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1. Results of TRIO-14, a phase II, multicenter, randomized, placebo-controlled trial of carboplatin-paclitaxel versus carboplatin-paclitaxel-ganitumab in newly diagnosed epithelial ovarian cancer

Author

Konecny, GE, Hendrickson, AE Wahner, Davidson, TM, Winterhoff, BJ, Ma, S, Mahner, S, Sehouli, J, Fasching, PA, Feisel-Schwickardi, G, Poelcher, M, Roman, LD, Rody, A, Karlan, BY, Mullany, SA, Chen, H, Ray-Coquard, IL, Provencher, DM, Yachnin, A, Cottu, PH, Glaspy, JA, Haluska, P, and Slamon, DJ

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Clinical Research, Clinical Trials and Supportive Activities, Cancer, Ovarian Cancer, Rare Diseases, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols, Biomarkers, Tumor, Carboplatin, Carcinoma, Ovarian Epithelial, Female, Humans, Insulin-Like Growth Factor Binding Protein 2, Middle Aged, Neoplasm Staging, Ovarian Neoplasms, Paclitaxel, Progression-Free Survival, Somatomedins, Ganitumab, IGFR1 inhibitor, Ovarian cancer, Insulin-like growth factor, Targeted therapy, Paediatrics and Reproductive Medicine, Oncology & Carcinogenesis, Clinical sciences, Oncology and carcinogenesis, Reproductive medicine
Abstract

PurposeInsulin-like growth factor (IGF) signaling is implicated in pathogenesis and chemotherapy resistance of epithelial ovarian cancer (EOC). We explored efficacy and safety of adding ganitumab, a monoclonal antibody targeting IGF-1R, to carboplatin/paclitaxel (CP) chemotherapy in patients with primary EOC.DesignPatients were randomly assigned to receive CP/ganitumab (18 mg/kg q3w) or CP/placebo for 6 cycles followed by 6 cycles of single agent ganitumab/placebo maintenance therapy as front-line therapy. Primary endpoint was progression free survival. Secondary endpoints were time to progression and overall survival. Pretreatment samples were prospectively collected for retrospective biomarker analyses.Results170 patients enrolled. 165 patients assessable for toxicity. Median PFS was 15.7 months with CP/ganitumab and 16.7 months with CP/placebo (HR 1.23; 95% CI 0.82-1.83, P = 0.313). All grade neutropenia (84.1% vs 71.4%), thrombocytopenia (75.3% vs 57.1%) and hyperglycemia (15.9% vs 2.6%) were more common in the ganitumab group compared to the placebo group. Ganitumab/placebo related serious adverse events were reported in 26.1% of the patients with ganitumab and in 6.5% with placebo. Non-progression related fatal events were more common with ganitumab (5 versus 2 patients). The ganitumab group experienced more dose delays which resulted in lower relative dose intensity of chemotherapy in the experimental group. In an exploratory model IGFBP2 expression was predictive of ganitumab response (treatment interaction; PFS, P = 0.03; OS, P = 0.01).ConclusionAddition of ganitumab to CP chemotherapy in primary EOC did not improve PFS. Our results do not support further study of ganitumab in unselected EOC patients.

Published
2021

2. Palbociclib plus letrozole as first-line therapy in estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer with extended follow-up

Author

Rugo, HS, Finn, RS, Diéras, V, Ettl, J, Lipatov, O, Joy, AA, Harbeck, N, Castrellon, A, Iyer, S, Lu, DR, Mori, A, Gauthier, ER, Bartlett, C Huang, Gelmon, KA, and Slamon, DJ

Subjects
Clinical Research, Estrogen, Breast Cancer, Cancer, Clinical Trials and Supportive Activities, Aging, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Antineoplastic Combined Chemotherapy Protocols, Breast Neoplasms, Double-Blind Method, Female, Humans, Letrozole, Piperazines, Postmenopause, Pyridines, Quality of Life, Receptor, ErbB-2, Receptors, Estrogen, Treatment Outcome, Breast cancer, ER, HER2-, Cyclin-dependent kinase inhibitor, Palbociclib, Receptor, erbB-2, ER+, HER2−, Clinical Sciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

PurposeIn the initial PALOMA-2 (NCT01740427) analysis with median follow-up of 23 months, palbociclib plus letrozole significantly prolonged progression-free survival (PFS) in women with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) [hazard ratio (HR) 0.58; P

Published
2019

3. Impact of palbociclib plus letrozole on patient-reported health-related quality of life: results from the PALOMA-2 trial

Author

Rugo, HS, Diéras, V, Gelmon, KA, Finn, RS, Slamon, DJ, Martin, M, Neven, P, Shparyk, Y, Mori, A, Lu, DR, Bhattacharyya, H, Bartlett, CHUANG, Iyer, S, Johnston, S, Ettl, J, and Harbeck, N

