#6059 Background: Two retrospective studies reported conflicting evidence for HER2 as a predictor of benefit from adjuvant A. In the MA.5 study (NEJM 354:2103-11 2006) patients (pts) with HER2 +ve tumors benefited: whereas in the BR9601 study (JCO in press) those with HER2/HER1-3 -ve tumors gained from A. As HER2 is on chromosome 17, and polysomy is a potential marker of chromosomal instability, we hypothesised that chromosome 17 polysomy (C17) could be the underlying mechanism of the link between HER2 and sensitivity to A .
 Methods:. Triple color FISH was performed in 2 central labs (BR9601 Bartlett & MA5 O'Malley for HER2/TOP2α/centromere 17, Abbott, IL, USA). Local laboratory ER and PgR receptor and grade (G) were noted. BR9601 tumours were scored with a minimum of one C17 signals/cell: in MA.5 a minimum of 2 C17 signals were required for cells to be scored. These methodological differences did not affect HER2/17 ratios (confirmed by central validation - Isola) but necessitated different definitions for C17 polysomy defined as >1.86 observed copies/cell for BR9601 (Watters BCRT 2003 77:109-14) and >2.25 for MA.5 ( Goetz 2004).
 Results: FISH was successful in 97.9% (925/944) of available cases. C17 polysomy was detected in 40.1% of tumors (MA5 - 41.3% & BR9601 - 37.6%). C17 polysomy was associated with poorer OS & DFS (p=0.039 & 0.007, respectively). However C17 polysomy was associated with increased DFS in cases treated with A compared to CMF in both MA.5 (HR 0.62 p=0.004 vs 1.01 NS) and BR9601 (HR 0.48, p=0.016 vs 0.7 NS) and in a combined analysis (HR 0.57, C.I. 0.43-0.77, p = 0.005 vs 0.94 C.I. 0.73-1.21, NS respectively). C17 polysomy was also associated with increased OS in pts treated with A in BR9601 (HR: 0.49, 95% C.I. 0.25-0.96; p=0.034). Multivariate Cox regression analysis (including grade, size, ER status, nodes, polysomy & HER2) showed a highly significant effect of treatment and C17 polysomy (p<0.001), with a significant treatment by marker interaction between C17 polysomy and use of A for OS & DFS (HR 1.61, C.I. 1.01-2.57, p=0.047 and 1.75 C.I. 1.15-2.64, p=0.008 respectively). No treatment by marker effect was observed for HER2 in this multivariate analysis.
 Conclusions: Combined analysis of 2 adjuvant trials with differing effects of HER2 as a predictive marker of benefit from A show that in both trials C17 polysomy predicted for enhanced benefit from A. This is confirmed by Multivariate regression analysis showing a significant interaction of C17 as a marker with treatment. Polysomy 17 may reflect either chromosomal instability or polyploidy & further analysis is warranted to test this unifying hypothesis for prediction of benefit from adjuvant A.
 Acknowledgments: Abbott Laboratories, Scottish Cancer Therapy Network & Institute for Statistics in Disease, Belgian Federation Against Cancer, Cancer Research UK, Les Amis de l'Institut Bordet, Pfizer. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6059.
