Publications by authors named "Mary Ellen Moynahan"

31 Publications

Alterations in and promote clinical resistance to alpelisib plus aromatase inhibitors.

Nat Cancer 2020 Apr 23;1(4):382-393. Epub 2020 Mar 23.

Human Oncology and Pathogenesis Program, MSKCC, New York, NY.

Alpelisib is a selective inhibitor of PI3Kα, shown to improve outcomes for mutant, hormone receptor positive (HR+) metastatic breast cancers (MBC) when combined with antiestrogen therapy. To uncover mechanisms of resistance, we conducted a detailed, longitudinal analysis of tumor and plasma circulating tumor DNA among such patients from a phase I/II trial combining alpelisib with an aromatase inhibitor (AI) (NCT01870505). The trial's primary objective was to establish safety with maculopapular rash emerging as the most common grade 3 adverse event (33%). Among 44 evaluable patients, the observed clinical benefit rate was 52%. Correlating genetic alterations with outcome, we identified loss-of-function mutations in 25% of patients with resistance. activating mutations also expanded in number and allele fraction during treatment and were associated with resistance. These data indicate that genomic alterations that mediate resistance to alpelisib or antiestrogen may promote disease progression and highlight loss as a recurrent mechanism of resistance to PI3Kα inhibition.
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http://dx.doi.org/10.1038/s43018-020-0047-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450824PMC
April 2020

Tumor PIK3CA Genotype and Prognosis in Early-Stage Breast Cancer: A Pooled Analysis of Individual Patient Data.

J Clin Oncol 2018 04 22;36(10):981-990. Epub 2018 Feb 22.

Dimitrios Zardavas and Debora Fumagalli, Breast International Group; Christos Sotiriou, Université Libre de Bruxelles, Brussels, Belgium; Luc te Marvelde and Roger L. Milne, Cancer Council; Roger L. Milne and Sherene Loi, University of Melbourne, Melbourne; Barry Iacopetta, University of Western Australia, Western Australia; Sandra O'Toole and Elena Lopez-Knowles, Garvan Institute of Medical Research, Darlinghurst, Australia; George Fountzilas and Vassiliki Kotoula, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, Thessaloniki; Evangelia Razis, Hygeia Hospital; George Papaxoinis, Hippokration Hospital, Athens, Greece; Heikki Joensuu, Helsinki University Hospital and University of Helsinki, Helsinki, Finland; Mary Ellen Moynahan, Memorial Sloan Kettering Cancer Center, New York, NY; Bryan T. Hennessy, Beaumont Hospital and Royal College of Surgeons, Dublin, Ireland; Ivan Bieche, Curie Institut, Paris; Thomas Bachelot, Centre de Recherche en Cancérologie de Lyon, Lyon; Stefan Michiels, Gustave Roussy and Inserm, Univ. Paris-Sud, Univ. Paris-Saclay, Villejuif, France; Lao H. Saal, Lund University, Lund; Olle Stal, Qing Wang, and Gizeh Perez-Tenorio, Linköping University, Linköping, Sweden; Jeanette Dupont Jensen, University of Southern Denmark, on behalf of the Danish Breast Cancer Cooperative Group, Odense, Denmark; Elena Lopez-Knowles, Royal Marsden NHS Trust and Institute of Cancer Research, London; Daniel W. Rea, University of Birmingham, Birmingham, United Kingdom; Mattia Barbaraeschi, Santa Chiara Hospital, Trento, Italy; Shinzaburo Noguchi, Osaka University, Osaka Japan; Hatem A. Azim Jr, American University of Beirut (AUB), Beirut, Lebanon; Enrique Lerma, Universitat Autònoma de Barcelona, Barcelona, Spain; Cornelis J.H. can de Velde, Leiden University Medical Center, Leiden, the Netherlands; Vicky Sabine, University of Guelph, Guelph; John M.S. Bartlett, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.

Purpose Phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha ( PIK3CA) mutations are frequently observed in primary breast cancer. We evaluated their prognostic relevance by performing a pooled analysis of individual patient data. Patients and Methods Associations between PIK3CA status and clinicopathologic characteristics were tested by applying Cox regression models adjusted for age, tumor size, nodes, grade, estrogen receptor (ER) status, human epidermal growth factor receptor 2 (HER2) status, treatment, and study. Invasive disease-free survival (IDFS) was the primary end point; distant disease-free survival (DDFS) and overall survival (OS) were also assessed, overall and by breast cancer subtypes. Results Data from 10,319 patients from 19 studies were included (median OS follow-up, 6.9 years); 1,787 patients (17%) received chemotherapy, 4,036 (39%) received endocrine monotherapy, 3,583 (35%) received both, and 913 (9%) received none or their treatment was unknown. PIK3CA mutations occurred in 32% of patients, with significant associations with ER positivity, increasing age, lower grade, and smaller size (all P < .001). Prevalence of PIK3CA mutations was 18%, 22%, and 37% in the ER-negative/HER2-negative, HER2-positive, and ER-positive/HER2-negative subtypes, respectively. In univariable analysis, PIK3CA mutations were associated with better IDFS (HR, 0.77; 95% CI, 0.71 to 0.84; P < .001), with evidence for a stronger effect in the first years of follow-up (0 to 5 years: HR, 0.73; 95% CI, 0.66 to 0.81; P < .001; 5 to 10 years: HR, 0.82; 95% CI, 0.68 to 0.99; P = .037); > 10 years: (HR, 1.15; 95% CI, 0.84 to 1.58; P = .38; P heterogeneity = .02). In multivariable analysis, PIK3CA genotype remained significant for improved IDFS ( P = .043), but not for the DDFS and OS end points. Conclusion In this large pooled analysis, PIK3CA mutations were significantly associated with a better IDFS, DDFS, and OS, but had a lesser prognostic effect after adjustment for other prognostic factors.
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http://dx.doi.org/10.1200/JCO.2017.74.8301DOI Listing
April 2018

ATM loss leads to synthetic lethality in BRCA1 BRCT mutant mice associated with exacerbated defects in homology-directed repair.

Proc Natl Acad Sci U S A 2017 07 28;114(29):7665-7670. Epub 2017 Jun 28.

Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065;

BRCA1 is essential for homology-directed repair (HDR) of DNA double-strand breaks in part through antagonism of the nonhomologous end-joining factor 53BP1. The ATM kinase is involved in various aspects of DNA damage signaling and repair, but how ATM participates in HDR and genetically interacts with BRCA1 in this process is unclear. To investigate this question, we used the mouse model carrying a mutation in the BRCA1 C-terminal domain of BRCA1. Whereas ATM loss leads to a mild HDR defect in adult somatic cells, we find that ATM inhibition leads to severely reduced HDR in cells. Consistent with a critical role for ATM in HDR in this background, loss of ATM leads to synthetic lethality of mice. Whereas both ATM and BRCA1 promote end resection, which can be regulated by 53BP1, deletion does not rescue the HDR defects of mutant cells, in contrast to mutant cells. These results demonstrate that ATM has a role in HDR independent of the BRCA1-53BP1 antagonism and that its HDR function can become critical in certain contexts.
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http://dx.doi.org/10.1073/pnas.1706392114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5530697PMC
July 2017

Correlation between PIK3CA mutations in cell-free DNA and everolimus efficacy in HR, HER2 advanced breast cancer: results from BOLERO-2.

Br J Cancer 2017 Mar 9;116(6):726-730. Epub 2017 Feb 9.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

Background: The current analysis was performed to evaluate the impact of PIK3CA hotspot mutations on everolimus efficacy in BOLERO-2 participants, using cell-free DNA (cfDNA) from plasma samples collected at the time of patient randomisation.

Methods: PIK3CA H1047R, E545K, and E542K mutations in plasma-derived cfDNA were analysed by droplet digital PCR (ddPCR). Median PFS was estimated for patient subgroups defined by PIK3CA mutations in each treatment arm.

Results: Among 550 patients included in cfDNA analysis, median PFS in everolimus vs placebo arms was similar in patients with tumours that had wild-type or mutant PIK3CA (hazard ratio (HR), 0.43 and 0.37, respectively). Everolimus also prolonged median PFS in patients with PIK3CA H1047R (HR, 0.37) and E545K/E542K mutations (HR=0.30) with a similar magnitude.

Conclusions: Mutation analysis of plasma-derived cfDNA by ddPCR suggests that PFS benefit of everolimus was maintained irrespective of PIK3CA genotypes, consistent with the previous analysis of archival tumour DNA by next-generation sequencing.
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http://dx.doi.org/10.1038/bjc.2017.25DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5355930PMC
March 2017

Robust homology-directed repair within mouse mammary tissue is not specifically affected by Brca2 mutation.

Nat Commun 2016 10 25;7:13241. Epub 2016 Oct 25.

Developmental Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA.

The mammary gland undergoes significant proliferative stages after birth, but little is known about how the developmental changes impact DNA double-strand break (DSB) repair. Mutations in multiple genes involved in homology-directed repair (HDR), considered a particularly accurate pathway for repairing DSBs, are linked to breast cancer susceptibility, including BRCA2. Using reporter mice that express an inducible endonuclease, we find that HDR is particularly robust in mammary tissue during puberty and pregnancy, accounting for 34-40% of detected repair events, more than in other tissues examined. Brca2 hypomorphic mutation leads to HDR defects in mammary epithelium during puberty and pregnancy, including in different epithelial lineages. Notably, a similar dependence on Brca2 is observed in other proliferative tissues, including small intestine epithelium. Our results suggest that the greater reliance on HDR in the proliferating mammary gland, rather than a specific dependence on BRCA2, may increase its susceptibility to tumorigenesis incurred by BRCA2 mutation.
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http://dx.doi.org/10.1038/ncomms13241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5093336PMC
October 2016

Prevalence of ESR1 Mutations in Cell-Free DNA and Outcomes in Metastatic Breast Cancer: A Secondary Analysis of the BOLERO-2 Clinical Trial.

JAMA Oncol 2016 Oct;2(10):1310-1315

Memorial Sloan Kettering Cancer Center, New York, New York.

Importance: Estrogen receptor α (ESR1) mutations found in metastatic breast cancer (MBC) promote ligand-independent receptor activation and resistance to estrogen-deprivation therapy in laboratory models. The prevalence of these mutations and their potential impact on clinical outcomes has not been established.

Objective: To determine the prevalence of ESR1 mutations (Y537S and D538G) in estrogen receptor (ER)-positive MBC and determine whether mutation is associated with inferior outcomes.

Design, Setting, And Participants: From December 16, 2014, to August 26, 2015, we analyzed cell-free DNA (cfDNA) from baseline plasma samples from participants in the BOLERO-2 double-blind phase 3 study that randomized patients from 189 centers in 24 countries with MBC to exemestane plus placebo or exemestane plus everolimus. The study enrolled postmenopausal women with a diagnosis of MBC and prior exposure to an aromatase inhibitor. Baseline plasma samples were available from 541 of 724 patients (74.7%). We assessed the effect of mutation on overall survival of the population and the effect of mutation on progression-free survival (PFS) by treatment arm.

Interventions: Patients were randomized to treatment with exemestane (25 mg oral daily) together with everolimus (10 mg oral daily) or with placebo.

Main Outcomes And Measures: The 2 most frequent mutations in ESR1 (Y537S and D538G) were analyzed from cfDNA using droplet digital polymerase chain reaction and samples scored as wild-type, D538G, Y537S, or double mutant. Cox-proportional hazards model was used to assess PFS in patient subgroups defined by mutations, and the effect of each mutation on overall survival.

Results: Of 541 evaluable patients, 156 (28.8%) had ESR1 mutation D538G (21.1%) and/or Y537S (13.3%), and 30 had both. These mutations were associated with shorter overall survival (wild-type, 32.1 months [95% CI, 28.09-36.40 months]; D538G, 25.99 months [95% CI, 19.19-32.36 months]; Y537S, 19.98 months [13.01-29.31 months]; both mutations, 15.15 months [95% CI, 10.87-27.43 months]). The D538G group (hazard ratio, 0.34 [95% CI, 0.02-0.57]) derived a similar PFS benefit as wild type from addition of everolimus to exemestane.

Conclusions And Relevance: ESR1 mutations are prevalent in ER-positive aromatase inhibitor-treated MBC. Both Y537S and D538G mutations are associated with more aggressive disease biology.