Subjects
Breast Cancer, Estrogen, Clinical Research, Aging, Clinical Trials and Supportive Activities, Cancer, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Good Health and Well Being, Antineoplastic Combined Chemotherapy Protocols, Breast Neoplasms, Double-Blind Method, Female, Humans, Letrozole, Middle Aged, Piperazines, Placebos, Postmenopause, Pyridines, Quality of Life, palbociclib, letrozole, health-related quality of life, metastatic breast cancer, ER+/HER2-, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

BackgroundPatient-reported outcomes are integral in benefit-risk assessments of new treatment regimens. The PALOMA-2 study provides the largest body of evidence for patient-reported health-related quality of life (QOL) for patients with metastatic breast cancer (MBC) receiving first-line endocrine-based therapy (palbociclib plus letrozole and letrozole alone).Patients and methodsTreatment-naïve postmenopausal women with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) MBC were randomized 2 : 1 to palbociclib plus letrozole (n = 444) or placebo plus letrozole (n = 222). Patient-reported outcomes were assessed at baseline, day 1 of cycles 2 and 3, and day 1 of every other cycle from cycle 5 using the Functional Assessment of Cancer Therapy (FACT)-Breast and EuroQOL 5 dimensions (EQ-5D) questionnaires.ResultsAs of 26 February 2016, the median duration of follow-up was 23 months. Baseline scores were comparable between the two treatment arms. No significant between-arm differences were observed in change from baseline in FACT-Breast Total, FACT-General Total, or EQ-5D scores. Significantly greater improvement in pain scores was observed in the palbociclib plus letrozole arm (-0.256 versus -0.098; P = 0.0183). In both arms, deterioration of FACT-Breast Total score was significantly delayed in patients without progression versus those with progression and patients with partial or complete response versus those without. No significant difference was observed in FACT-Breast and EQ-5D index scores in patients with and without neutropenia.ConclusionsOverall, women with MBC receiving first-line endocrine therapy have a good QOL. The addition of palbociclib to letrozole maintains health-related QOL and improves pain scores in treatment-naïve postmenopausal patients with ER+/HER2- MBC compared with letrozole alone. Significantly greater delay in deterioration of health-related QOL was observed in patients without progression versus those who progressed and in patients with an objective response versus non-responders. ClinicalTrials.gov: NCT01740427 (https://clinicaltrials.gov/ct2/show/NCT01740427).

Published
2018

4. Activity of the multikinase inhibitor dasatinib against ovarian cancer cells

Author

Konecny, GE, Glas, R, Dering, J, Manivong, K, Qi, J, Finn, RS, Yang, GR, Hong, K-L, Ginther, C, Winterhoff, B, Gao, G, Brugge, J, and Slamon, DJ

Subjects
Ovarian Cancer, Rare Diseases, Cancer, Orphan Drug, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Antineoplastic Combined Chemotherapy Protocols, Apoptosis, Cell Cycle, Cell Growth Processes, Cell Line, Tumor, Cell Movement, Dasatinib, Female, Flow Cytometry, Focal Adhesion Kinase 1, Gene Expression Profiling, Humans, Inhibitory Concentration 50, Ovarian Neoplasms, Phosphorylation, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-yes, Pyrimidines, Receptor, EphA2, Thiazoles, src-Family Kinases, Src, Eph2A, FAK, uPA, dasatinib, ovarian cancer, Oncology and Carcinogenesis, Public Health and Health Services, Oncology & Carcinogenesis
Abstract

BackgroundHere, we explore the therapeutic potential of dasatinib, a small-molecule inhibitor that targets multiple cytosolic and membrane-bound tyrosine kinases, including members of the Src kinase family, EphA2, and focal adhesion kinase for the treatment of ovarian cancer.MethodsWe examined the effects of dasatinib on proliferation, invasion, apoptosis, cell-cycle arrest, and kinase activity using a panel of 34 established human ovarian cancer cell lines. Molecular markers for response prediction were studied using gene expression profiling. Multiple drug effect/combination index (CI) isobologram analysis was used to study the interactions with chemotherapeutic drugs.ResultsConcentration-dependent anti-proliferative effects of dasatinib were seen in all ovarian cancer cell lines tested, but varied significantly between individual cell lines with up to a 3 log-fold difference in the IC(50) values (IC(50) range: 0.001-11.3 micromol l(-1)). Dasatinib significantly inhibited invasion, and induced cell apoptosis, but less cell-cycle arrest. At a wide range of clinically achievable drug concentrations, additive and synergistic interactions were observed for dasatinib plus carboplatin (mean CI values, range: 0.73-1.11) or paclitaxel (mean CI values, range: 0.76-1.05). In this study, 24 out of 34 (71%) representative ovarian cancer cell lines were highly sensitive to dasatinib, compared with only 8 out of 39 (21%) representative breast cancer cell lines previously reported. Cell lines with high expression of Yes, Lyn, Eph2A, caveolin-1 and 2, moesin, annexin-1, and uPA were particularly sensitive to dasatinib.ConclusionsThese data provide a clear biological rationale to test dasatinib as a single agent or in combination with chemotherapy in patients with ovarian cancer.

