Showing papers by "Joan S. Brugge published in 2013"

Chaperone-mediated autophagy degrades mutant p53

Abstract: Missense mutations in the gene TP53, which encodes p53, one of the most important tumor suppressors, are common in human cancers. Accumulated mutant p53 proteins are known to actively contribute to tumor development and metastasis. Thus, promoting the rem

Abstract S1-02: Final analysis of a phase II 3-arm randomized trial of neoadjuvant trastuzumab or lapatinib or the combination of trastuzumab and lapatinib, followed by six cycles of docetaxel and carboplatin with trastuzumab and/or lapatinib in patients with HER2+ breast cancer (TRIO-US B07)

Abstract: BACKGROUND: The BCIRG006 study (Slamon, et al. N Engl J Med 2011) demonstrated similar efficacy and superior safety of adjuvant docetaxel, carboplatin, and trastuzumab (TCH) over an anthracycline regimen in HER2+ BC. Dual HER2-blockade with lapatinib (Ty) and H demonstrated synergism preclinically and significant activity in the metastatic and neoadjuvant settings (Blackwell, et al. J Clin Oncol 2012; Baselga, et al. Lancet 2012). This study evaluates the clinical and molecular effects of neoadjuvant TC plus H and/or Ty in HER2+ BC. METHODS: This is an open-label, randomized phase II study in which pts with stage I-III, operable BC were assigned to 1 of 3 arms: Arm 1-TCH, Arm 2-TCTy, and Arm 3-TCHTy. To test the safety of TCHTy, the first 20 pts received TCHTy. The remaining pts were randomized (1:1:1) to the 3 arms. Pts received a run-in cycle of Ty (1000 mg/d days 1-21) and/or H (8 mg/kg iv), followed by 6 cycles of q3-wkly TC (T: 75 mg/m2, C: AUC 5 or 6) plus H (6 mg/kg) and/or Ty (1000 mg/d d1-21). The first 6 pts were part of a dose-escalation evaluation of C and received AUC5. The remaining pts received C at AUC6. Biopsies were taken at baseline, post run-in cycle, and at surgery. The primary endpoint was pCR rate in each arm (defined as the absence of viable tumor cells in both the breast and axillary lymph nodes). Safety evaluation, molecular effects, and cardiac events were secondary endpoints. RESULTS: From October 2008 to December 2012, 130 pts were enrolled at 13 centers in the US. Two pts withdrew from study prior to starting any Tx (1 ineligible, 1 withdrew consent) and are excluded from analyses. As of May 2013, complete data was available for 106 pts: 32 in Arm 1, 27 in Arm 2 and 47 in Arm 3. Of these, 16 patients came off study tx prior to surgery (6 in Arm 2, 10 Arm 3) but are included in the ITT analyses. Median age was 48 years (range 27-76). Hormone receptors were both negative (HR-) in 43 pts (41%) and were ER and/or PR positive (HR+) in 63 (59%). At presentation, 5 (5%) pts had clinical stage I, 71 (67%) stage II and 30 (28%) stage III BC. The overall pCR was 42% (45/106), including 43% (13/30) in Arm 1, 25% (7/28) in Arm 2 and 52% (25/48) in Arm 3 (Chi-squared test P = 0.069). Using a pair-wise comparison, pCR is significantly lower in Arm 2 than in Arm 3 (p = 0.021) but no difference was detected between Arms 1 and 2 (p = 0.14) or 1 and 3 (p = 0.45) The pCR in HR+ and HR- tumors were 33% HR+ vs 58% HR- for Arm 1, 13% HR+ vs 42% HR- for Arm 2, and 41% HR+ vs 68% HR- for Arm 3. There were no deaths and no episodes of CHF reported. LVEF decreased >10% from baseline and below the lower limits of normal in 5 pts (1 pt in Arm 1, 3 in Arm 2, 1 in Arm 3). The most common gr >3 AEs in Arms 1/2/3 respectively were pain (10%, 25%, 17%), diarrhea (3%, 11%, 27%), neutropenia (7%, 11%, 13%), anemia (10%, 11%, 4%) hypokalemia (7%, 7%, 8%), and infection (7%, 11%, 6%). CONCLUSIONS: To our knowledge, this is the first report of this 4–drug combination in the neoadjuvant setting. Final efficacy, safety and molecular analyses from all 128 pts will be presented. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S1-02.

Evidence for a multipotent mammary progenitor with pregnancy-specific activity

Abstract: The mouse mammary gland provides a powerful model system for studying processes involved in epithelial tissue development. Although markers that enrich for mammary stem cells and progenitors have been identified, our understanding of the mammary developmental hierarchy remains incomplete. We used the MMTV promoter linked to the reverse tetracycline transactivator to induce H2BGFP expression in the mouse mammary gland. Mammary epithelial cells (MECs) from virgin mice were sorted by flow cytometry for expression of the mammary stem cell/progenitor markers CD24 and CD29, and H2BGFP. Sorted populations were analyzed for in vivo repopulation ability, expression of mammary lineage markers, and differential gene expression. The reconstituting activity of CD24+/CD29+ cells in cleared fat pad transplantation assays was not distinguished in GFP+ compared to GFP- subpopulations. However, within the CD24+/CD29lo luminal progenitor-enriched population, H2BGFP+, but not H2BGFP-, MECs formed mammary structures in transplantation assays; moreover, this activity was dramatically enhanced in pregnant recipients. These outgrowths contained luminal and myoepithelial mammary lineages and produced milk, but lacked the capacity for serial transplantation. Transcriptional microarray analysis revealed that H2BGFP+/CD24+/CD29lo MECs are distinct from H2BGFP-/CD24+/CD29lo MECs and enriched for gene expression signatures with both the stem cell (CD24+/CD29+) and luminal progenitor (CD24+/CD29lo/CD61+) compartments. We have identified a population of MECs containing pregnancy-activated multipotent progenitors that are present in the virgin mammary gland and contribute to the expansion of the mammary gland during pregnancy.