/or the PI3K pathway, in acquisition of resistance to tamoxifen. Invasive primary and recurrent tamoxifen-resistant tumours from the same patient (n=77) were assessed for changes in ER, progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2), IGF1R, stathmin, PTEN expression and PIK3CA mutations where possible. ER and PgR levels were significantly reduced at recurrence with 22 and 45\%, respectively, showing negative status at this time. Acquisition of HER2 overexpression occurred in 6\% of cases. IGF1R expression was significantly reduced in both ER+ and ER- recurrences and stathmin levels increased. A positive association between stathmin and IGF1R emerged in recurrent samples, despite their opposing relationships with ER, suggesting some coalescence of their activities may be acquired. The data confirm loss of ER and PgR and gain of HER2 in some tamoxifen-resistant tumours. There is no evidence for IGF1R gain in tamoxifen resistance; increases in stathmin levels suggest that activation of the PI3K pathway may have contributed, but PTEN loss and PIK3CA hotspot mutations were relatively rare.

Changes in breast cancer biomarkers in the IGF1R/PI3K pathway in recurrent breast cancer after tamoxifen treatment.

MARCHIO', Caterina;
2011

Abstract

Development of resistance to the antioestrogen tamoxifen occurs in a large proportion of patients with oestrogen receptor-positive (ER+) breast cancer and is an important clinical challenge. While loss of ER occurs in c.20\% of tamoxifen-resistant tumours, this cannot be the sole explanation for tamoxifen treatment failure. PI3K pathway activation, including by insulin-like growth factor receptor 1 (IGF1R), has been implicated in some resistance models. The primary aim was to determine whether evidence exists in clinical breast cancer for a role of IGF1R and/or the PI3K pathway, in acquisition of resistance to tamoxifen. Invasive primary and recurrent tamoxifen-resistant tumours from the same patient (n=77) were assessed for changes in ER, progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2), IGF1R, stathmin, PTEN expression and PIK3CA mutations where possible. ER and PgR levels were significantly reduced at recurrence with 22 and 45\%, respectively, showing negative status at this time. Acquisition of HER2 overexpression occurred in 6\% of cases. IGF1R expression was significantly reduced in both ER+ and ER- recurrences and stathmin levels increased. A positive association between stathmin and IGF1R emerged in recurrent samples, despite their opposing relationships with ER, suggesting some coalescence of their activities may be acquired. The data confirm loss of ER and PgR and gain of HER2 in some tamoxifen-resistant tumours. There is no evidence for IGF1R gain in tamoxifen resistance; increases in stathmin levels suggest that activation of the PI3K pathway may have contributed, but PTEN loss and PIK3CA hotspot mutations were relatively rare.
18
5
565
577
http://dx.doi.org/10.1530/ERC-10-0046
Breast Neoplasms; blood/drug therapy/metabolism, Drug Resistance; Neoplasm, Epidermal Growth Factor; blood, Estrogen Antagonists; therapeutic use, Female, Humans, Immunohistochemistry, Middle Aged, Neoplasm Recurrence; Local; blood/metabolism, PTEN Phosphohydrolase; blood/metabolism, Phosphatidylinositol 3-Kinases; blood/metabolism, Receptor; IGF Type 1; blood/metabolism, Receptors; Estrogen; blood, Receptors; Progesterone; blood, Retrospective Studies, Stathmin; blood, Tamoxifen; therapeutic use, Tissue Array Analysis, Tumor Markers; Biological; blood
S. C. Drury;S. Detre;A. Leary;J. Salter;J. Reis-Filho;V. Barbashina;C. Marchio;E. Lopez-Knowles;Z. Ghazoui;K. Habben;S. Arbogast;S. Johnston;M. Dowsett
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/139808
Citazioni
  • ???jsp.display-item.citation.pmc??? 37
  • Scopus 69
  • ???jsp.display-item.citation.isi??? 66
social impact