Published
2009

5. Activity of lapatinib a novel HER2 and EGFR dual kinase inhibitor in human endometrial cancer cells.

Author

Konecny, GE, Venkatesan, N, Yang, G, Dering, J, Ginther, C, Finn, R, Rahmeh, M, Fejzo, M Schoenberg, Toft, D, Jiang, S-W, Slamon, DJ, and Podratz, KC

Subjects
Cell Line, Tumor, Humans, Endometrial Neoplasms, Quinazolines, Extracellular Signal-Regulated MAP Kinases, Receptor, Epidermal Growth Factor, Receptor, erbB-2, Antineoplastic Combined Chemotherapy Protocols, Protein Kinase Inhibitors, Drug Screening Assays, Antitumor, Signal Transduction, Female, Oncogene Protein v-akt, ErbB Receptors, Lapatinib, Receptor, ErbB-2, HER2/neu, EGFR, endometrial cancer, lapatinib, Cell Line, Tumor, Receptor, Epidermal Growth Factor, erbB-2, Drug Screening Assays, Antitumor, ErbB-2, Oncology and Carcinogenesis, Public Health and Health Services, Oncology & Carcinogenesis
Abstract

In this study, we explore the therapeutic potential of lapatinib a selective inhibitor of both the EGFR and HER2 tyrosine kinases for the treatment of endometrial cancer. The effect of lapatinib on tumour cell growth and receptor activation was studied in a panel of human endometrial cancer cell lines. Candidate molecular markers predicting sensitivity were assessed by baseline gene expression profiling, ELISA, and western blot analyses. Multiple drug effect/combination index (CI) isobologram analysis was used to study the interactions between chemotherapeutic drugs and lapatinib. Concentration-dependent anti-proliferative effects of lapatinib were seen in all endometrial cancer cell lines tested, but varied significantly between individual cell lines (IC(50) range: 0.052-10.9 micromol). HER2 overexpression or increased expression of EGFR was significantly associated with in vitro sensitivity (P=0.024 or 0.011, respectively). Lapatinib exerts growth inhibition in a PTEN-independent manner. Sensitive cell lines also exhibited increased expression of EGFR ligands or HER3. In contrast, lapatinib-resistant cell lines exhibited high androgen receptor (AR) levels or epithelial-to-mesenchymal transition (post-EMT) features. In endometrial cancer cells, at a wide range of clinically achievable drug concentrations, additive and synergistic interactions were observed for lapatinib plus carboplatin, paclitaxel, docetaxel, and doxorubicin. These observations provide a clear biologic rational to test lapatinib as a single agent or in combination with chemotherapy in endometrial cancer with HER2 overexpression. Expression of EGFR, its ligands, HER3, AR, and post-EMT markers warrant further evaluation to help define patients with HER2-nonoverexpressing endometrial cancer most likely to benefit from lapatinib.

Published
2008

6. Overall Survival with Palbociclib and Fulvestrant in Women with HR+/HER2- ABC: Updated Exploratory Analyses of PALOMA-3, a Double-blind, Phase III Randomized Study

Author

Cristofanilli, M, Rugo, HS, Im, S-A, Slamon, DJ, Harbeck, N, Bondarenko, I, Masuda, N, Colleoni, M, DeMichele, A, Loi, S, Iwata, H, O'Leary, B, Andre, F, Loibl, S, Bananis, E, Liu, Y, Huang, X, Kim, S, Frean, MJL, Turner, NC, Cristofanilli, M, Rugo, HS, Im, S-A, Slamon, DJ, Harbeck, N, Bondarenko, I, Masuda, N, Colleoni, M, DeMichele, A, Loi, S, Iwata, H, O'Leary, B, Andre, F, Loibl, S, Bananis, E, Liu, Y, Huang, X, Kim, S, Frean, MJL, and Turner, NC

Abstract

PURPOSE: To conduct an updated exploratory analysis of overall survival (OS) with a longer median follow-up of 73.3 months and evaluate the prognostic value of molecular analysis by circulating tumor DNA (ctDNA). PATIENTS AND METHODS: Patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC) were randomized 2:1 to receive palbociclib (125 mg orally/day; 3/1 week schedule) and fulvestrant (500 mg intramuscularly) or placebo and fulvestrant. This OS analysis was performed when 75% of enrolled patients died (393 events in 521 randomized patients). ctDNA analysis was performed among patients who provided consent. RESULTS: At the data cutoff (August 17, 2020), 258 and 135 deaths occurred in the palbociclib and placebo groups, respectively. The median OS [95% confidence interval (CI)] was 34.8 months (28.8-39.9) in the palbociclib group and 28.0 months (23.5-33.8) in the placebo group (stratified hazard ratio, 0.81; 95% CI, 0.65-0.99). The 6-year OS rate (95% CI) was 19.1% (14.9-23.7) and 12.9% (8.0-19.1) in the palbociclib and placebo groups, respectively. Favorable OS with palbociclib plus fulvestrant compared with placebo plus fulvestrant was observed in most subgroups, particularly in patients with endocrine-sensitive disease, no prior chemotherapy for ABC and low circulating tumor fraction and regardless of ESR1, PIK3CA, or TP53 mutation status. No new safety signals were identified. CONCLUSIONS: The clinically meaningful improvement in OS associated with palbociclib plus fulvestrant was maintained with >6 years of follow-up in patients with HR+/HER2- ABC, supporting palbociclib plus fulvestrant as a standard of care in these patients.