BACKGROUND Patients with hormone receptor-positive (HR+) locally advanced or metastatic breast cancer (LA/MBC) and non-visceral metastases (non-VM) generally have a better prognosis than patients with visceral metastases (VM). However, in the absence of visceral crisis, endocrine therapy (ET) remains an effective treatment option in both patient groups. This descriptive analysis examined the treatment effect of fulvestrant 500 mg vs comparators in postmenopausal patients with HR+ LA/MBC, with or without VM. METHODS Three randomized studies of fulvestrant 500 mg for postmenopausal HR+ LA/MBC were included. The Phase 3 FALCON study (NCT01602380) compared fulvestrant 500 mg with anastrozole in patients without any prior ET (n=462; fulvestrant 500 mg: 58.7% with VM; anastrozole: 51.3% with VM). The Phase 2 FIRST study (NCT00274469) compared fulvestrant 500 mg with anastrozole in patients who had not received ET for advanced disease (n=205; fulvestrant 500 mg: 47.1% with VM; anastrozole: 56.3% with VM). The Phase 3 CONFIRM study (NCT00099437) compared fulvestrant 500 mg with fulvestrant 250 mg (n=736; fulvestrant 500 mg: 56.6% with VM; fulvestrant 250 mg: 52.9% with VM); patients had received prior ET for adjuvant/advanced disease. The treatment effect of fulvestrant 500 mg vs comparator ET was determined using log-rank tests. RESULTS In FALCON, there was a greater treatment effect with fulvestrant 500 mg vs anastrozole for progression-free survival (PFS) in the non-VM group (hazard ratio [HR] 0.59) vs the VM group (HR 0.99). A consistent treatment effect was observed for fulvestrant 500 mg vs comparator for PFS in FIRST (non-VM HR 0.58; VM HR 0.82) and CONFIRM (non-VM HR 0.72; VM HR 0.86). Median PFS of fulvestrant 500 mg vs comparator in non-VM and VM subgroups was: 22.3 months (m) vs 13.8 m and 13.8 m vs 15.9 m, respectively, in FALCON; 34.0 m vs 21.3 m and 9.8 m vs 9.9 m in FIRST; and 10.4 m vs 5.9 m and 4.7 m vs 4.0 m in CONFIRM. Clinical benefit rate with fulvestrant 500 mg vs anastrozole in FALCON was 87.4% vs 75.2% in the non-VM group, and 71.9% vs 73.1% in the VM group. Overall survival (OS) in FALCON (31% maturity) showed a greater treatment effect with fulvestrant 500 mg vs anastrozole in the non-VM group vs the VM group (HR 0.60 vs 1.09). In terms of OS, in FIRST there was a greater treatment effect with fulvestrant 500 mg vs anastrozole in the non-VM group compared with the VM group (HR 0.68 vs 0.86). In CONFIRM, improved OS was observed with fulvestrant 500 mg vs fulvestrant 250 mg; this treatment effect was consistent in non-VM (HR 0.78) and VM subgroups (HR 0.83). CONCLUSIONS In three studies, an improved treatment effect of fulvestrant 500 mg vs comparator ET for HR+ LA/MBC was observed in patients with non-VM. The treatment effect of fulvestrant 500 mg vs comparator for PFS across all three studies appeared consistent. A reduced treatment effect of fulvestrant 500 mg vs comparator was generally seen in patients with VM, although fulvestrant 500 mg was still as effective as, or slightly more effective than, the comparator. These data suggest that patients without VM may benefit more from fulvestrant 500 mg than patients with VM. Citation Format: Roberston JFR, Di Leo A, Fazal M, Lichfield J, Ellis MJ. Fulvestrant for hormone receptor-positive advanced breast cancer in patients with visceral vs non-visceral metastases: Findings from FALCON, FIRST, and CONFIRM [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD5-09.
#705 Background: Retrospective studies have suggested that HER2 and topoisomerase II α (TOP2A) might predict sensitivity to anthracyclines (A)
 Methods: Four phase III trials comparing A with CMF in early breast cancer (EBC) patients (pts), and with available primary tumor samples, were identified. HER2 and TOP2A genes were evaluated locally by FISH (amplification if ratio ≥ 2). Data were centralized at the statistical office (IDDI, Belgium). On-site visits were performed to check data quality and laboratory procedures. HER2 and TOP2A local scores were validated by submitting randomly selected samples to a central lab (CL) (University of Tampere – Finland), for a 3 color FISH test (HER2, TOP2A, centromere 17, Abbott Labs, IL, USA). Estrogen (ER), progesterone (PgR) receptors, and grade (G) were evaluated locally (no score validation at the CL).
 Results: We present the results of the planned interim analysis on 1944 pts. Final results (± 3500 pts) will be presented when tumor sample collection for the UK trial is complete. HER2 local scores were validated at the CL in 137 cases (discordance: 8/137, 5.8%). TOP2A local scores were validated in 123 cases (discordance 38/123, 30.8%). Half of the TOP2A discordant cases were locally deleted-centrally normal or vice versa.
 
 A planned exploratory analysis evaluated the TOP2A predictivity in 4 biologically homogeneous groups: highly or moderately hormone sensitive, HER2+ and ER/PgR negative, triple negative (TN). This analysis did not enhance the TOP2A predictivity in any of the 4 groups. In the TN group (294 pts), the DFS HR was 0.77 (0.54-1.09), suggesting that benefit from A might not be confined to HER2+ pts.