Trial Registration: clinicaltrials.gov Identifier: NCT00863655.
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http://dx.doi.org/10.1001/jamaoncol.2016.1279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5063698PMC
October 2016

PARP Inhibitors in Clinical Use Induce Genomic Instability in Normal Human Cells.

PLoS One 2016 18;11(7):e0159341. Epub 2016 Jul 18.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.

Poly(ADP-ribose) polymerases (PARPs) are the first proteins involved in cellular DNA repair pathways to be targeted by specific inhibitors for clinical benefit. Tumors harboring genetic defects in homologous recombination (HR), a DNA double-strand break (DSB) repair pathway, are hypersensitive to PARP inhibitors (PARPi). Early phase clinical trials with PARPi have been promising in patients with advanced BRCA1 or BRCA2-associated breast, ovary and prostate cancer and have led to limited approval for treatment of BRCA-deficient ovary cancer. Unlike HR-defective cells, HR-proficient cells manifest very low cytotoxicity when exposed to PARPi, although they mount a DNA damage response. However, the genotoxic effects on normal human cells when agents including PARPi disturb proficient cellular repair processes have not been substantially investigated. We quantified cytogenetic alterations of human cells, including primary lymphoid cells and non-tumorigenic and tumorigenic epithelial cell lines, exposed to PARPi at clinically relevant doses by both sister chromatid exchange (SCE) assays and chromosome spreading. As expected, both olaparib and veliparib effectively inhibited poly-ADP-ribosylation (PAR), and caused marked hypersensitivity in HR-deficient cells. Significant dose-dependent increases in SCEs were observed in normal and non-tumorigenic cells with minimal residual PAR activity. Clinically relevant doses of the FDA-approved olaparib led to a marked increase of SCEs (5-10-fold) and chromatid aberrations (2-6-fold). Furthermore, olaparib potentiated SCE induction by cisplatin in normal human cells. Our data have important implications for therapies with regard to sustained genotoxicity to normal cells. Genomic instability arising from PARPi warrants consideration, especially if these agents will be used in people with early stage cancers, in prevention strategies or for non-oncologic indications.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0159341PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4948780PMC
July 2017

When Genome Maintenance Goes Badly Awry.

Mol Cell 2016 06;62(5):777-87

Developmental Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA. Electronic address:

Genetic abnormalities are present in all tumor types, although the frequency and type can vary. Chromosome abnormalities include highly aberrant structures, particularly chromothriptic chromosomes. The generation of massive sequencing data has illuminated the scope of the mutational burden in cancer genomes, identifying patterns of mutations (mutation signatures), which have the potential to shed light on the relatedness and etiologies of cancers and impact therapy response. Some mutation patterns are clearly attributable to disruptions in pathways that maintain genomic integrity. Here we review recent advances in our understanding of genetic changes occurring in cancers and the roles of genome maintenance pathways.
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http://dx.doi.org/10.1016/j.molcel.2016.05.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4966655PMC
June 2016

Phase III Trial Evaluating Letrozole As First-Line Endocrine Therapy With or Without Bevacizumab for the Treatment of Postmenopausal Women With Hormone Receptor-Positive Advanced-Stage Breast Cancer: CALGB 40503 (Alliance).

J Clin Oncol 2016 08 2;34(22):2602-9. Epub 2016 May 2.

Maura N. Dickler, Mary Ellen Moynahan, Diana E. Lake, and Clifford A. Hudis, Memorial Sloan Kettering Cancer Center, New York, NY; William T. Barry, Dana-Farber Cancer Institute; Eric P. Winer, Dana-Farber/Partners Cancer Care, Boston, MA; Constance T. Cirrincione, Duke University, Durham, NC; Matthew J. Ellis, Baylor College of Medicine; Debasish Tripathy, The University of Texas MD Anderson Cancer Center, Houston, TX; Federico Innocenti and Lisa A. Carey, University of North Carolina at Chapel Hill, Chapel Hill, NC; Arti Hurria, City of Hope, Duarte; Hope S. Rugo, University of California at San Francisco, San Francisco, CA; Olwen Hahn, Alliance for Clinical Trials in Oncology, Chicago, IL; and Bryan P. Schneider, Indiana University School of Medicine, Indianapolis, IN.

Purpose: To investigate whether anti-vascular endothelial growth factor therapy with bevacizumab prolongs progression-free survival (PFS) when added to first-line letrozole as treatment of hormone receptor-positive metastatic breast cancer (MBC).

Patients And Methods: Women with hormone receptor-positive MBC were randomly assigned 1:1 in a multicenter, open-label, phase III trial of letrozole (2.5 mg orally per day) with or without bevacizumab (15 mg/kg intravenously once every 3 weeks) within strata defined by measurable disease and disease-free interval. This trial had 90% power to detect a 50% improvement in median PFS from 6 to 9 months. Using a one-sided α = .025, a target sample size of 352 patients was planned.

Results: From May 2008 to November 2011, 350 women were recruited; 343 received treatment and were observed for efficacy and safety. Median age was 58 years (range, 25 to 87 years). Sixty-two percent had measurable disease, and 45% had de novo MBC. At a median follow-up of 39 months, the addition of bevacizumab resulted in a significant reduction in the hazard of progression (hazard ratio, 0.75; 95% CI, 0.59 to 0.96; P = .016) and a prolongation in median PFS from 15.6 months with letrozole to 20.2 months with letrozole plus bevacizumab. There was no significant difference in overall survival (hazard ratio, 0.87; 95% CI, 0.65 to 1.18; P = .188), with median overall survival of 43.9 months with letrozole versus 47.2 months with letrozole plus bevacizumab. The largest increases in incidence of grade 3 to 4 treatment-related toxicities with the addition of bevacizumab were hypertension (24% v 2%) and proteinuria (11% v 0%).

Conclusion: The addition of bevacizumab to letrozole improved PFS in hormone receptor-positive MBC, but this benefit was associated with a markedly increased risk of grade 3 to 4 toxicities. Research on predictive markers will be required to clarify the role of bevacizumab in this setting.
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http://dx.doi.org/10.1200/JCO.2015.66.1595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5012690PMC
August 2016

Phase II study of paclitaxel given once per week along with trastuzumab and pertuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer.