Published
2022

7. Targeting CDK4 and 6 in Cancer Therapy: Emerging Preclinical Insights Related to Abemaciclib

Author

Wander, SA, O'Brien, N, Litchfield, LM, O'Dea, D, Guimaraes, CM, Slamon, DJ, Goel, S, Wander, SA, O'Brien, N, Litchfield, LM, O'Dea, D, Guimaraes, CM, Slamon, DJ, and Goel, S

Abstract

Pharmacologic inhibitors of cyclin-dependent kinases 4 and 6 (CDK4 and 6) are approved for the treatment of subsets of patients with hormone receptor positive (HR+) breast cancer (BC). In metastatic disease, strategies involving endocrine therapy combined with CDK4 and 6 inhibitors (CDK4 and 6i) improve clinical outcomes in HR+ BCs. CDK4 and 6i prevent retinoblastoma tumor suppressor protein phosphorylation, thereby blocking the transcription of E2F target genes, which in turn inhibits both mitogen and estrogen-mediated cell proliferation. In this review, we summarize preclinical data pertaining to the use of CDK4 and 6i in BC, with a particular focus on several of the unique chemical, pharmacologic, and mechanistic properties of abemaciclib. As research efforts elucidate the novel mechanisms underlying abemaciclib activity, potential new applications are being identified. For example, preclinical studies have demonstrated abemaciclib can exert antitumor activity against multiple tumor types and can cross the blood-brain barrier. Abemaciclib has also demonstrated distinct activity as a monotherapeutic in the treatment of BC. Accordingly, we also discuss how a greater understanding of mechanisms related to CDK4 and 6 blockade highlight abemaciclib's unique in-class properties, and could pave new avenues for enhancing its therapeutic efficacy.

Published
2022

8. Long-term Pooled Safety Analysis of Palbociclib in Combination With Endocrine Therapy for HR+/HER2-Advanced Breast Cancer

Author

Dieras, V, Rugo, HS, Schnell, P, Gelmon, K, Cristofanilli, M, Loi, S, Colleoni, M, Lu, DR, Mori, A, Gauthier, E, Huang Bartlett, C, Slamon, DJ, Turner, NC, Finn, RS, Dieras, V, Rugo, HS, Schnell, P, Gelmon, K, Cristofanilli, M, Loi, S, Colleoni, M, Lu, DR, Mori, A, Gauthier, E, Huang Bartlett, C, Slamon, DJ, Turner, NC, and Finn, RS

Abstract

BACKGROUND: Palbociclib administered with endocrine therapy was tolerable when the overall incidence of toxicities was assessed separately for three PALOMA studies. This study analyzed pooled, longer-term PALOMA safety data longitudinally. METHODS: Data were pooled from three randomized phase II and III studies (ClinicalTrials.gov: NCT00721409, NCT01740427, NCT01942135) of hormone receptor-positive/human epidermal growth factor receptor 2‒negative advanced breast cancer patients. Front-line patients were randomly assigned to receive letrozole with/without palbociclib (PALOMA-1) or letrozole plus palbociclib/placebo (PALOMA-2). In PALOMA-3, patients with prior endocrine resistance received fulvestrant plus palbociclib/placebo. The cumulative event rates of adverse events (AEs), reporting up to 50 months of treatment, were assessed over time. RESULTS: Patients who received endocrine therapy (n = 1343) were included in this pooled analysis (872 were also treated with palbociclib, and 471 were not). The most common AEs with palbociclib plus endocrine therapy were neutropenia and infections (any grade, 80.6% and 54.7%, respectively), which were higher than in the endocrine monotherapy arm (any grade, 5.3% and 36.9%). The most common hematologic AEs (≥15.0% in the palbociclib arm) were more likely to be reported in the initial months of the study, after which time the cumulative event rate did not substantially increase. With palbociclib plus endocrine therapy, any grade AEs leading to permanent discontinuation over three years occurred in only 8.3% of patients. CONCLUSIONS: Based on these long-term safety analyses, there is no evidence of specific cumulative or delayed toxicities with palbociclib plus endocrine therapy, supporting the ongoing investigation of palbociclib plus endocrine therapy in early breast cancer (NCT02513394).

