North American fossil anguid lizards

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Lower vertebrates from the late Cretaceous Hell Creek Formation, McCone County, Montana

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Abstract PD1-6: A randomized phase II neoadjuvant study of cisplatin, paclitaxel with or without everolimus (an mTOR inhibitor) in patients with stage II/III triple-negative breast cancer (TNBC)

Abstract Background: mTOR inhibitors can activate p73, a pro-apoptotic member of the p53 family, and enhance the sensitivity of breast cancer cells to cisplatin and paclitaxel. Thus, we hypothesized that combined use of the mTOR inhibitor everolimus, cisplatin, and paclitaxel would have synergistic anti-tumor effects in TNBC. Methods: Patients with clinical stage II/III TNBC were assigned (2:1) to weekly cisplatin 25 mg/m2 + paclitaxel 80 mg/m2 ± daily everolimus 5 mg for 12 weeks, until definitive surgery. Biopsy specimens were obtained in 100% of patients at baseline, at day 5 of cycle 1 and at surgery. Primary endpoint was pathological complete response (pCR). The study design provided 90% power to detect a difference in pCR rate of 35% vs. 20% with a two-sided significance level equal to 0.1 (type I error) for each arm. Results: A total of 145 patients were accrued between 2009 and 2013. To date, 14 patients have not yet completed surgery, and 11 patients were not evaluable (study discontinuation due to disease progression, toxicity or withdrawal). Baseline characteristics between arms were similar and well balanced: median age was 52 (28 – 81), median breast tumor size was 2 cm (0.1 – 7.6), 72% of tumors were histologic grade III, and 70% of patients had clinical stage III disease. Clinical outcomes are summarized in Table 1. Clinical outcomesEvaluable patientsEverolimusN = 82PlaceboN = 38OverallN = 120Pathological responseN%N%N%pCR (pT0N0)293516424538Near pCR (pT1aN0)17215132218Residual disease364417455344Clinical ResponseN%N%N%CR465721556759PR232814373629SD1113381511PD220-21 Despite similar rates of pCR and clinical response in both arms, the combination of cisplatin/paclitaxel provided comparable pCR rates to anthracycline/cyclophosphamide/taxane containing regimens administered for longer periods of time. Most common adverse events are summarized in Table 2. Adverse events(%)Grade 1 and 2Grade 3 and 4 EvePlacEvePlacNeutropenia26272611Thrombocytopenia409  Anemia5975 2Rash4927 2Fatigue61753 Nausea6064 2Diarrhea30292 Dyspepsia3035  Mucositis3920  Hyperglycemia5140 2Transaminase elevation60183 Pneumonitis1    TNBC subtyping (Lehmann et al. JCI 2009), DNA mutations and alterations, as well as markers of proliferation, apoptosis, PI3K/mTOR and DNA damage response signaling will be presented. Preliminary analysis of Ki67 in a subset of tumors suggest that a reduction in Ki67 (day 5 biopsy) is associated with increased pCR rate. Tumors with androgen receptor expression exhibited a very low pCR rate. Conclusion: To our knowledge, this is the largest randomized neoadjuvant study in TNBC with a PI3K/mTOR pathway inhibitor. Results suggest that the paclitaxel/cisplatin combination is well tolerated and active in TNBC. The addition of Everolimus was associated with more adverse events and did not improve pCR or clinical response rates. A molecular signature or biomarker predictive of benefit from the paclitaxel/cisplatin combination is currently under investigation, and will be presented at the time of the meeting. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD1-6.</jats:p

Short Preoperative Treatment With Erlotinib Inhibits Tumor Cell Proliferation in Hormone Receptor Positive Breast Cancers

PURPOSE: To administer the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib to patients with operable untreated breast cancer during the immediate preoperative period and to measure an antiproliferative and/or a proapoptotic effect in the post-therapy specimen and determine a biomarker profile associated with evidence of erlotinib-mediated cellular activity. PATIENTS AND METHODS: Newly diagnosed patients with stages I to IIIA invasive breast cancer were treated with erlotinib 150 mg/d orally for 6 to 14 days until the day before surgery. Erlotinib plasma levels were measured by tandem mass spectrometry the day of surgery. Drug-induced changes in tumor cell proliferation and apoptosis were assessed by Ki67 immunohistochemistry and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling analysis, respectively, in biopsies from the pretherapy and surgical specimens. Biopsies were also evaluated for P-EGFR, P-HER-2, P-MAPK, P-Akt, P-S6, and S118 P-ERalpha. RESULTS: In drug-sensitive PC9 xenografts, 5 days of treatment with erlotinib were enough to induce a maximal inhibition of cell proliferation and induction of apoptosis. Forty-one patients completed preoperative treatment with erlotinib. Grade </= 2 rash and diarrhea were the main toxicities. Erlotinib inhibited tumor cell proliferation (Ki67), P-EGFR, and P-HER-2. The inhibition of proliferation occurred in estrogen receptor (ER) -positive but not in human epidermal growth factor receptor 2 (HER-2) -positive or triple-negative cancers. Treatment was associated with a significant reduction of P-MAPK, P-Akt, P-S6, and S118 P-ERalpha in hormone receptor-positive cancers. CONCLUSION: A presurgical approach to evaluate cellular responses to new drugs is feasible in breast cancer. EGFR inhibitors are worthy of testing against ER-positive breast cancers but are unlikely to have clinical activity against HER-2\Npositive or triple-negative breast cancers