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Background: Src kinase plays an important role in proliferation, survival, angiogenesis and metastasis in several malignancies including breast cancer. Therefore, inhibition of Src and other tyrosine kinases (TKs) represents a novel therapeutic approach. Dasatinib is a potent inhibitor of 5 oncogenic TKs, inhibits VEGF-stimulated proliferation, has potent bone anti-resorptive activity and selectively inhibits basal-type breast cancer growth. Preclinically, the combination of dasatinib and paclitaxel had superior antitumor activity to either agent alone. In a previous phase I study, we determined that, in combination with weekly paclitaxel, the optimum dose of dasatinib was 120mg. Of note, 4/9 (44%) patients treated at or above this dasatinib dose level had objective tumor response. We now present results from the phase II trial of this combination. Methods: Patients with MBC, ECOG PS 0-1, normal hepatic, renal, marrow function were eligible. Patients had measurable, HER2-negative metastatic breast cancer (MBC), ≤2 prior therapies for MBC. Treatment consisted of weekly paclitaxel 80 mg/m² IV 3/4 weeks + Dasatinib 120mg orally daily. Response was assessed by RECIST after every 8 weeks of therapy. Simon's two-stage optimal design was used to test the null hypothesis of a 15% response rate (RR) against the alternative of a 30% RR. In stage I, planned enrollment was 23 patients based on Type I and Type II errors of 10%. If 4 or more responses are observed, enrollment will be extended to 55 patients. Exploratory correlative biomarkers of clinical benefit include Src phosphorylation (p-Src) in peripheral blood mononuclear cells, plasma levels of VEGFR2 and collagen Type IV, circulating tumor cells (CTCs) and tumor gene expression profiling. Results: 21 patients (19 females, 2 male) have enrolled; median age 48 (range 30-79). Patients received a median of 1 prior therapy for MBC (range 0-2). 6 patients are not assessable for response: 1 has received <8 weeks treatment, 5 came off study for toxicity (2 hypersensitivity reaction to paclitaxel, 1 infection, 1 diarrhea/nausea, 1 bleeding likely related to anticoagulation). Among the 15 patients assessable for response, best response to date is as follows: 2 (13%) patients partial response, 11 (73%) patients stable disease (SD) and 2 (13%) patients progression of disease. Of patients with SD, 6/11 (55%) continue on treatment after median of 2 months (range 2-10) and 5/11 (45%) patients have come off study after median of 10 months (range 3-21). Most toxicities have been hematological and low grade. Diarrhea and neuropathy have generally been low grade and no new toxicities related to the combination have occurred since expansion into the phase II. Potential biomarkers of clinical benefit including, p-Src, VEGFR2, collagen Type IV, and CTCs will be presented. Conclusion: Data from this phase II has demonstrated preliminary evidence of activity for weekly paclitaxel and dasatinib 120mg in patients with MBC. These findings are consistent with data from this dose level in the earlier phase I study. Predictive biomarkers of clinical benefit are under investigation. [ABSTRACT FROM AUTHOR]

Background: Pertuzumab (P) is a monoclonal antibody which binds to extracellular domain II of HER2 distally from trastuzumab (H), disrupting HER2 dimerization and signaling. The CLEOPATRA phase III trial showed that HP + docetaxel in HER2+ metastatic breast cancer (MBC) prolonged progression-free survival (PFS) compared to placebo + H + docetaxel. We report preliminary results of a phase II study to evaluate the safety and efficacy of weekly paclitaxel with HP (THP). Methods: Patients (pts) with HER2+ MBC with 0-1 prior treatment (Rx) are eligible. Pts receive weekly (w) paclitaxel (80mg/m²), q3w trastuzumab (loading dose 8mg/kg → 6mg/kg), and q3w pertuzumab (flat loading dose 840mg → flat dose 420mg). The primary endpoint is PFS at 6 months (mo). Secondary endpoints include response, safety (including cardiac events), and tolerability. Evaluable pts are those who have started study Rx and are assessed at 6 mo for PFS. Left ventricular ejection fraction (LVEF) is monitored by echocardiogram every 3 mo. Cardiac events are defined as symptomatic LV systolic dysfunction (LVSD), non-LVSD cardiac death, or probable cardiac death. Results: As of 6-1 -12, 38 of the planned 69 pts were enrolled and 20 pts were evaluable at 6 mo. Median age is 52 years (range 32 to 72). A total of 11 pts (55%) previously received trastuzumab in the adjuvant or metastatic setting, and 8 pts (40%) were being treated in the second-line metastatic setting. Of the 20 evaluable pts, G 3/4 toxicities were sepsis (1 pt, 5%), cholecystitis (1 pt, 5%), fatigue (1 pt, 5%), skin ulceration (1 pt, 5%) and cystic macular degeneration (1 pt with prior prolonged Rx with paclitaxel, 5%). Common G 1/2 toxicities included alopecia (20 pts, 100%), peripheral neuropathy (20 pts, 100%), fatigue (18 pts, 90%), ALT/AST elevation (17 pts, 85%), diarrhea (15 pts, 75%), rash (13 pts, 65%), nail changes (10 pts, 50%), mucositis (9 pts, 45%), dry skin (8 pts, 40%), and nausea (8 pts, 40%). Median LVEF was 64% at baseline (range 50% to 69%), 60% at 3mo (range 50% to 73%), and 60% at 6mo (range 49% to 67%). There were no cardiac events. At 6 mo, 15/20 pts (75%) were progression-free (2 CR, 8 PR and 5 SD); 5 pts had progressed. The 6 mo PFS results for all 38 enrolled patients will be updated. Conclusions: Our single-center phase II study continues to accrue, with no clinically significant diarrhea or signal of increased cardiac toxicity to date. Pertuzumab was recently FDA-approved in combination with trastuzumab and docetaxel. If the estimate of safety and activity is similar to results with docetaxel in CLEOPATRA, this study will provide support for weekly paclitaxel as an alternative option in combination with trastuzumab and pertuzumab in this setting. [ABSTRACT FROM AUTHOR]