Published
2019

12. Abstract PD3-11: HER2/ERBB2 status in “HER2 equivocal” breast cancers by FISH and ASCO-CAP guidelines: False-positives due to heterozygous deletions of alternative control loci

Author

Press, MF, primary, Seoane, JA, additional, Curtis, C, additional, Quinaux, E, additional, Guzman, R, additional, Sauter, G, additional, Eiermann, W, additional, Mackey, JR, additional, Robert, N, additional, Pienkowski, T, additional, Crown, J, additional, Martin, M, additional, Valero, V, additional, Bee, V, additional, Ma, Y, additional, Villalobos, I, additional, and Slamon, DJ, additional

Published
2019
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14. Abstract P6-18-07: Ribociclib + endocrine therapy in patients with hormone receptor-positive, HER2-negative advanced breast cancer presenting with visceral metastases: Subgroup analysis of phase III MONALEESA trials

Author

Yardley, DA, primary, Chan, A, additional, Nusch, A, additional, Sonke, GS, additional, Yap, Y-S, additional, Bachelot, T, additional, Esteva, FJ, additional, Slamon, DJ, additional, Burris, HA, additional, Gaur, A, additional, Kong, O, additional, Diaz-Padilla, I, additional, Rodriguez Lorenc, K, additional, and Wheatley-Price, P, additional

Published
2019
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15. Abstract P6-18-05: First-line ribociclib + endocrine therapy in hormone receptor-positive, HER2-negative advanced breast cancer: A pooled efficacy analysis

Author

Tripathy, D, primary, Hortobagyi, G, additional, Chan, A, additional, Im, S-A, additional, Chia, S, additional, Yardley, D, additional, Esteva, FJ, additional, Hurvitz, S, additional, Kong, O, additional, Bao, W, additional, Rodriguez Lorenc, K, additional, Diaz-Padilla, I, additional, and Slamon, DJ, additional

Published
2019
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16. Abstract P6-18-03: Biomarker analysis of CDK 4/6 and endocrine pathways in hormone-receptor positive (HR+) advanced breast cancer (ABC) bone only disease patients: A joint analysis of PALOMA-2 and PALOMA-3 studies

Author

Finn, RS, primary, Turner, NC, additional, Liu, Y, additional, Rugo, HS, additional, Loibl, S, additional, Diéras, V, additional, Slamon, DJ, additional, André, F, additional, Gelmon, K, additional, DeMichele, A, additional, Loi, S, additional, Zhang, Z, additional, Giorgetti, C, additional, Gauthier, E, additional, Huang Bartlett, C, additional, and Cristofanilli, M, additional

Published
2019
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17. Ribociclib (RIB) + fulvestrant (FUL) in postmenopausal women with hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC): Results from MONALEESA-3

Author

Slamon, DJ, additional, Neven, P, additional, Chia, S, additional, Im, SA, additional, Fasching, PA, additional, De Laurentiis, M, additional, Petrakova, K, additional, Bianchi, GV, additional, Esteva, FJ, additional, Martin, M, additional, Pivot, X, additional, Vidam, G, additional, Wang, Y, additional, Rodriguez Lorenc, K, additional, Miller, M, additional, Taran, T, additional, and Jerusalem, G, additional

Published
2018
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19. Abstract PD5-01: Final results of NeoMONARCH: A phase 2 neoadjuvant study of abemaciclib in postmenopausal women with hormone receptor positive (HR+), HER2 negative breast cancer (BC)

Author

Martin, M, primary, Hurvitz, SA, additional, Chan, D, additional, Fernandez-Abad, M, additional, Petru, E, additional, Rostorfer, R, additional, Guarneri, V, additional, Huang, C-S, additional, Press, MF, additional, Costigan, TM, additional, Caldwell, CW, additional, Wijayawardana, S, additional, Turner, PK, additional, Barriga, S, additional, and Slamon, DJ, additional

Published
2018
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20. Abstract P5-21-03: Palbociclib (PAL) + letrozole (LET) as first-line therapy in estrogen receptor–positive (ER+)/human epidermal growth factor receptor 2–negative (HER2−) advanced breast cancer (ABC): Efficacy and safety updates with longer follow-up across patient subgroups

Author

Rugo, HS, primary, Finn, RS, additional, Dieras, V, additional, Ettl, J, additional, Lipatov, O, additional, Joy, A, additional, Harbeck, N, additional, Castrellon, A, additional, Lu, DR, additional, Mori, A, additional, Gauthier, ER, additional, Huang, C, additional, Gelmon, KA, additional, and Slamon, DJ, additional

Published
2018
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23. Abstract P1-12-07: Phase Ib/II single-arm trial evaluating the combination of everolimus, lapatinib and capecitabine for the treatment of patients with HER2-positive metastatic breast cancer with progression in the CNS after trastuzumab (TRIO-US B-09)

Author

Hurvitz, SA, primary, Martinez, DA, additional, Singh, R, additional, Taguchi, J, additional, Chan, D, additional, Dichmann, R, additional, Castrellon, A, additional, Barstis, J, additional, Hu, E, additional, Berkowitz, J, additional, Mani, A, additional, DiCarlo, B, additional, Smalberg, I, additional, Hobbs, E, additional, and Slamon, DJ, additional

