Gill Coombes

Fulvestrant plus anastrozole or placebo versus exemestane alone after progression on non-steroidal aromatase inhibitors in postmenopausal patients with hormone-receptor-positive locally advanced or metastatic breast cancer (SoFEA): a composite, multicentre, phase 3 randomised trial

BACKGROUND The optimum endocrine treatment for postmenopausal women with advanced hormone-receptor-positive breast cancer that has progressed on non-steroidal aromatase inhibitors (NSAIs) is unclear. The aim of the SoFEA trial was to assess a maximum double endocrine targeting approach with the steroidal anti-oestrogen fulvestrant in combination with continued oestrogen deprivation. METHODS In a composite, multicentre, phase 3 randomised controlled trial done in the UK and South Korea, postmenopausal women with hormone-receptor-positive breast cancer (oestrogen receptor [ER] positive, progesterone receptor [PR] positive, or both) were eligible if they had relapsed or progressed with locally advanced or metastatic disease on an NSAI (given as adjuvant for at least 12 months or as first-line treatment for at least 6 months). Additionally, patients had to have adequate organ function and a WHO performance status of 0-2. Participants were randomly assigned (1:1:1) to receive fulvestrant (500 mg intramuscular injection on day 1, followed by 250 mg doses on days 15 and 29, and then every 28 days) plus daily oral anastrozole (1 mg); fulvestrant plus anastrozole-matched placebo; or daily oral exemestane (25 mg). Randomisation was done with computer-generated permuted blocks, and stratification was by centre and previous use of an NSAI as adjuvant treatment or for locally advanced or metastatic disease. Participants and investigators were aware of assignment to fulvestrant or exemestane, but not of assignment to anastrozole or placebo. The primary endpoint was progression-free survival (PFS). Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, numbers NCT00253422 (UK) and NCT00944918 (South Korea). FINDINGS Between March 26, 2004, and Aug 6, 2010, 723 patients underwent randomisation: 243 were assigned to receive fulvestrant plus anastrozole, 231 to fulvestrant plus placebo, and 249 to exemestane. Median PFS was 4·4 months (95% CI 3·4-5·4) in patients assigned to fulvestrant plus anastrozole, 4·8 months (3·6-5·5) in those assigned to fulvestrant plus placebo, and 3·4 months (3·0-4·6) in those assigned to exemestane. No difference was recorded between the patients assigned to fulvestrant plus anastrozole and fulvestrant plus placebo (hazard ratio 1·00, 95% CI 0·83-1·21; log-rank p=0·98), or between those assigned to fulvestrant plus placebo and exemestane (0·95, 0·79-1·14; log-rank p=0·56). 87 serious adverse events were reported: 36 in patients assigned to fulvestrant plus anastrozole, 22 in those assigned to fulvestrant plus placebo, and 29 in those assigned to exemestane. Grade 3-4 adverse events were rare; the most frequent were arthralgia (three in the group assigned to fulvestrant plus anastrozole; seven in that assigned to fulvestrant plus placebo; eight in that assigned to exemestane), lethargy (three; 11; 11), and nausea or vomiting (five; two; eight). INTERPRETATION After loss of response to NSAIs in postmenopausal women with hormone-receptor-positive advanced breast cancer, maximum double endocrine treatment with 250 mg fulvestrant combined with oestrogen deprivation is no better than either fulvestrant alone or exemestane.

Antiproliferative Effect of Lapatinib in HER2-Positive and HER2-Negative/HER3-High Breast Cancer: Results of the Presurgical Randomized MAPLE Trial (CRUK E/06/039)

Purpose: Not all breast cancers respond to lapatinib. A change in Ki67 after short-term exposure may elucidate a biomarker profile for responsive versus nonresponsive tumors. Experimental Design: Women with primary breast cancer were randomized (3:1) to 10 to 14 days of preoperative lapatinib or placebo in a multicenter phase II trial (ISRCTN68509377). Biopsies pre-/posttreatment were analyzed for Ki67, apoptosis, HER2, EGFR, ER, PgR, pAKT, pERK, and stathmin by IHC. Further markers were measured by RT-PCR. Primary endpoint was change in Ki67. HER2+ was defined as 2+/3+ by IHC and FISH+. Results: One hundred twenty-one patients (lapatinib, 94; placebo, 27) were randomized; of these, 21% were HER2+, 78% were HER2− nonamplified, 26% were EGFR+. Paired samples containing tumor were obtained for 98% (118 of 121). Ki67 fell significantly with lapatinib (−31%; P < 0.001), but not with placebo (−3%). Whereas Ki67 reduction with lapatinib was greatest in HER2+ breast cancer (−46%; P = 0.003), there was a significant Ki67 decrease in HER2− breast cancer (−27%; P = 0.017) with 14% of HER2− breast cancer demonstrating ≥50% Ki67 reduction with lapatinib. Among HER2+ patients, the only biomarker predictive of Ki67 response was the EGFR/HER4 ligand epiregulin (EREG) (rho = −0.7; P = 0.002). Among HER2− tumors, only HER3 mRNA levels were significantly associated with Ki67 response on multivariate analysis (P = 0.01). In HER2− breast cancer, HER2 and HER3 mRNA levels were highly correlated (rho = 0.67, P < 0.001), with all Ki67 responders having elevated HER3 and HER2 expression. Conclusions: Lapatinib has antiproliferative effects in a subgroup of HER2− nonamplified tumors characterized by high HER3 expression. The possible role of high HER2:HER3 heterodimers in predicting response to lapatinib merits investigation in HER2− tumors. Clin Cancer Res; 21(13); 2932–40. ©2014 AACR. See related commentary by Campbell and Moasser, p. 2886