J Clin Oncol 2015 Feb 29;33(5):442-7. Epub 2014 Dec 29.

All authors: Memorial Sloan Kettering Cancer Center, New York, NY.

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.
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http://dx.doi.org/10.1200/JCO.2014.57.1745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5747317PMC
February 2015

A phase II open-label study of ganetespib, a novel heat shock protein 90 inhibitor for patients with metastatic breast cancer.

Clin Breast Cancer 2014 Jun 28;14(3):154-60. Epub 2013 Dec 28.

Memorial Sloan-Kettering Cancer Center, New York, NY; Weil Cornell Medical College. Electronic address:

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.
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http://dx.doi.org/10.1016/j.clbc.2013.12.012DOI Listing
June 2014

Phase II trial of bicalutamide in patients with androgen receptor-positive, estrogen receptor-negative metastatic Breast Cancer.

Clin Cancer Res 2013 Oct 21;19(19):5505-12. Epub 2013 Aug 21.

Authors' Affiliations: Breast Cancer Medicine Service, Departments of Pathology, Biostatistics, and Radiology, Memorial Sloan-Kettering Cancer Center; Weill Medical College of Cornell University, New York; Dana-Farber Cancer Institute; Massachusetts General Hospital, Boston, Massachusetts; Mayo Clinic, Rochester, Minnesota; Georgetown Lombardi Comprehensive Cancer Center, Washington, District of Columbia; University of North Carolina at Chapel Hill, Chapel Hill; Duke University Medical Center, Durham, North Carolina; University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, California; University of Alabama at Birmingham, Birmingham, Alabama; and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, Maryland.

Purpose: Patients with hormone receptor-negative breast cancer generally do not benefit from endocrine-targeted therapies. However, a subset with androgen receptor (AR) expression is predicted to respond to antiandrogen therapies. This phase II study explored bicalutamide in AR-positive, estrogen receptor (ER), and progesterone receptor (PgR)-negative metastatic breast cancer.

Experimental Design: Tumors from patients with ER/PgR-negative advanced breast cancer were tested centrally for AR [immunohistochemistry (IHC) > 10% nuclear staining considered positive]. If either the primary or a metastatic site was positive, patients were eligible to receive the AR antagonist bicalutamide at a dose of 150 mg daily. Clinical benefit rate (CBR), the primary endpoint, was defined as the total number of patients who show a complete response (CR), partial response (PR), or stable disease (SD) > 6 months; secondary endpoints included progression-free survival (PFS) and toxicity. Correlative studies included measurement of circulating endocrine markers and IHC surrogates for basal-like breast cancer.

Results: Of 424 patients with ER/PgR-negative breast cancer, 12% tested AR-positive. The 6-month CBR was 19% [95% confidence interval (CI), 7%-39%] for bicalutamide. The median PFS was 12 weeks (95% CI, 11-22 weeks). Bicalutamide was well-tolerated with no grade 4/5 treatment-related adverse events observed.

Conclusion: AR was expressed in 12% of patients with ER/PgR-negative breast cancer screened for this trial. The CBR of 19% observed with bicalutamide shows proof of principle for the efficacy of minimally toxic androgen blockade in a select group of patients with ER/PgR-negative, AR-positive breast cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-12-3327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4086643PMC
October 2013

Randomized phase II trial of weekly vs. every 2 weeks vs. every 3 weeks nanoparticle albumin-bound paclitaxel with bevacizumab as first-line chemotherapy for metastatic breast cancer.

Clin Breast Cancer 2013 Aug;13(4):239-246.e1

Memorial Sloan-Kettering Cancer Center, Department of Medicine, Division of Solid Tumor Oncology, New York, NY 10065, USA.

Background: Nanoparticle albumin-bound paclitaxel (nab-P) and bevacizumab have each demonstrated efficacy in patients with MBC. This trial was designed to further develop nab-P by evaluating its efficacy and safety using every 3 weeks (q3w), every 2 weeks (q2w), or weekly scheduling in combination with bevacizumab as first-line treatment of MBC.

Patients And Methods: This open-label phase II study randomized patients to nab-P 260 mg/m(2) q3w (arm A) vs. 260 mg/m(2) q2w with filgrastim (arm B) vs. 130 mg/m(2) weekly uninterrupted, all with bevacizumab (15 mg/kg q3w arm A, 10 mg/kg q2w arms B and C). The primary endpoints were overall response rate (ORR) and toxicity. Time to tumor progression (TTP) and overall survival were secondary endpoints.

Results: Of 212 patients randomized, 208 (arm A, 75; arm B, 54; arm C, 79) were treated. Arm B was closed early due to toxicity, with more grade ≥ 2 fatigue (arm A, 46%; arm B, 62%; arm C, 62%) and bone pain (arm A, 11%; arm B, 23%; arm C, 5%). Neurotoxicity grade ≥ 2 was equivalent across the arms (> 50%) and reversible for most patients. Febrile neutropenia occurred in ≤ 3% of patients in all arms. ORR was similar among the arms (arm A, 45%; arm B, 41%; arm C, 46%). Median TTP was slightly longer in arm C (9.0 months) vs. arms A (8.0 months) and B (5.8 months) (overall, P = .105).

Conclusions: Significant antitumor activity was observed in all the arms. Weekly nab-P with bevacizumab appeared to have the highest therapeutic index. However, sensory neuropathy was treatment limiting, which suggests that a 3 weeks on and 1 week off schedule should be explored.
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http://dx.doi.org/10.1016/j.clbc.2013.02.008DOI Listing
August 2013

Double-strand break repair by homologous recombination in primary mouse somatic cells requires BRCA1 but not the ATM kinase.

Proc Natl Acad Sci U S A 2013 Apr 18;110(14):5564-9. Epub 2013 Mar 18.

Developmental Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.

