Vascular endothelial growth factor receptor 2 and downstream p38 mitogen-activated protein kinase are possible candidate markers of intrinsic resistance to adjuvant endocrine treatment in steroid receptor positive breast cancer.
A cross talk between tyrosine kinase receptors and mitogen-activated protein kinases (MAPKs) is proposed as involved in endocrine resistance. We wanted to investigate intratumoral levels of vascular endothelial growth factor receptor 2 (VEGFR2) and p38 MAPK in relation to relapse-free (RFS) and breast cancer corrected survival (BCCS) after adjuvant endocrine treatment, mainly tamoxifen for 2 or 5 years. We also wanted to investigate these markers in relation to early and late recurrences. VEGFR2 (n = 381) and p38 (n = 174) were determined by enzyme-linked immuno-sorbent assays in tumor homogenates from primary BC diagnosed 1993-1996. Wide ranges of VEGFR2 and p38 proteins were found; median 0.72 pg/μg DNA (range 0.0-11.66), and 0.04 pg/μg DNA (range 0.0-6.79), respectively. Detectable levels of p38 were registered in 65% and classified positive. Higher VEGFR2 were correlated to higher VEGF (P = 0.005), p38 MAPK (P = 0.018), negative ER (P = 0.008), larger tumors (P = 0.001), histopathological grade III (P = 0.018), distant metastasis (P = 0.044), shorter RFS (P = 0.013), and shorter BCCS (P = 0.017). Expression of p38 was significantly correlated with negative PgR (P = 0.044) and with early relapses (P = 0.021), while no difference was seen during the later follow-up period (P = 0.73). Higher VEGFR2 had a significant negative impact on both early (P = 0.029) and later recurrences (P = 0.018), while VEGF only predicted later relapses (P = 0.037). Our preliminary results suggest higher intratumoral levels of VEGFR2 and p38 MAPK as candidate markers of intrinsic resistance for adjuvant endocrine therapy.
Department of Oncology, Sahlgrenska University Hospital, 41345, Gothenburg, Sweden. barbro.linderholm@ki.se
Barbro K
BK
Linderholm
Henrik
H
Hellborg
Ulla
U
Johansson
Lambert
L
Skoog
Janne
J
Lehtiö
D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D019008:Drug Resistance, Neoplasm; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D009364:Neoplasm Recurrence, Local; D011379:Prognosis; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism*; D015398:Signal Transduction; D015996:Survival Rate; D013629:Tamoxifen / Q000627:therapeutic use*; D016896:Treatment Outcome; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D018931:Antineoplastic Agents, Hormonal; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D013629:Tamoxifen; D040301:Vascular Endothelial Growth Factor Receptor-2; D048051:p38 Mitogen-Activated Protein Kinases