Abstract PD5-06: Effects of perioperative lapatinib in early HER2+ breast cancer - The UK EPHOS-B trial (CRUK/08/002)

Abstract Background: Patients diagnosed with primary breast cancer (BC) often have a couple weeks interval between diagnosis and definitive surgery. This time window provides the opportunity for assessing biological drug effects in a treatment naive population. The EPHOS-B trial was designed to measure the effect of pre-operative anti-HER2 therapy on proliferation and apoptosis in HER2+ BC patients. Patients &amp; methods: EPHOS-B is a multicentre, 2-part randomized trial in patients with operable newly diagnosed HER2+ primary BC. In Part 1 patients were randomized (1:2:2) to no perioperative treatment (control), trastuzumab only or lapatinib only (11 days pre-operative therapy). Emerging evidence on the efficacy and safety of combination anti-HER2 therapy led to Part 2 in which patients were allocated to control, perioperative trastuzumab only or lapatinib and trastuzumab (1:1:2). The IDMC have agreed release of data from lapatinib Part 1 patients only. Tissue samples were taken at the time of diagnostic core biopsy and surgery, and analysed centrally for Ki67, apoptosis (activated caspase 3), PgR, HER3 and Bcl2 by immunohistochemistry (IHC). Local ER and PgR status were also recorded. Primary endpoint is change in Ki67 and/or apoptosis. Response is defined by a drop in Ki67 of ≥30% or a rise in apoptosis of ≥30% from baseline. Results: Between Nov-2010 and Jul-2013, 51 patients (pts) were allocated to perioperative lapatinib, with 49 (96.1%) receiving at least 1 dose. All pts were HER2+ (90% 3+ by IHC and 10% amplified by FISH, locally assessed) at entry. Median age was 51 years (IQR 48-60); 65% had tumours &amp;gt;2cm and 51% were grade 3 at surgery. According to local assessment, 61% were ER+ and 43% PgR+. Only 2 pts (4%) had a dose reduction and 1 pt (2%) discontinued lapatinib in the 3 days prior to surgery due to toxicity (rash, 3pts; nausea, 1pt). There were no delays in surgery. Paired samples were valid for analysis in 43/51 (84%); invalid pairs were mostly due to inadequate samples for scoring. Overall, 67% (95% CI: 52% to 81%) of pts demonstrated a ≥30% fall in Ki67 whilst a ≥30% rise in apoptosis was observed only in 30% of pts (95% CI: 17% to 46%). When assessed as continuous variables, Ki67 fell significantly from pre-treatment but there was no significant change in apoptosis detected (results in table). No correlation was observed between Ki67 change and change in apoptosis (p=0.5). Neither HER-3 expression nor BCL2 predicted response.  ER- HER2+, n=18ER+ PR- HER2+, n=7ER+PR+HER2+, n=17All, n=43*Ki67 % change from pre treatment-51% (-69% to -21%), p&amp;lt;0.001-53% (-78% to -11%), p=0.02-38% (-58% to -24%), p&amp;lt;0.001-45% (-57% to -32%), p&amp;lt;0.001Apoptosis % change from pre treatment-24% (-37% to +30%), p=0.27-13% (-48% to +125%), p=0.61-13% (-65% to +43%), p=0.19 Median % change (95% confidence interval), p-value: Wilcoxon signed-rank test. *1 pt missing ER status Conclusion: EPHOS-B demonstrates that ∼11 days' lapatinib has a marked anti-proliferative effect in HER2+ve breast cancers. The trial is ongoing and when complete will provide a definitive analysis of the relative biological effects of perioperative treatment with different anti-HER2 therapies (trastuzumab, lapatinib and their combination) in patients with HER2+ BC. Citation Format: Bundred N, Cameron D, Kalaitzaki E, Morley R, Cramer A, Webster-Smith M, Narayanan S, Brunt M, Horgan K, Hanby A, Ooi J, Hong A, Naik J, Evans A, Shaaban A, Bliss J. Effects of perioperative lapatinib in early HER2+ breast cancer - The UK EPHOS-B trial (CRUK/08/002). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr PD5-06.</jats:p

Poor-prognosis estrogen receptor-positive breast cancer identified by histopathologic subclassification

Purpose: Identification of biologically and clinically distinct breast cancer subtypes could improve prognostic assessment of primary tumors. The characteristics of ''molecular'' breast cancer subtypes suggest that routinely assessed histopathologic features in combination with limited biomarkers may provide an informative classification for routine use. Experimental Design: Hierarchical cluster analysis based on components of histopathologic grade (tubule formation, nuclear pleomorphism, and mitotic score), expression of ER, cytokeratin 5/6, and HER2 amplification identified four breast cancer subgroups in a cohort of 270 cases. Cluster subgroup membership was compared with observed and Adjuvant! Online predicted 10-year survival. Survival characteristics were confirmed in an independent cohort of 300 cases assigned to cluster subgroups using a decision tree model. Results: Four distinct breast cancer cluster subgroups (A-D) were identified that were analogous to molecular tumor types and showed a significant association with survival in both the original and validation cohorts (

Supplementary Figure S1 from Poor-Prognosis Estrogen Receptor–Positive Breast Cancer Identified by Histopathologic Subclassification

Supplementary Figure S1 from Poor-Prognosis Estrogen Receptor–Positive Breast Cancer Identified by Histopathologic Subclassificatio

Poor-prognosis estrogen receptor-positive breast cancer identified by histopathologic subclassification

Purpose: Identification of biologically and clinically distinct breast cancer subtypes could improve prognostic assessment of primary tumors. The characteristics of ‘molecular’ breast cancer subtypes suggest that routinely assessed histopathologic featur

SREB, a GATA Transcription Factor That Directs Disparate Fates in Blastomyces dermatitidis Including Morphogenesis and Siderophore Biosynthesis

Blastomyces dermatitidis belongs to a group of human pathogenic fungi that exhibit thermal dimorphism. At 22 degrees C, these fungi grow as mold that produce conidia or infectious particles, whereas at 37 degrees C they convert to budding yeast. The ability to switch between these forms is essential for virulence in mammals and may enable these organisms to survive in the soil. To identify genes that regulate this phase transition, we used Agrobacterium tumefaciens to mutagenize B. dermatitidis conidia and screened transformants for defects in morphogenesis. We found that the GATA transcription factor SREB governs multiple fates in B. dermatitidis: phase transition from yeast to mold, cell growth at 22 degrees C, and biosynthesis of siderophores under iron-replete conditions. Insertional and null mutants fail to convert to mold, do not accumulate significant biomass at 22 degrees C, and are unable to suppress siderophore biosynthesis under iron-replete conditions. The defect in morphogenesis in the SREB mutant was independent of exogenous iron concentration, suggesting that SREB promotes the phase transition by altering the expression of genes that are unrelated to siderophore biosynthesis. Using bioinformatic and gene expression analyses, we identified candidate genes with upstream GATA sites whose expression is altered in the null mutant that may be direct or indirect targets of SREB and promote the phase transition. We conclude that SREB functions as a transcription factor that promotes morphogenesis and regulates siderophore biosynthesis. To our knowledge, this is the first gene identified that promotes the conversion from yeast to mold in the dimorphic fungi, and may shed light on environmental persistence of these pathogens