Homology-directed repair (HDR) is a critical pathway for the repair of DNA double-strand breaks (DSBs) in mammalian cells. Efficient HDR is thought to be crucial for maintenance of genomic integrity during organismal development and tumor suppression. However, most mammalian HDR studies have focused on transformed and immortalized cell lines. We report here the generation of a Direct Repeat (DR)-GFP reporter-based mouse model to study HDR in primary cell types derived from diverse lineages. Embryonic and adult fibroblasts from these mice as well as cells derived from mammary epithelium, ovary, and neonatal brain were observed to undergo HDR at I-SceI endonuclease-induced DSBs at similar frequencies. When the DR-GFP reporter was crossed into mice carrying a hypomorphic mutation in the breast cancer susceptibility gene Brca1, a significant reduction in HDR was detected, showing that BRCA1 is critical for HDR in somatic cell types. Consistent with an HDR defect, Brca1 mutant mice are highly sensitive to the cross-linking agent mitomycin C. By contrast, loss of the DSB signaling ataxia telangiectasia-mutated (ATM) kinase did not significantly alter HDR levels, indicating that ATM is dispensable for HDR. Notably, chemical inhibition of ATM interfered with HDR. The DR-GFP mouse provides a powerful tool for dissecting the genetic requirements of HDR in a diverse array of somatic cell types in a normal, nontransformed cellular milieu.
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http://dx.doi.org/10.1073/pnas.1216824110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3619303PMC
April 2013

Reduced proficiency in homologous recombination underlies the high sensitivity of embryonal carcinoma testicular germ cell tumors to Cisplatin and poly (adp-ribose) polymerase inhibition.

PLoS One 2012 12;7(12):e51563. Epub 2012 Dec 12.

Department of Biomedicine and Prevention, Section of Anatomy, University of Rome Tor Vergata, Rome, Italy.

Testicular Germ Cell Tumors (TGCT) and patient-derived cell lines are extremely sensitive to cisplatin and other interstrand cross-link (ICL) inducing agents. Nevertheless, a subset of TGCTs are either innately resistant or acquire resistance to cisplatin during treatment. Understanding the mechanisms underlying TGCT sensitivity/resistance to cisplatin as well as the identification of novel strategies to target cisplatin-resistant TGCTs have major clinical implications. Herein, we have examined the proficiency of five embryonal carcinoma (EC) cell lines to repair cisplatin-induced ICLs. Using γH2AX staining as a marker of double strand break formation, we found that EC cell lines were either incapable of or had a reduced ability to repair ICL-induced damage. The defect correlated with reduced Homologous Recombination (HR) repair, as demonstrated by the reduction of RAD51 foci formation and by direct evaluation of HR efficiency using a GFP-reporter substrate. HR-defective tumors cells are known to be sensitive to the treatment with poly(ADP-ribose) polymerase (PARP) inhibitor. In line with this observation, we found that EC cell lines were also sensitive to PARP inhibitor monotherapy. The magnitude of sensitivity correlated with HR-repair reduced proficiency and with the expression levels and activity of PARP1 protein. In addition, we found that PARP inhibition strongly enhanced the response of the most resistant EC cells to cisplatin, by reducing their ability to overcome the damage. These results point to a reduced proficiency of HR repair as a source of sensitivity of ECs to ICL-inducing agents and PARP inhibitor monotherapy, and suggest that pharmacological inhibition of PARP can be exploited to target the stem cell component of the TGCTs (namely ECs) and to enhance the sensitivity of cisplatin-resistant TGCTs to standard treatments.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0051563PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3520950PMC
June 2013

PIK3CA mutations rarely demonstrate genotypic intratumoral heterogeneity and are selected for in breast cancer progression.

Breast Cancer Res Treat 2011 Sep 27;129(2):635-43. Epub 2011 May 27.

Department of Medicine and the Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA.

PIK3CA gene mutations are the most common activating mutations in human breast cancer. Its association with hormone receptor-positive breast cancer makes it a prime target for clinical therapeutic advances to maintain anti-estrogen responsiveness. In anticipation of this therapeutic approach, we have evaluated intratumoral heterogeneity in primary breast cancers with regard to PIK3CA mutation status. In addition, we have assessed for the presence of the mutation in paired pre-invasive breast cancer and metastases. To assess for intratumoral heterogeneity, separate tumor blocks from primary breast cancers (n = 63) were genotyped for PIK3CA mutations. Available paired tissue samples from breast tumors known to harbor mutations underwent massARRAY genotyping (n = 70) to identify PIK3CA and AKT1(E17K) mutations. Cores were macro-dissected from matched tissue, including normal breast, benign lymph nodes (LN), ductal carcinoma in situ, regional LN metastases, and distant metastases. Matched samples underwent genetic fingerprinting by multiple SNP genotyping to confirm genetic identity. Intratumoral heterogeneity is minimal with a concordance rate of 95.2% between two different blocks from primary breast cancers. Complete concordance of PIK3CA mutations is noted between primary breast cancer and DCIS. PIK3CA mutations in primary breast cancer are detected in matched regional LNs (91.7%) and distant metastases (100%). Mutation detection by massARRAY genotyping is sensitive but may be affected by sample quality. Intratumoral heterogeneity as measured by PIK3CA genotype is rare; PIK3CA mutations occur early and are selected for in breast cancer progression. HapMap analysis is an essential control for paired sample analysis. This data is clinically important, particularly, for the design of therapies targeting the PI3K/AKT pathway, as it offers confidence that the detection of PIK3CA mutations in the invasive primary tumor will accurately reflect breast cancer biology.
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http://dx.doi.org/10.1007/s10549-011-1601-4DOI Listing
September 2011

Breast cancer methylomes establish an epigenomic foundation for metastasis.

Sci Transl Med 2011 Mar;3(75):75ra25

Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.

Cancer-specific alterations in DNA methylation are hallmarks of human malignancies; however, the nature of the breast cancer epigenome and its effects on metastatic behavior remain obscure. To address this issue, we used genome-wide analysis to characterize the methylomes of breast cancers with diverse metastatic behavior. Groups of breast tumors were characterized by the presence or absence of coordinate hypermethylation at a large number of genes, demonstrating a breast CpG island methylator phenotype (B-CIMP). The B-CIMP provided a distinct epigenomic profile and was a strong determinant of metastatic potential. Specifically, the presence of the B-CIMP in tumors was associated with low metastatic risk and survival, and the absence of the B-CIMP was associated with high metastatic risk and death. B-CIMP loci were highly enriched for genes that make up the metastasis transcriptome. Methylation at B-CIMP genes accounted for much of the transcriptomal diversity between breast cancers of varying prognosis, indicating a fundamental epigenomic contribution to metastasis. Comparison of the loci affected by the B-CIMP with those affected by the hypermethylator phenotype in glioma and colon cancer revealed that the CIMP signature was shared by multiple human malignancies. Our data provide a unifying epigenomic framework linking breast cancers with varying outcome and transcriptomic changes underlying metastasis. These findings significantly enhance our understanding of breast cancer oncogenesis and aid the development of new prognostic biomarkers for this common malignancy.
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http://dx.doi.org/10.1126/scitranslmed.3001875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3146366PMC
March 2011

Homology-directed Fanconi anemia pathway cross-link repair is dependent on DNA replication.