 Conclusions: The interim analysis shows that HER2 and TOP2A have a clinically modest and a statistically borderline predictive value. In triple negative disease A may be superior to CMF.
 Acknowledgments: Abbott Laboratories, Belgian Federation Against Cancer, Cancer Research UK, Les Amis de l'Institut Bordet, Pfizer, Scottish BC trials group. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 705.
Introduction: TK1 plays a crucial role in DNA synthesis and is a well-established marker of cell proliferation. We and others have previously described the potential role of TK1 activity (TKa) as predictive biomarker of response to endocrine therapy in HR+/HER2 negative metastatic breast cancer patients. TK1 synthesis is regulated by the E2F pathway, the target pathway of CDK4/6 inhibitors, and TKa has recently been reported as a potential circulating pharmacodynamic marker of CDK4/6 inhibition in breast cancer. However, modulations of TK1 levels and activity during palbociclib treatment and in the development of treatment resistance are unknown. Here, we report how TK1 expression and TKa are modulated in response to palbociclib in a panel of HR+ breast cancer cell lines: both palbociclib-sensitive (PDS) and with acquired resistance to (PDR). Material and methods: We used a panel of 7 PDR HR+ breast cancer models previously developed in our lab via chronic exposure of parental cells (MCF7, T47D, ZR75-1, BT474, MDAMB361 and two MCF7 endocrine resistant derivatives) to escalating doses of palbociclib, from a Starting Treatment Concentration (STC) of 50 nM or 350 nM according to the cell line, up to 1 μM. We analyzed gene expression profiles of PDS cells treated with drug vehicle (DMSO) as a control or palbociclib at STC for 3 days, and PDR cells grown with palbociclib 1 μM. Cell proliferation was assessed by methylene blue assay in MCF7 and BT474 PDS and PDR treated for 3, 6 and 9 days with DMSO, palbociclib STC and 1 μM. In parallel, TKa was measured in cell lysates at 3 days of treatment using the DiviTumTM assay (Biovica, Sweden). Results: Among E2F target genes, gene expression data demonstrated that TK1 was one of the most differentially expressed genes between PDR and PDS treated cells. In PDS cells compared to control, treatment with palbociclib resulted in reduced TK1 expression, with the HER2 positive models (BT474 and MDAMB361) showing the highest reduction. In PDR cells, TK1 expression was higher, but remained slightly inhibited compared to untreated PDS cells. TKa was significantly reduced in PDS cells treated with palbociclib for 3 days compared to vehicle (p<0.05). TKa response to palbociclib was more dramatic in BT474 cells as compared to MCF7. As expected, palbociclib inhibited cell proliferation in PDS models, with a significant reduction observed only after 6 days of treatment, suggesting that TKa may be an early marker of growth inhibition in response to palbociclib. No significant alterations in TKa were observed in PDR cells, at any dose of palbociclib. Similarly, proliferation rate was not affected by palbociclib in PDR cells. Conclusions: TK1 expression and activity are regulated by palbociclib in HR+ breast cancer cell lines, particularly in HER2 positive models. Ongoing studies of TKa in patients treated with palbociclib will assess the role of TKa as a circulating biomarker for predicting and monitoring response to CDK4/6 inhibitors. Citation Format: Bonechi M, Migliaccio I, Benelli M, Romagnoli D, Bergqvist M, Mattsson K, Boccalini G, Capaccioli G, De Luca F, Galardi F, Biagioni C, Risi E, McCartney A, Rossi L, Osborne CK, Schiff R, De Angelis C, Guarducci C, Di Leo A, Malorni L. Effects of palbociclib on thymidine kinase-1 (TK1) in hormone receptor positive (HR+) breast cancer cell lines [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-09-02.