Published
2017
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24. Abstract P3-04-15: The PI3K-inhibitor, copanlisib, has selective activity in luminal breast cancer cell lines and shows robust combined activity with hormonal blockade and CDK-4/6 inhibition in ER+ breast cancer cell line xenografts

Author

O'Brien, NA, primary, Conklin, D, additional, Luo, T, additional, Ayala, R, additional, Issakhanian, S, additional, Kalous, O, additional, Von Euw, E, additional, Politz, O, additional, Wilhelm, S, additional, Childs, BH, additional, Hurvitz, SA, additional, and Slamon, DJ, additional

Published
2017
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25. Refined histopathological predictors of BRCA1 and BRCA2 mutation status: A large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia

Author

Spurdle, AB, Couch, FJ, Parsons, MT, McGuffog, L, Barrowdale, D, Bolla, MK, Wang, Q, Healey, S, Schmutzler, RK, Wappenschmidt, B, Rhiem, K, Hahnen, E, Engel, C, Meindl, A, Ditsch, N, Arnold, N, Plendl, H, Niederacher, D, Sutter, C, Wang-Gohrke, S, Steinemann, D, Preisler-Adams, S, Kast, K, Varon-Mateeva, R, Ellis, S, Frost, D, Platte, R, Perkins, J, Gareth Evans, D, Izatt, L, Eeles, R, Adlard, J, Davidson, R, Cole, T, Scuvera, G, Manoukian, S, Bonanni, B, Mariette, F, Fortuzzi, S, Viel, A, Pasini, B, Papi, L, Varesco, L, Balleine, R, Nathanson, KL, Domchek, SM, Offitt, K, Jakubowska, A, Lindor, N, Thomassen, M, Jensen, UB, Rantala, J, Borg, Å, Andrulis, IL, Miron, A, Hansen, TVO, Caldes, T, Neuhausen, SL, Toland, AE, Nevanlinna, H, Montagna, M, Garber, J, Godwin, AK, Osorio, A, Factor, RE, Terry, MB, Rebbeck, TR, Karlan, BY, Southey, M, Rashid, MU, Tung, N, Pharoah, PDP, Blows, FM, Dunning, AM, Provenzano, E, Hall, P, Czene, K, Schmidt, MK, Broeks, A, Cornelissen, S, Verhoef, S, Fasching, PA, Beckmann, MW, Ekici, AB, Slamon, DJ, Bojesen, SE, and Nordestgaard, BG

Subjects
endocrine system diseases, skin and connective tissue diseases
Abstract

© 2014 Spurdle et al. Introduction: The distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have utility for mutation prediction, including statistical modeling to assess pathogenicity of BRCA1 or BRCA2 variants of uncertain clinical significance. We analyzed large pathology datasets accrued by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC) to reassess histopathological predictors of BRCA1 and BRCA2 mutation status, and provide robust likelihood ratio (LR) estimates for statistical modeling. Methods: Selection criteria for study/center inclusion were estrogen receptor (ER) status or grade data available for invasive breast cancer diagnosed younger than 70 years. The dataset included 4,477 BRCA1 mutation carriers, 2,565 BRCA2 mutation carriers, and 47,565 BCAC breast cancer cases. Country-stratified estimates of the likelihood of mutation status by histopathological markers were derived using a Mantel-Haenszel approach. Results: ER-positive phenotype negatively predicted BRCA1 mutation status, irrespective of grade (LRs from 0.08 to 0.90). ER-negative grade 3 histopathology was more predictive of positive BRCA1 mutation status in women 50 years or older (LR = 4.13 (3.70 to 4.62)) versus younger than 50 years (LR = 3.16 (2.96 to 3.37)). For BRCA2, ER-positive grade 3 phenotype modestly predicted positive mutation status irrespective of age (LR = 1.7-fold), whereas ER-negative grade 3 features modestly predicted positive mutation status at 50 years or older (LR = 1.54 (1.27 to 1.88)). Triple-negative tumor status was highly predictive of BRCA1 mutation status for women younger than 50 years (LR = 3.73 (3.43 to 4.05)) and 50 years or older (LR = 4.41 (3.86 to 5.04)), and modestly predictive of positive BRCA2 mutation status in women 50 years or older (LR = 1.79 (1.42 to 2.24)). Conclusions: These results refine likelihood-ratio estimates for predicting BRCA1 and BRCA2 mutation status by using commonly measured histopathological features. Age at diagnosis is an important variable for most analyses, and grade is more informative than ER status for BRCA2 mutation carrier prediction. The estimates will improve BRCA1 and BRCA2 variant classification and inform patient mutation testing and clinical management.

