title: Biological effects of fulvestrant on estrogen receptor positive human breast cancer: short, medium and long-term effects based on sequential biopsies.
abstract: We report the first study of the biological effect of fulvestrant on ER positive clinical breast cancer using sequential biopsies through to progression. Thirty-two locally/systemically advanced breast cancers treated with first-line fulvestrant (250 mg/month) were biopsied at therapy initiation, 6 weeks, 6 months and progression and immunohistochemically-analyzed for Ki67, ER, EGFR and HER2 expression/signaling activity. This series showed good fulvestrant responses (duration of response [DoR] = 25.8 months; clinical benefit = 81%). Ki67 fell (p < 0.001) in 79% of tumours by 6 months and lower Ki67 at all preprogression time-points predicted for longer DoR. ER and PR significantly decreased in all tumours by 6 months (p < 0.001), with some declines in ER (serine 118) phosphorylation and Bcl-2 (p = 0.007). There were modest HER2 increases (p = 0.034, 29% tumours) and loss of any detectable EGFR phosphorylation (p = 0.024, 50% tumours) and MAP kinase (ERK1/2) phosphorylation (p = 0.019, 65% tumours) by 6 months. While ER remained low, there was some recovery of Ki67, Bcl-2 and (weakly) EGFR/MAPK activity in 45-67% patients at progression. Fulvestrant's anti-proliferative impact is related to DoR, but while commonly downregulating ER and indicators of its signaling and depleting EGFR/MAPK signaling in some patients, additional elements must determine response duration. Residual ER at fulvestrant relapse explains reported sensitivity to further endocrine therapies. Occasional modest treatment-induced HER2 and weakly detectable EGFR/HER2/MAPK signaling at relapse suggests targeting of such activity might have value alongside fulvestrant in some patients. However, unknown pathways must drive relapse in most. Ki67 has biomarker potential to predict fulvestrant outcome and as a quantitative measure of response.
authors.affiliation: Division of Breast Surgery, School of Graduate Entry Medicine and Health, Royal Derby Hospital, University of Nottingham, Derby, DE22 3DT, United Kingdom.|Cambridge Breast Unit, Cambridge University Hospitals, Cambridge, CB2 0QQ, United Kingdom.
authors.forename: Amit
authors.initials: A
authors.lastname: Agrawal
authors.affiliation: Division of Breast Surgery, School of Graduate Entry Medicine and Health, Royal Derby Hospital, University of Nottingham, Derby, DE22 3DT, United Kingdom.
authors.forename: John F R
authors.initials: JF
authors.lastname: Robertson
authors.affiliation: Division of Breast Surgery, School of Graduate Entry Medicine and Health, Royal Derby Hospital, University of Nottingham, Derby, DE22 3DT, United Kingdom.
authors.forename: Kwok L
authors.initials: KL
authors.lastname: Cheung
authors.affiliation: University of Nottingham, Nottingham City Hospital, NG5 1PB, United Kingdom.
authors.forename: Eleanor
authors.initials: E
authors.lastname: Gutteridge
authors.affiliation: University of Nottingham, Nottingham City Hospital, NG5 1PB, United Kingdom.
authors.forename: Ian O
authors.initials: IO
authors.lastname: Ellis
authors.affiliation: Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, CF10 3NB, United Kingdom.
authors.forename: Robert I
authors.initials: RI
authors.lastname: Nicholson
authors.affiliation: Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, CF10 3NB, United Kingdom.
authors.forename: Julia M W
authors.initials: JM
authors.lastname: Gee
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology* / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001706:Biopsy; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D065171:Estrogen Receptor Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D000077267:Fulvestrant; D015870:Gene Expression; D006801:Humans; D053208:Kaplan-Meier Estimate; D009367:Neoplasm Staging; D010766:Phosphorylation; D011379:Prognosis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism
chemical_list: D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D065171:Estrogen Receptor Antagonists; D019253:Proto-Oncogene Proteins c-bcl-2; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D000077267:Fulvestrant; D004958:Estradiol
keywords: biology; breast cancer; endocrine resistance; fulvestrant