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.
Highlights
Median DoR 5 median duration of response between fulvestrant treatment commencement and disease progression on this agent for All-patients Median DoR in CB patients (DoCB)= median duration of response to fulvestrant in patients with clinical benefit (CB) CB patients were subdivided into EP or CONR/ LP sub-sets
Our series had substantial ERregulated proteins, modest EGFR/HER2 signaling and elevated Ki67 expression, a profile equated to better outcome for other anti-hormones
The estrogen receptor-alpha (ER) downregulation we observed with fulvestrant at 6 weeks is consistent with previous short-term (
Summary
The steroidal agent fulvestrant prevents estradiol binding to estrogen receptor-alpha (ER) to a stronger extent than tamoxifen It has a distinct mode of action that causes severe receptor conformational changes, promoting receptor degradation and downregulation of ER protein level and depletion of ER transcriptional activation.[1] Clinically, fulvestrant retains activity in postmenopausal tamoxifen or nonsteroidal aromatase inhibitor (AI) resistant estrogen receptor positive (ER1) breast cancers.[2,3,4,5] Fulvestrant, at 250 mg, had similar time to progression, survival and response rate to use of tamoxifen/ AIs in Phase III trials.[2,3,4,6] Following observations of dosedependent decline in ER after short-term fulvestrant treatment of clinical breast cancer,[7] additional studies including the CONFIRM trial[5] provided evidence of further benefit with fulvestrant at 500 mg in ER1 disease following prior endocrine failure.
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