Importance: Diagnosing the site of origin for cancer is a pillar of disease classification that has directed clinical care for more than a century. Even in an era of precision oncologic practice, in which treatment is increasingly informed by the presence or absence of mutant genes responsible for cancer growth and progression, tumor origin remains a critical factor in tumor biologic characteristics and therapeutic sensitivity., Objective: To evaluate whether data derived from routine clinical DNA sequencing of tumors could complement conventional approaches to enable improved diagnostic accuracy., Design, Setting, and Participants: A machine learning approach was developed to predict tumor type from targeted panel DNA sequence data obtained at the point of care, incorporating both discrete molecular alterations and inferred features such as mutational signatures. This algorithm was trained on 7791 tumors representing 22 cancer types selected from a prospectively sequenced cohort of patients with advanced cancer., Results: The correct tumor type was predicted for 5748 of the 7791 patients (73.8%) in the training set as well as 8623 of 11 644 patients (74.1%) in an independent cohort. Predictions were assigned probabilities that reflected empirical accuracy, with 3388 cases (43.5%) representing high-confidence predictions (>95% probability). Informative molecular features and feature categories varied widely by tumor type. Genomic analysis of plasma cell-free DNA yielded accurate predictions in 45 of 60 cases (75.0%), suggesting that this approach may be applied in diverse clinical settings including as an adjunct to cancer screening. Likely tissues of origin were predicted from targeted tumor sequencing in 95 of 141 patients (67.4%) with cancers of unknown primary site. Applying this method prospectively to patients under active care enabled genome-directed reassessment of diagnosis in 2 patients initially presumed to have metastatic breast cancer, leading to the selection of more appropriate treatments, which elicited clinical responses., Conclusions and Relevance: These results suggest that the application of artificial intelligence to predict tissue of origin in oncologic practice can act as a useful complement to conventional histologic review to provide integrated pathologic diagnoses, often with important therapeutic implications.

Background: Overexpression and activation of tyrosine kinase Src has been linked to breast carcinogenesis and bone metastases. We showed the feasibility of combining the SRC inhibitor dasatinib with weekly paclitaxel in patients with metastatic breast cancer (MBC) and herein report the subsequent phase II trial., Patients and Methods: Patients had received ≤ 2 chemotherapy regimens for measurable, HER2-negative MBC. Patients received paclitaxel and dasatinib (120 mg daily) and were assessed according to Response Evaluation Criteria in Solid Tumors for overall response rate (ORR), the primary end point. Secondary end points included progression-free survival (PFS) and overall survival (OS). A 30% ORR (n = 55) was deemed worthy of further investigation. Exploratory biomarkers included N-telopeptide (NTX) and plasma vascular epidermal growth factor (VEGF) receptor 2 as predictors of clinical benefit., Results: From March 2010 to March 2014, 40 patients, including 2 men enrolled. The study was stopped early because of slow accrual. Overall, 32 patients (80%) had estrogen receptor-positive tumors and 23 (58%) had previously received taxanes. Of the 35 assessable patients, 1 (3%) had complete response and 7 (20%) partial response, resulting in an ORR of 23%. The median PFS and OS was 5.2 (95% confidence interval [CI], 2.9-9.9) and 20.6 (95% CI, 12.9-25.2) months, respectively. As expected, fatigue (75%), neuropathy (65%), and diarrhea (50%) were common side effects, but were generally low-grade. Median baseline NTX was similar in patients who had clinical benefit (8.2 nmol BCE) and no clinical benefit (10.9 nmol BCE). Similarly, median baseline VEGF levels were similar between the 2 groups; 93.0 pg/mL versus 83.0 pg/mL., Conclusion: This phase II study of dasatinib and paclitaxel was stopped early because of slow accrual but showed some clinical activity. Further study is not planned., (Copyright © 2018 Elsevier Inc. All rights reserved.)