Nat Struct Mol Biol 2011 Apr 20;18(4):500-3. Epub 2011 Mar 20.

Developmental Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

Homologous recombination (also termed homology-directed repair, HDR) is a major pathway for the repair of DNA interstrand cross-links (ICLs) in mammalian cells. Cells from individuals with Fanconi anemia (FA) are characterized by extreme ICL sensitivity, but their reported defect in HDR is mild. Here we examined ICL-induced HDR using a GFP reporter and observed a profound defect in ICL-induced HDR in FA cells, but only when the reporter could replicate.
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http://dx.doi.org/10.1038/nsmb.2029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3273992PMC
April 2011

A feasibility study of bevacizumab plus dose-dense doxorubicin-cyclophosphamide (AC) followed by nanoparticle albumin-bound paclitaxel in early-stage breast cancer.

Clin Cancer Res 2011 May 24;17(10):3398-407. Epub 2011 Feb 24.

Breast Cancer Medicine Service, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York, New York 10065, USA.

Purpose: Bevacizumab confers benefits in metastatic breast cancer but may be more effective as adjuvant therapy. We evaluated the cardiac safety of bevacizumab plus dose-dense doxorubicin-cyclophosphamide (ddAC) → nanoparticle albumin-bound (nab)-paclitaxel in human epidermal growth factor receptor 2 normal early-stage breast cancer.

Experimental Design: Eighty patients with normal left ventricular ejection fraction (LVEF) were enrolled. Bevacizumab was administered for 1 year, concurrently with ddAC → nab-paclitaxel then as a single agent. LVEF was evaluated at months 0, 2, 6, 9, and 18. This regimen was considered safe if fewer than three cardiac events or fewer than two deaths from left ventricular dysfunction occurred. Correlative studies of cardiac troponin (cTn) and plasma renin activity (PRA) were conducted.

Results: The median age was 48 years (range, 27-75 years), and baseline LVEF was 68% (53%-82%). After 39 months' median follow-up (5-45 months): median LVEF was 68% (53%-80%) at 2 months (n = 78), 64% (51%-77%) at 6 months (n = 66), 63% (48%-77%) at 9 months (n = 61), and 66% (42%-76%) at 18 months (n = 54). One patient developed symptomatic LV dysfunction at month 15. Common toxicities necessitating treatment discontinuation were hypertension (HTN, 4%), wound-healing complications (4%), and asymptomatic LVEF declines (4%). Neither cTn nor PRA predicted congestive heart failure (CHF) or HTN, respectively.

Conclusions: Bevacizumab with ddAC → nab-paclitaxel had a low rate of cardiac events; cTn and PRA levels are not predictive of CHF or HTN, respectively. The efficacy of bevacizumab as adjuvant treatment will be established in several ongoing phase III trials.
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http://dx.doi.org/10.1158/1078-0432.CCR-10-1969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4994894PMC
May 2011

Loss of 53BP1 is a gain for BRCA1 mutant cells.

Cancer Cell 2010 May;17(5):423-5

Developmental Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.

Mutations in BRCA1 predispose to tumorigenesis presumably from the inability to accurately repair DNA double-strand breaks by homologous recombination. Two new papers shed light on how loss of the DNA damage response protein 53BP1 reverses phenotypes of BRCA1 mutant cells, with potential clinical implications.
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http://dx.doi.org/10.1016/j.ccr.2010.04.021DOI Listing
May 2010

Mitotic homologous recombination maintains genomic stability and suppresses tumorigenesis.

Nat Rev Mol Cell Biol 2010 Mar;11(3):196-207

Developmental Biology Program, New York, New York 10065, USA.

Mitotic homologous recombination promotes genome stability through the precise repair of DNA double-strand breaks and other lesions that are encountered during normal cellular metabolism and from exogenous insults. As a result, homologous recombination repair is essential during proliferative stages in development and during somatic cell renewal in adults to protect against cell death and mutagenic outcomes from DNA damage. Mutations in mammalian genes encoding homologous recombination proteins, including BRCA1, BRCA2 and PALB2, are associated with developmental abnormalities and tumorigenesis. Recent advances have provided a clearer understanding of the connections between these proteins and of the key steps of homologous recombination and DNA strand exchange.
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http://dx.doi.org/10.1038/nrm2851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3261768PMC
March 2010

BRCA gene structure and function in tumor suppression: a repair-centric perspective.

Cancer J 2010 Jan-Feb;16(1):39-47

Breast Cancer Medicine Service, Memorial Sloan-Kettering Cancer Center, New York City, NY 10065, USA.

Germline mutations in the BRCA1 and BRCA2 genes are characterized by deficient repair of DNA double-strand breaks by homologous recombination. Defective DNA double-strand break repair has been not only implicated as a key contributor to tumorigenesis in mutation carriers but also represents a potential target for therapy. The transcriptional similarities between BRCA1-deficient tumors and sporadic tumors of the basal-like subtype have led to the investigation of homologous recombination repair-directed therapy in triple-negative tumors, which demonstrates overlap with the basal-like subtype. We broaden the scope of this topic by addressing a "repair-defective" rather than "BRCA1-like" phenotype. We discuss structural and functional aspects of key repair proteins including BRCA1, BRCA2, BRCA1 interacting protein C-terminal helicase 1, and partner and localizer of BRCA2 and describe the phenotypic consequences of their loss at the cellular, tissue, and organism level. We review potential mechanisms of repair pathway dysfunction in sporadic tumors and address how the identification of such defects may guide the application of repair-directed therapies.
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http://dx.doi.org/10.1097/PPO.0b013e3181cf0204DOI Listing
May 2010

PIK3CA mutation associates with improved outcome in breast cancer.