Abstract PD07-07: Prediction of antiproliferative response to lapatinib by HER3 in an exploratory analysis of HER2-non-amplified (HER2−) breast cancer in the MAPLE presurgical study (CRUK E/06/039)

Aim: To identify pretreatment biomarker predictors of Ki67 response to lapatinib in women with HER2− primary breast cancer. Background: Lapatinib is an EGFR/HER2 inhibitor. Its clinical use is restricted to HER2 overexpressing disease. The MAPLE (Molecular Antiproliferative Predictors of Lapatinib9s Effects) presurgical window of opportunity study of lapatinib vs placebo was conducted in women with HER2-amplified (HER2+) or HER2− primary disease. Ki67 (primary end-point) was reduced by a geomean 46% (95%CI 23–63%, p = 0.002) and 27% (95%CI 8–42%, p = 0.008) in HER2+ and HER2− disease, respectively (Leary et al, AACR 2012). We have now assessed whether predictive biomarkers of the antiproliferative response in HER2− disease could be identified. Methods: 121 primary breast cancer patients were randomized (3:1) to 14 days of 1500mg/d lapatinib or placebo before surgery. Biopsies were taken before treatment and at surgery. Ki67 responders were defined as having a >/=50% reduction in Ki67 compared to baseline (Ellis, P et al, Breast Cancer Res Treat 1998, 48, 107). ER, PgR, HER2, EGFR, pAKT, pERK1/2 (nuclear and cytoplasmic), stathmin and apoptosis (TUNEL) were assessed by IHC (+FISH for HER2[all cases]) and scored visually by continuous methods. HER2, HER3, epiregulin (epir), amphiregulin (amphir) and neuregulin (neur) were assessed by qrtPCR. Results: Three of the 121 patients were excluded because of inadequate biopsy material. Ninety-one of the remaining 118 patients received lapatinib: 7/19 (37%) HER2+ cases and 10/72 (14%) HER2− cases were Ki67 responders. Thus while the proportion of Ki67 responders was higher for HER2+ disease there was a similar or higher absolute number of responders with HER2− disease. All of the following relates to patients with HER2− disease. None of the pretreatment levels of ER, PgR, pAKT, pERK1/2, EGFR, epir, amphir or neur were associated with Ki67 response (p > 0.20). However, HER3 (p = 0.01) and HER2 (p = 0.06) mRNA levels were associated with greater Ki67 response. There was a tendency for Ki67 response to be greater with lower baseline Ki67 (p = 0.07). Multivariate analysis showed only HER3 mRNA levels to be independently significant. HER2 and HER3 mRNA levels were highly correlated (rho = 0.67, p Conclusions: Lapatinib is antiproliferative in a subgroup of HER2− tumours. This exploratory analysis indicates that they are characterized by high HER3 expression. The possible importance of high HER2:HER3 heterodimers in predicting this response is supported by the relationship between HER2 and HER3 expression. Further exploration of lapatinib is merited in HER2− cases with high HER3 expression. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD07-07.

Abstract LB-222: Lapatinib has antiproliferative effects in both HER2 positive (+) and HER2 negative (-) breast cancer (BC): results from the MAPLE short-term pre-surgical trial (CRUK E/06/039)

Not all patients (pts) with HER2 positive (+) breast cancer (BC) benefit from treatment (tx) with EGFR/HER2 tyrosine kinase inhibitor lapatinib (L) & it is not known whether HER2 over-expression or amplification are obligate requirements for L response. Assessment of in vivo biomarkers of drug activity, e.g. change in Ki67, after short-term pre-surgical tx may elucidate the differential molecular profile of sensitive vs. resistant tumors. Aims: i) Determine whether L induces anti-proliferative effects in HER2+ & HER2 negative (-) BC & ii) identify biomarkers of sensitivity/resistance to anti-proliferative effects of L. Methods: Women with newly diagnosed BC were randomized (3:1) to receive 10-14 days of pre-operative L (1500mg/day) or placebo (P) in a multicentre phase II trial (ISRCTN68509377). Paired core biopsies before & after tx were analyzed for Ki67, TUNEL, HER2, EGFR, ER, PgR, pAkt, pErk, & stathmin (candidate marker of PI3K/Akt activation) by IHC +/− FISH. HER2, HER3 & ligands EREG, AREG & NRG1 mRNA was measured by RT-PCR. The primary endpoint was change in Ki67. HER2+ was defined as 3+ or 2+ by IHC and FISH+. Differences in geometric means were assessed by Mann-Whitney & correlations by Spearman rank. Results: 121 pts (L=94, P=27) were randomized between 12/2007-04/2011, 70% were ER+/PgR+, 13% ER+/PgR- & 17% ER-; 22% were HER2+ (including one 2+/FISH+) & 26% were EGFR+. L pts reported significantly more frequent G1-2 (64%) or G3 (6%) rash, & G1 diarrhea (56%); the only other G3 toxicity was infection in 1 pt. There were no delays in surgery. Paired samples containing tumor were obtained for 98% (118/121) of randomized pts. Ki67 fell significantly in the L group (relative reduction in post- vs. pre-tx samples = -31%, 95%CI: -44 to -16; p Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-222. doi:1538-7445.AM2012-LB-222