Neoadjuvant chemotherapy and trastuzumab versus neoadjuvant chemotherapy followed by post-operative trastuzumab for patients with HER2-positive breast cancer

Neoadjuvant chemotherapy plus trastuzumab (NCT) increases the rate of pathological complete response (pCR) and event-free survival (EFS) compared to neoadjuvant chemotherapy (NC) alone in women with HER2 positive breast cancer (BC). pCR in this setting is associated with improved EFS. Whether NCT preferentially improves EFS in comparison to NC followed by adjuvant trastuzumab initiated postoperatively (NCAT) has not been addressed. Using clinical data from women with HER2 positive BC treated at 7 European institutions between 2007 and 2010 we sought to investigate the impact on breast cancer outcomes of concomitant (NCT) versus sequential (NCAT) treatment in HER2 positive early BC. The unadjusted hazard ratio (HR) for event free survival with NCT compared with NCAT was 0.63 (95% CI 0.37–1.08; p = 0.091). Multivariable analysis revealed that treatment group, tumour size and ER status were significantly associated with EFS from diagnosis. In the whole group NCT was associated with a reduced risk of an event relative to NCAT, an effect that was confined to ER negative (HR: 0.25; 95% CI, 0.10–0.62; p = 0.003) as opposed to ER positive tumours (HR: 1.07; 95% CI, 0.46–2.52; p = 0.869). HER2 positive/ER negative BC treated with NC gain greatest survival benefit when trastuzumab is administered in both the neoadjuvant and adjuvant period rather than in the adjuvant period alone. These data support the early introduction of targeted combination therapy in HER2 positive/ER negative BC

Expression of steroid receptor coactivator 3 in ovarian epithelial cancer is a poor prognostic factor and a marker for platinum resistance

BACKGROUND: Steroid receptor coactivator 3 (SRC3) is an important coactivator of a number of transcription factors and is associated with a poor outcome in numerous tumours. Steroid receptor coactivator 3 is amplified in 25% of epithelial ovarian cancers (EOCs) and its expression is higher in EOCs compared with non-malignant tissue. No data is currently available with regard to the expression of SRC-3 in EOC and its influence on outcome or the efficacy of treatment. METHODS: Immunohistochemistry was performed for SRC3, oestrogen receptor-α, HER2, PAX2 and PAR6, and protein expression was quantified using automated quantitative immunofluorescence (AQUA) in 471 EOCs treated between 1991 and 2006 with cytoreductive surgery followed by first-line treatment platinum-based therapy, with or without a taxane. RESULTS: Steroid receptor coactivator 3 expression was significantly associated with advanced stage and was an independent prognostic marker. High expression of SRC3 identified patients who have a significantly poorer survival with single-agent carboplatin chemotherapy, while with carboplatin/paclitaxel treatment such a difference was not seen. CONCLUSION: Steroid receptor coactivator 3 is a poor prognostic factor in EOCs and appears to identify a population of patients who would benefit from the addition of taxanes to their chemotherapy regimen, due to intrinsic resistance to platinum therapy

Differential oestrogen receptor binding is associated with clinical outcome in breast cancer.

Oestrogen receptor-α (ER) is the defining and driving transcription factor in the majority of breast cancers and its target genes dictate cell growth and endocrine response, yet genomic understanding of ER function has been restricted to model systems. Here we map genome-wide ER-binding events, by chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq), in primary breast cancers from patients with different clinical outcomes and in distant ER-positive metastases. We find that drug-resistant cancers still recruit ER to the chromatin, but that ER binding is a dynamic process, with the acquisition of unique ER-binding regions in tumours from patients that are likely to relapse. The acquired ER regulatory regions associated with poor clinical outcome observed in primary tumours reveal gene signatures that predict clinical outcome in ER-positive disease exclusively. We find that the differential ER-binding programme observed in tumours from patients with poor outcome is not due to the selection of a rare subpopulation of cells, but is due to the FOXA1-mediated reprogramming of ER binding on a rapid timescale. The parallel redistribution of ER and FOXA1 binding events in drug-resistant cellular contexts is supported by histological co-expression of ER and FOXA1 in metastatic samples. By establishing transcription-factor mapping in primary tumour material, we show that there is plasticity in ER-binding capacity, with distinct combinations of cis-regulatory elements linked with the different clinical outcomes