By slow reaction between colorless Ag I W 2 O 2 F 9 and elemental F 2 in liquid anhydrous HF, violet platelike single crystals of Ag(WOF 5 ) 2 were grown. The crystal structure of Ag(WOF 5 ) 2 consists of layers built from Ag 2+ cations bridged by [WOF 5 ] - anions and not, as previously assumed, from infinite [Ag II -F] + ∞ chains and [W 2 O 2 F 9 ] - anions. A majority (97%) of the disordered Ag II cations are found with square-planar coordination of F/O ligands within the same layer, and they form additional long contacts with O/F atoms originating from the neighboring layers. The remaining 3% the of Ag(II) ions are coordinated only by F atoms in a square-planar fashion. The magnetic moments of Ag 2+ from the same layer are almost perfectly antiferromagnetically aligned. Weak ferromagnetic interlayer interactions cause a small tilt (∼1.5°) of the magnetic moments, resulting in canted antiferromagnetism. Because of the lowering of the symmetry of [WOF 5 ] - in the solid state, the vibrational spectra show more bands than expected for regular C 4v symmetry. The electronic spectrum of Ag(WOF 5 ) 2 is reported and analyzed.

Purpose: The CLEOPATRA (Clinical Evaluation of Trastuzumab and Pertuzumab) study demonstrated superior progression-free survival (PFS) and overall survival when pertuzumab was added to trastuzumab and docetaxel. Paclitaxel given once per week is effective and less toxic than docetaxel. We performed a phase II study to evaluate the efficacy and safety of pertuzumab and trastuzumab with paclitaxel given once per week., Patients and Methods: Patients with metastatic human epidermal growth factor receptor 2-positive breast cancer with zero to one prior therapy were enrolled. Treatment consisted of paclitaxel 80 mg/m(2) once per week plus trastuzumab (8 mg/kg loading dose → 6 mg/kg) once every 3 weeks plus pertuzumab (840 mg loading dose → 420 mg) once every 3 weeks, all given intravenously. The primary end point was 6-month PFS assessed by Kaplan-Meier methods., Results: From January 2011 to December 2013, we enrolled 69 patients: 51 (74%) and 18 (26%) treated in first- and second-line metastatic settings, respectively. At a median follow-up of 21 months (range, 3 to 38 months), 6-month PFS was 86% (95% CI, 75% to 92%). The median PFS was 19.5 months (95% CI, 14 to 26 months) overall. PFS was 24.2 months (95% CI, 14 months to not reached [NR]) and 16.4 months (95% CI, 8.5 months to NR) for those without and with prior treatment, respectively. At 1 year, Kaplan-Meier PFS was 70% (95% CI, 56% to 79%) overall, 71% (95% CI, 55% to 82%) for those without prior therapy, and 66% (95% CI, 40% to 83%) for those with prior therapy. Treatment was well-tolerated; there was no febrile neutropenia or symptomatic left ventricular systolic dysfunction., Conclusion: Paclitaxel given once per week with trastuzumab and pertuzumab is highly active and well tolerated and seems to be an effective alternative to docetaxel-based combination therapy., (© 2014 by American Society of Clinical Oncology.)

Background: Ganetespib is a small molecule, nongeldanamycin HSP90 inhibitor with potent inhibitory effects on HSP90-dependent oncoproteins of relevance to breast cancer pathogenesis. We therefore tested ganetespib in an unselected cohort of patients with MBC., Patients and Methods: Patients were treated with single agent ganetespib at 200 mg/m(2) once weekly for 3 weeks, on a 28-day cycle. Therapy was continued until disease progression. The primary end point was ORR using Reponse Evaluation Criteria in Solid Tumors version 1.1., Results: Twenty-two patients were enrolled with a median age of 51(range, 38-70) years and a median Eastern Cooperative Oncology Group performance status of 0 (range, 0-1). Most patients had at least 2 previous lines of chemotherapy in the metastatic setting. Most common toxicities, largely grade 1/2, were diarrhea, fatigue, nausea, and hypersensitivity reaction. The ORR in this unselected population was 9%, with all responses coming from the subset of patients with HER2-positive MBC (2/13; 15%). One patient with TNBC had objective tumor regression in the lung metastases. The clinical benefit rate (complete response + partial response + stable disease > 6 months) was 9%, median progression-free survival was 7 weeks (95% confidence interval [CI], 7-19), and median overall survival was 46 weeks (95% CI, 27-not applicable)., Conclusion: The study did not meet the prespecified criteria for ORR in the first stage of the Simon 2-stage model in this heavily pretreated unselected population of MBC. However, activity was observed in trastuzumab-refractory HER2-positive and TNBC. Ganetespib was well tolerated and responses in more targeted populations harboring specific HSP90-dependent oncoproteins justifies its further study, particularly as part of rational combinations., (Copyright © 2014 Elsevier Inc. All rights reserved.)