Clin Cancer Res 2009 Aug 11;15(16):5049-59. Epub 2009 Aug 11.

Breast Cancer Medicine Service, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.

Purpose: In breast cancer, somatic mutations in the PIK3CA gene are common. The prognostic implication of these activating mutations remains uncertain as moderately sized studies have yielded variable outcomes. Our aim was to determine the prognostic implications of PIK3CA mutations in breast cancer.

Experimental Design: Archival formalin-fixed paraffin-embedded primary breast tumors, from 590 patients selected for known vital status with a median follow-up of 12.8 years and a tumor >1 cm, were genotyped for PIK3CA mutations. Mutation rates and associations between mutation site and clinicopathologic characteristics were assessed. Progression-free survival, overall survival, and breast cancer-specific survival were examined using Kaplan-Meier or competing risk methodology.

Results: PIK3CA mutation is identified in 32.5% of breast cancers. PIK3CA mutation significantly associates with older age at diagnosis, hormone receptor positivity, HER2 negativity, lower tumor grade and stage, and lymph node negativity. Patients with PIK3CA mutated tumors have significant improvement in overall survival (P = 0.03) and breast cancer-specific survival (P = 0.004). Analysis for PIK3CA mutation site-specific associations reveals that the H1047R kinase domain mutation highly associates with node negativity (P = 0.007), whereas helical domain hotspot mutations associate with older age at diagnosis (P = 0.004).

Conclusion: This study defines the positive prognostic significance of PIK3CA mutations. This work is clinically relevant, as it will significantly affect the design of clinical trials planned for phosphatidylinositol 3-kinase-targeted therapy. Future work may define a population of older age breast cancer patients in whom therapy can be minimized.
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http://dx.doi.org/10.1158/1078-0432.CCR-09-0632DOI Listing
August 2009

Prolonged dose-dense epirubicin and cyclophosphamide followed by paclitaxel in breast cancer is feasible.

Clin Breast Cancer 2008 Oct;8(5):418-24

Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.

Purpose: We conducted a pilot study of dose-dense epirubicin/cyclophosphamide (EC) x 6 --> paclitaxel (P) x 6 with pegfilgrastim. A previous dose-dense trial of FEC (5-fluorouracil [5-FU]/EC) x 6 with filgrastim --> by weekly paclitaxel alternating with docetaxel x 18 was not feasible because of pneumonitis (with dose-dense FEC) and pericardial/pleural effusion (taxane phase). Dose-dense EC (without the 5-FU) is not associated with pneumonitis, and dose-dense paclitaxel (alone) is feasible. Primary objective was feasibility.

Patients And Methods: Patients with resectable breast cancer were enrolled, regardless of surgery status, tumor size, or nodal status. Treatment regimen consisted of every-2-week EC (100/600 mg/m2) x 6 --> by 2-weekly P (175 mg/m2) x 6 with pegfilgrastim 6 mg on day 2.

Results: Between November 2004 and May 2005, 38 patients were enrolled. The median age was 47 years (range, 30-72 years); 33 of 38 (87%) were treated in the adjuvant setting and 27 of 33 (81%) had involved nodes (range, 1-46); 5 of 38 (13%) were treated pre-operatively; 33 of 38 (87%) completed all chemotherapy as planned; the remaining patients (13%) had treatment modifications for toxicity. Febrile neutropenia occurred in 6 of 38 patients (16 %) and only during EC. There were 12 hospitalizations in 9 of 38 patients (24%) enrolled.

Conclusion: Dose-dense every-2-week EC x 6 --> P x 6 with pegfilgrastim is feasible based on our prospective definition.
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http://dx.doi.org/10.3816/CBC.2008.n.050DOI Listing
October 2008

The safety of dose-dense doxorubicin and cyclophosphamide followed by paclitaxel with trastuzumab in HER-2/neu overexpressed/amplified breast cancer.

J Clin Oncol 2008 Mar;26(8):1216-22

Department of Medicine, Memorial Sloan- Kettering Cancer Center, 1275 York Ave, Howard 713, New York, NY 10021, USA.

Purpose: Dose-dense (dd) doxorubicin and cyclophosphamide (AC) followed by paclitaxel (P) is superior to every 3-weekly AC followed by P. Given the demonstrated cardiac safety for trastuzumab (T) with conventionally scheduled AC followed by P, we tested the safety of dd AC followed by P with T. The primary end point was cardiac safety, and the secondary end points were time to recurrence and overall survival.

Methods: Patients with HER-2/neu immunohistochemistry (IHC) 3+ or fluorescent in situ hybridization (FISH)-amplified breast cancer and baseline left ventricular ejection fraction (LVEF) of >or= 55% were enrolled, regardless of tumor size or nodal status. Treatment consisted of AC (60/600 mg/m(2)) x 4 followed by P (175 mg/m(2)) x 4 every 2-weekly with pegfilgrastim (6 mg on day 2) + T x1 year. LVEF by radionuclide scan was obtained at baseline, at months 2, 6, 9, and 18.

Results: From January 2005 to November 2005, 70 patients were enrolled. The median age was 49 years (range, 27 to 72 years); median LVEF at baseline was 68% (range, 55% to 81%). At month 2 in 70 of 70 patients, the median LVEF was 67% (range, 58% to 79%); at month 6 in 67 of 70 patients, it was 66% (range, 52% to 75%); at month 9 in 68 of 70 patients, it was 65% (range, 50% to 75%); and at month 18 in 48 of 70 patients, it was 66% (range, 57% to 75%). As of December 1, 2007, the median follow-up was 28 months (range, 25 to 35 months). One patient (1%) experienced congestive heart failure (CHF). There were no cardiac deaths.

Conclusion: Dose-dense AC followed by P/T followed by T is feasible and is not likely to increase the incidence of cardiac events compared to established regimens.
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http://dx.doi.org/10.1200/JCO.2007.12.0733DOI Listing
March 2008

A phase II trial of imatinib mesylate monotherapy in patients with metastatic breast cancer.

Breast Cancer Res Treat 2005 Mar;90(2):157-63

Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.

Background: Imatinib mesylate is a potent inhibitor of Abl, KIT, and PDGFR tyrosine kinases. Breast cancer has variable expression of KIT and PDGFR therefore we conducted a phase II trial to evaluate the safety and efficacy of imatinib in patients with metastatic breast cancer (MBC).