Published
2014

26. Mesenchymal gene program-expressing ovarian cancer spheroids exhibit enhanced mesothelial clearance

Author

Davidowitz, RA, Selfors, LM, Iwanicki, MP, Elias, KM, Karst, A, Piao, H, Ince, TA, Drage, MG, Dering, J, Konecny, GE, Matulonis, U, Mills, GB, Slamon, DJ, Drapkin, R, and Brugge, JS

Subjects
Epithelial-Mesenchymal Transition, Immunology, Protein Array Analysis, Medical and Health Sciences, Epithelium, Mesoderm, Rare Diseases, Genetics, 2.1 Biological and endogenous factors, Humans, Neoplasm Invasiveness, Aetiology, Peritoneal Neoplasms, Cancer, Ovarian Neoplasms, Homeodomain Proteins, Cultured, Twist-Related Protein 1, Nuclear Proteins, Zinc Finger E-box-Binding Homeobox 1, Ovarian Cancer, Tumor Cells, Gene Knockdown Techniques, Female, Cellular, Snail Family Transcription Factors, Spheroids, Transcriptome, Biotechnology, Transcription Factors
Abstract

Metastatic dissemination of ovarian tumors involves the invasion of tumor cell clusters into the mesothelial cell lining of peritoneal cavity organs; however, the tumor-specific factors that allow ovarian cancer cells to spread are unclear. We used an in vitro assay that models the initial step of ovarian cancer metastasis, clearance of the mesothelial cell layer, to examine the clearance ability of a large panel of both established and primary ovarian tumor cells. Comparison of the gene and protein expression profiles of clearance-competent and clearance-incompetent cells revealed that mesenchymal genes are enriched in tumor populations that display strong clearance activity, while epithelial genes are enriched in those with weak or undetectable activity. Overexpression of transcription factors SNAI1, TWIST1, and ZEB1, which regulate the epithelial-to-mesenchymal transition (EMT), promoted mesothelial clearance in cell lines with weak activity, while knockdown of the EMT-regulatory transcription factors TWIST1 and ZEB1 attenuated mesothelial clearance in ovarian cancer cell lines with strong activity. These findings provide important insights into the mechanisms associated with metastatic progression of ovarian cancer and suggest that inhibiting pathways that drive mesenchymal programs may suppress tumor cell invasion of peritoneal tissues.

Published
2014

27. Abstract P4-13-01: PALOMA3: Phase 3 trial of fulvestrant with or without palbociclib in pre- and postmenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer that progressed on prior endocrine therapy—confirmed efficacy and safety

Author

Cristofanilli, M, primary, Bondarenko, I, additional, Ro, J, additional, Im, S-A, additional, Masuda, N, additional, Colleoni, M, additional, DeMichele, AM, additional, Loi, S, additional, Verma, S, additional, Iwata, H, additional, Huang Bartlett, C, additional, Zhang, K, additional, Puyana Theall, K, additional, Turner, NC, additional, and Slamon, DJ, additional

Published
2016
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28. Abstract OT2-01-02: Phase III study of ribociclib (LEE011) in combination with fulvestrant for the treatment of postmenopausal patients (pts) with hormone receptor-positive (HR+), HER2-negative (HER2–) advanced breast cancer (aBC) who have received no or only one line of prior endocrine treatment: MONALEESA-3

Author

Fasching, PA, primary, Jerusalem, G, additional, Pivot, X, additional, Martin, M, additional, De Laurentiis, M, additional, Blackwell, K, additional, Esteva, FJ, additional, Paquet-Luzy, T, additional, Tang, Z, additional, Lorenc, KR, additional, and Slamon, DJ, additional

Published
2016
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30. Abstract P6-03-09: Genetic polymorphism and correlation with treatment induced cardiotoxicity and prognosis in HER2 amplified early breast cancer patients

Author

Peddi, PF, primary, Hurvitz, SA, additional, Fasching, PA, additional, Wang, L, additional, Cunningham, J, additional, Weinshilboum, RM, additional, Liu, D, additional, Quinaux, E, additional, Fourmanoir, H, additional, Robert, NJ, additional, Valero, V, additional, Crown, J, additional, Falkson, C, additional, Brufsky, A, additional, Pienkowski, T, additional, Eiermann, W, additional, Martin, M, additional, Bee, V, additional, and Slamon, DJ, additional

Published
2016
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32. Signal Transduction: A Technical Overview

Author

Slamon Dj and Arboleda Mj

Subjects
Cell signaling, Downstream (manufacturing), Cancer cell, Biology, Signal transduction, Receptor, Intracellular, Malignant phenotype, Cell biology
Abstract

Delineation of downstream signal transduction pathways is important for determining which intracellular signals contribute to the malignant phenotype of cancer cells. In this review, we discuss current methodologies used to study cell signaling. A number of factors that may influence the specificity of signaling will also be taken into consideration. Furthermore, because the HER-2 receptor is amplified and overexpressed in ovarian cancers, we refer to this receptor and its downstream signaling pathways as model systems throughout this review.