Estrogens exert a protective effect against atherosclerosis. It is well known that hormone replacement therapy (HRT) can effectively decrease LDL-cholesterol and increase HDL-cholesterol and Apo-Al serum levels. Some recent studies have suggested that estrogens alone or in association with progestins may exert an antioxidant effect on lipids. Besides sex steroids, also vitamins exert an antioxidant effect on LDL and may preserve the endogenous antioxidants of LDL. The aim of our study was to evaluate whether HRT can improve alpha-tocopherol and beta-carotene serum levels in post-menopausal women. Fifteen postmenopausal women with climacteric symptoms were treated with 50 micrograms/24 h estradiol transdermally applied twice a week for 21 days. A daily dose of 10 mg oral medroxyprogesterone acetate was added for 12 days in each treatment cycle. This therapy lasted 6 months. A significant reduction was found in total cholesterol and LDL-cholesterol after treatment. Besides, our study has shown that alpha-toc/LDL and beta-car/LDL ratios significatively increased after treatment, while alpha-tocopherol and beta-carotene serum levels did not change significantly after therapy. These preliminary findings suggest that HRT can preserve the content of alpha-tocopherol and beta-carotene in LDL particles and keep the LDL in a reduced antioxidant state.
The clinical utility of tumor-infiltrating lymphocytes (TIL) is actively being investigated in breast cancer (BC). It is unclear whether TIL spatial location and organization in tertiary lymphoid structures (TLS) have an impact on prognosis. Additionally, the significance of PD-1 and PD-L1 expression is being debated due to conflicting data from several studies. We hypothesize that the presence, extent and spatial location of multiple immune biomarkers, reflecting ongoing immune responses, will be consistently associated with a good prognosis in highly infiltrated BC [triple-negative (TNBC) and HER2+]. The relationship between these immune biomarkers and clinical outcome was examined in the TNBC and HER2+ cohorts of node-positive BC patients enrolled in the BIG 02-98 adjuvant phase III trial with available material for immunohistochemical (IHC) labeling (N=113 and N=136, respectively). HER2+ patients did not receive trastuzumab. Dual IHC staining was performed on full-face consecutive tissue sections. Scoring was independently performed by two pathologists, blinded to the clinical data, and included: global, intratumoral and stromal TIL and TLS, assessed on CD3/CD20 slides; the percentage and location of PD-1 and PD-L1 expression, assessed on PD-1/PD-L1 slides. TIL were considered as a categorical variable with different cut-offs used for each parameter and for each cohort (TNBC and HER2+). Invasive disease-free survival (I-DFS) and overall survival (OS) were analyzed (median follow-up: 10 years). Cox proportional hazard models were used for survival analyses. The TNBC cohort revealed an association between global TIL and outcome [adjusted hazard ratio (HR) for I-DFS: 0.27 (0.15-0.51); OS: 0.26 (0.13-0.53)]. Similar results were observed for stromal and intratumoral TIL. PD-L1 expression within TLS was an independent predictor of OS, after adjustment for tumor size and age [HR: 0.30 (0.09-0.99)]. Multivariate analysis reveals this effect was principally driven by high stromal TIL (>17.5% based on CD3/CD20 assessment) (χ2 OS: p=0.009). In contrast, no significant prognostic associations were found in the overall HER2+ cohort. However high T cell TIL were associated with improved I-DFS and OS in the ER-/HER2+ group [I-DFS: 0.34 (0.14-0.80); OS: 0.32 (0.12-0.86)] and stromal TIL were associated with improved I-DFS in the ER+/HER2+ group [HR: 0.29 (0.09-0.94)] (univariate analyses). No significant associations between the number of TLS nor the expression of PD-1 with outcomes were observed in either cohorts. The presence of PD-L1+ TLS, driven by high baseline TIL, was associated with an excellent prognosis in node-positive TNBC. This observation might reflect specific immune activities taking place in these mini lymph node-like structures adjacent to the tumor bed where specific antitumor memory immune responses could be generated. No different prognostic impact was observed when analyzing TIL spatial location. Although the statistical power of the study might be limited, in line with previous findings our data reveal that, among the immune parameters evaluated, TIL are the strongest predictor of outcome in TNBC, while PD-L1+ TLS could be a new and important parameter that requires further investigation. Citation Format: Solinas C, de Wind A, Van den Eynden G, Ameye L, Garaud S, De Silva P, Boisson A, Noel G, Langouo Fontsa M, Buisseret L, de Azambuja E, Francis PA, Di Leo A, Crown JP, Sotiriou C, Larsimont D, Paesmans M, Piccart-Gebhart M, Willard-Gallo K. Immune parameters associated with survival in triple negative and HER2-positive breast cancer patients with 10 years of follow-up [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD5-09.
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