Patients And Methods: Eligible patients had measurable and progressive MBC, with no limits on prior chemo- or hormonal therapy. Imatinib was initially administered at a dose of 400 mg orally twice a day with provisions for dose reductions based on toxicities. The primary endpoint was clinical benefit based on RECIST criteria. Tumor specimens were tested for expression of KIT and PDGFR tyrosine kinases.

Results: Sixteen patients were enrolled and treated. Median age was 55 years (range: 35-73); median number of prior chemotherapy regimens for MBC was 4 (range 1-8). The main non-hematologic toxicities were (Grades 1/2; Grade 3): fatigue (56%; 6%), edema (38%; 19%), nausea (31%; 19%), vomiting (38%; 0%), anorexia (38%; 0%), diarrhea (19%; 6%), and rash (25%; 6%). Grade 3/4 hematologic and biochemical abnormalities were minimal. There was no evidence of clinical benefit. The median duration of therapy on trial was 28 days (range 2-71). Of the 13 testable cases: 1 was KIT positive and 4 were PDGFR positive.

Conclusion: Imatinib therapy at doses of 800 mg/day was associated with significant toxicity in patients with heavily pre-treated MBC. Our results do not indicate activity for imatinib monotherapy in these unselected patients.
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http://dx.doi.org/10.1007/s10549-004-3974-0DOI Listing
March 2005

Involvement of mammalian Mus81 in genome integrity and tumor suppression.

Science 2004 Jun;304(5678):1822-6

Ontario Cancer Institute, 620 University Avenue, Suite 706, Toronto, Ontario, Canada M5G 2C1.

Mus81-Eme1 endonuclease has been implicated in the rescue of stalled replication forks and the resolution of meiotic recombination intermediates in yeast. We used gene targeting to study the physiological requirements of Mus81 in mammals. Mus81-/- mice are viable and fertile, which indicates that mammalian Mus81 is not essential for recombination processes associated with meiosis. Mus81-deficient mice and cells were hypersensitive to the DNA cross-linking agent mitomycin C but not to gamma-irradiation. Remarkably, both homozygous Mus81-/- and heterozygous Mus81+/- mice exhibited a similar susceptibility to spontaneous chromosomal damage and a profound and equivalent predisposition to lymphomas and other cancers. These studies demonstrate a critical role for the proper biallelic expression of the mammalian Mus81 in the maintenance of genomic integrity and tumor suppression.
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http://dx.doi.org/10.1126/science.1094557DOI Listing
June 2004

Eme1 is involved in DNA damage processing and maintenance of genomic stability in mammalian cells.

EMBO J 2003 Nov;22(22):6137-47

Advanced Medical Discovery Institute, Ontario Cancer Institute, 620 University Avenue, Suite 706, Toronto, Ontario M5G 2C1, Canada.

Yeast and human Eme1 protein, in complex with Mus81, constitute an endonuclease that cleaves branched DNA structures, especially those arising during stalled DNA replication. We identified mouse Eme1, and show that it interacts with Mus81 to form a complex that preferentially cleaves 3'-flap structures and replication forks rather than Holliday junctions in vitro. We demonstrate that Eme1-/- embryonic stem (ES) cells are hypersensitive to the DNA cross-linking agents mitomycin C and cisplatin, but only mildly sensitive to ionizing radiation, UV radiation and hydroxyurea treatment. Mammalian Eme1 is not required for the resolution of DNA intermediates that arise during homologous recombination processes such as gene targeting, gene conversion and sister chromatid exchange (SCE). Unlike Blm-deficient ES cells, increased SCE was seen only following induced DNA damage in Eme1-deficient cells. Most importantly, Eme1 deficiency led to spontaneous genomic instability. These results reveal that mammalian Eme1 plays a key role in DNA repair and the maintenance of genome integrity.
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http://dx.doi.org/10.1093/emboj/cdg580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC275438PMC
November 2003

BARD1 participates with BRCA1 in homology-directed repair of chromosome breaks.

Mol Cell Biol 2003 Nov;23(21):7926-36

Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.

The BRCA1 tumor suppressor has been implicated in the maintenance of chromosomal stability through homology-directed repair of DNA double-strand breaks. Much of the BRCA1 in cells forms a heterodimeric complex with a structurally related protein BARD1. We report that expression of truncated mouse or human BARD1 peptides capable of interacting with Brca1 results in a homologous-repair deficiency. Repair is mildly reduced in Brca1 wild-type cells and severely reduced in cells that harbor a Brca1 splice product deleted for exon 11. Nuclear localization of the Brca1 or BARD1 peptides is not compromised, implying that the repair deficiency is caused by a more direct effect on repair. The tumor suppressor activity of BRCA1 may require the participation of BARD1 to maintain chromosome integrity through the homologous-repair pathway.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC207645PMC
http://dx.doi.org/10.1128/MCB.23.21.7926-7936.2003DOI Listing
November 2003

The cancer connection: BRCA1 and BRCA2 tumor suppression in mice and humans.

Oncogene 2002 Dec;21(58):8994-9007

Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.

BRCA1 and BRCA2 mutations are estimated to be responsible for the great majority of familial breast and ovarian cancers. Much progress has been made toward the understanding of the function of these proteins through genetic, biochemical, and structural studies. The embryonic lethality encountered in the knockout mouse initially hindered the development of mouse models aimed at studying tumor suppression. However, mice that harbor hypomorphic Brca1 and Brca2 alleles and cre-mediated tissue-specific deletions for Brca1 and Brca2 have been generated. Mice deficient for either Brca1 or Brca2 sustain a wide range of carcinoma and mammary epithelium deleted for Brca1 or Brca2 is highly susceptible to mammary tumorigenesis. Mammary (and other) tumors occur at long latency as compared to oncogene-induced mouse tumors. p53 deficiency is highly cooperative with both Brca1 and Brca2 in promoting tumorigenesis. Analysis of Brca1-associated mammary tumors reveals significant similarities to BRCA1-associated breast cancer in regard to high tumor grade, hormone receptor negativity, a high incidence of p53 mutations and genetic instability.
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http://dx.doi.org/10.1038/sj.onc.1206177DOI Listing
December 2002
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