Published
2003

33. 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)

Author

Hurvitz, SA, primary, Miller, JM, additional, Dichmann, R, additional, Perez, AT, additional, Patel, R, additional, Zehngebot, LM, additional, Allen, H, additional, Bosserman, LD, additional, DiCarlo, BA, additional, Kennedy, A, additional, Giuliano, A, additional, Calfa, CJ, additional, Molthrop, DC, additional, Mani, A, additional, Dering, J, additional, Wang, H-J, additional, Adams, B, additional, Martinez, D, additional, Chen, H-W, additional, Zoeller, J, additional, Brugge, JS, additional, and Slamon, DJ, additional

Published
2013
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35. Abstract S1-03: Primary results from BETH, a phase 3 controlled study of adjuvant chemotherapy and trastuzumab ± bevacizumab in patients with HER2-positive, node-positive or high risk node-negative breast cancer

Author

Slamon, DJ, primary, Swain, SM, additional, Buyse, M, additional, Martin, M, additional, Geyer, CE, additional, Im, Y-H, additional, Pienkowski, T, additional, Kim, S-B, additional, Robert, NJ, additional, Steger, G, additional, Crown, J, additional, Verma, S, additional, Eiermann, W, additional, Costantino, JP, additional, Im, S-A, additional, Mamounas, EP, additional, Schwartzberg, L, additional, Paterson, A, additional, Mackey, JR, additional, Provencher, L, additional, Press, MF, additional, Thirlwell, M, additional, Bee-Munteanu, V, additional, Henschel, V, additional, Crepelle-Flechais, A, additional, and Wolmark, N, additional

Published
2013
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37. Abstract S1-6: Results of a randomized phase 2 study of PD 0332991, a cyclin-dependent kinase (CDK) 4/6 inhibitor, in combination with letrozole vs letrozole alone for first-line treatment of ER+/HER2− advanced breast cancer (BC)

Author

Finn, RS, primary, Crown, JP, additional, Lang, I, additional, Boer, K, additional, Bondarenko, IM, additional, Kulyk, SO, additional, Ettl, J, additional, Patel, R, additional, Pinter, T, additional, Schmidt, M, additional, Shparyk, Y, additional, Thummala, AR, additional, Voytko, NL, additional, Breazna, A, additional, Kim, ST, additional, Randolph, S, additional, and Slamon, DJ, additional

Published
2012
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38. Abstract P4-08-01: PI3K/mTOR inhibition overcomes in vitro and in vivo trastuzumab resistance independent of feedback activation of pAKT

Author

O'Brien, NA, primary, McDonald, K, additional, Tong, L, additional, Von Euw, E, additional, Conklin, D, additional, Kalous, O, additional, Di Tomaso, E, additional, Schnell, C, additional, Linnartz, R, additional, Hurvitz, SA, additional, Finn, RS, additional, Hirawat, S, additional, and Slamon, DJ, additional

Published
2012
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40. P1-17-05: Preliminary Results of a Randomized Phase 2 Study of PD 0332991, a Cyclin-Dependent Kinase (CDK) 4/6 Inhibitor, in Combination with Letrozole for First-Line Treatment of Patients (pts) with Post-Menopausal, ER+, HER2−Negative (HER2–) Advanced Breast Cancer.

Author

Finn, RS, primary, Crown, JP, additional, Boer, K, additional, Lang, I, additional, Parikh, RJ, additional, Patel, R, additional, Schmidt, M, additional, Hagenstad, C, additional, Lim, H, additional, Pinter, T, additional, Amadori, D, additional, Chan, D, additional, Dichmann, RA, additional, Walshe, J, additional, Breazna, A, additional, Kim, ST, additional, Randolph, S, additional, and Slamon, DJ, additional

Published
2011
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42. Abstract P1-11-12: Phase II Trial of Presurgical Treatment with Trastuzumab (H) or Lapatinib (Ty) or the Combination of Trastuzumab and Lapatinib (H+Ty), Followed by Six Cycles of Docetaxel (T) and Carboplatin (C) with Trastuzumab (TCH) or Lapatinib (TCTy) or the Combination of Trastuzumab and Lapatinib (TCHTy) in Patients with HER2+ Breast Cancer

Author

Callahan, RD, primary, Patel, R, additional, Chan, D, additional, Allison, MA, additional, DiCarlo, B, additional, Bosserman, LD, additional, Kennedy, A, additional, Zehngebot, LM, additional, Miller, J, additional, Giuliano, AE, additional, Spivack, B, additional, Lin, L-s, additional, Slamon, DJ, additional, and Hurvitz, SA., additional

Published
2010
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45. Abstract PD10-02: Round-Robin Review of HER2 Testing in the Context of Adjuvant Therapy for Breast Cancer (NCCTG N9831/BCIRG006/BCIRG005)

Author

Perez, EA, primary, Dueck, AC, additional, Press, MF, additional, Chen, B, additional, Jenkins, RB, additional, Paik, S, additional, Kim, C, additional, Wiktor, AE, additional, Meyer, RG, additional, Ketterling, RP, additional, Villalobos, I, additional, Finnigan, M, additional, Buyse, M, additional, Zujewski, J, additional, Shing, M, additional, Stern, H, additional, Lingle, WL, additional, Reinholz, MM, additional, and Slamon, DJ., additional

Published
2010
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