Biological effects of fulvestrant on estrogen receptor positive human breast cancer: short, medium and long-term effects based on sequential biopsies.

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.

The effects of gefitinib in tamoxifen-resistant and hormone-insensitive breast cancer: a phase II study.

Estrogen receptor (ER)-positive acquired tamoxifen-resistant (TAM-R) MCF-7 breast cancer cell lines exhibit epidermal growth factor receptor (EGFR) expression/signaling and are growth-inhibited by gefitinib (IRESSA). We examined the effect of gefitinib on ER-positive TAM-R and ER-negative hormone-insensitive breast cancer in a Phase II study. Fifty-four patients with breast cancer [ER-positive/acquired TAM-R (n = 28); ER-negative (n = 26)] received oral gefitinib 500 mg/day. Tumor biopsies were taken pre- (n = 28) and 8 weeks post-treatment (n = 14 matched samples). Gefitinib was well tolerated and the clinical benefit rate (objective response or stable disease >24 weeks) was 33.3% overall (n = 18/54), and 53.6 and 11.5% in ER-positive/TAM-R and ER-negative patients, respectively. Pretreatment ER and progesterone receptor-positivity were associated with response (p < 0.001 and 0.016, respectively) and longer progression-free survival (PFS; p= 0.001 and 0.013, respectively). All patients expressed EGFR, but high pretreatment levels predicted poorer outcome (p = 0.005) and shorter PFS (p = 0.012) with gefitinib. In patients with clinical benefit, reduced Ki67 staining during treatment (p = 0.024) was commonly observed, and those with >10% decline in EGFR phosphorylation demonstrated parallel decreases in ERK1/2 MAPK phosphorylation. Acquired tamoxifen resistance appears in part mediated through EGFR signaling and can be blocked with gefitinib.

Imaging overview of metaplastic carcinomas of the breast: a large study of 71 cases.

OBJECTIVE:: To review the clinical presentation, baseline imaging features, surgical management and final surgical pathology of metaplastic carcinoma of the breast. METHODS:: A total of 71 cases were identified over a 10-year period from two major UK breast cancer institutions. Imaging at diagnosis including mammography, ultrasound, MRI and CT scans and histological diagnosis were reviewed. Follow-up data including local and systemic recurrence were retrieved. RESULTS:: Of the 71 cases, 60 (84.5%) cases presented with a palpable lump. 60 (84.5%) cases showed a mass on mammography, of whom 47 (78.3%) cases were ill defined and 17.0% cases showed calcifications associated with a mass lesion. All 71 cases were seen as a mass on ultrasound. The imaging score was R3 or R4 in 26 cases and R5 in 47 cases. 16 patients underwent MRI with most (93.8%) showing a solid mass with central necrosis. No metastatic disease was seen in the 13 patients who underwent staging CT. Despite having a larger size, 50% of the cases successfully underwent breast conservative surgery. Positive axillary lymph nodes were seen in 11 (15.5%) cases. CONCLUSION:: In this series, metaplastic cancers were palpable in 85% cases, tended to be large at the time of presentation and imaging showed characteristics of malignancy. Only 11 (15.5%) cases had nodal involvement. ADVANCES IN KNOWLEDGE:: Metaplastic carcinomas are often palpable and of large size at the time of presentation. Metaplastic carcinomas raise the concern for malignancy on mammography and ultrasound, warranting further biopsy. Metaplastic carcinomas tend to be grade 3 and triple receptor negative.