Abstract P2-10-22: Phosphorylation of Steroid Receptor Coactivator 3 (SRC3) at Ser543 is a novel independent prognostic marker in breast cancer

Abstract Introduction: Steroid receptor coactivator 3 (SRC3) acts as a coactivator of nuclear receptors including estrogen receptor-alpha (ER). SRC3 has been implicated in the pathogenesis of breast cancer (BC) as well as in resistance to endocrine therapy. SRC3 is phosphorylated at a number of residues following the stimulation of growth factors or hormones. Tyr24 and Ser543 are both phosphorylated upon estrogen stimulation, while Tyr24 is modulated by JNK and Ser543 by both p38 and JNK. To date, the importance and potential role of phosphorylation at these residues has not been explored in BC. In this study we assessed the protein expression of SRC3, pTyr24 and pSer543 and association with clinico-pathological features and outcome in a well defined breast cancer series. Methods: The expressions of SRC3, pTyr24 and pSer543 were assessed in the Nottingham Tenovus Primary Breast Cancer Series which consists of 1650 cases of primary invasive. SRC3, pTyr24 and pSer543 were correlated with clinico-pathological data as well as outcome. Results: SRC3 expression was significantly associated with unfavourable clinicopathological features including ER -ve (p = 0.02), PR –ve (p = .038), HER2 overexpression (p &amp;lt; 0.0001), Triple negative phenotype (p = 0.001), high proliferation (p &amp;lt; 0.0001), high histological grade (p &amp;lt; 0.001), and lympho-vascular invasion. On contrast, the expression of pSer543 was significantly associated with a luminal phenotype, well differentiation, low proliferation (low mitotic index, low Ki67 and low SPAG5; p &amp;lt; 0.0001), hormonal receptors (ERα+ve/PR+ve/AR+ve), absence of both ER-B1 and ER-B5 (p &amp;lt; 0.01), high expression of ER-α associated proteins (cyclin D1 and Bcl2; p &amp;lt; 0.0001), high expression of c-jun (p &amp;lt; 0.0001), JNK (p &amp;lt; 0.0001), SRC3 (p &amp;lt; 0.0001), T24 (p &amp;lt; 0.001) and active p53 transcriptional pathways that regulate cell cycle progression and apoptosis (MDM2+ve, MDM4+ve and Bax+ve; p &amp;lt; 0.01) and absence of basal like phenotypes (p &amp;lt; 0.01). The absence of pSer543 was significantly associated with loss of expression of the key DNA repair proteins including XRCC1 (p &amp;lt; 0.0001), BRCA1 (p &amp;lt; 0.0001), ATM (p = 0.008) and TOP2A (p &amp;lt; 0.0001) reflecting a higher risk of genomic instability. Moreover, absence of pSer543 was more common in BC with a triple negative phenotype (p &amp;lt; 0.001). With regard to outcome, no association with outcome based on the expression of SRC3 either with or without tamoxifen was observed. However, expression of pSer543 was associated with significantly longer disease free survival (DFS) (p &amp;lt; 0.00001) and breast cancer specific survival (BCSS) (p = 0.0001). Furthermore, absence of pSer543 was associated with both a shorter DFS (p = 0.007) and BCSS (p = 0.01) in ER+ ve high risk BC. pSer534 was confirmed as an independent prognostic factor after adjustment for endocrine therapy and other validated prognostic factors and absent of pSer534 was associated with a two-fold increased risk of recurrence (HR = 1.9, CI 95%= 1.2–3.1). Data on Tyr24 will also be presented. Conclusion: Phosphorylation at Ser543 is associated with a luminal phenotype, positive prognostic factors and sensitivity to tamoxifen. Furthermore, it is an independent prognostic factor. pS543 is a novel prognostic marker in BC and warrants further investigation. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-10-22.</jats:p