Browsing by Subject "Targeted therapy"
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Item Current Landscape of Targeted Therapies for Hormone-Receptor Positive, HER2 Negative Metastatic Breast Cancer(Frontiers, 2018-08-10) Ballinger, Tarah J.; Meier, Jason B.; Jansen, Valerie; Medicine, School of MedicineThe majority of deaths from MBC are in patients with hormone receptor (HR) positive, HER2 negative disease. Endocrine therapy (ET) remains the backbone of treatment in these cases, improving survival and quality of life. However, treatment can lose effectiveness due to primary or acquired endocrine resistance. Analysis of mechanisms of ET resistance has led to the development of a new generation of targeted therapies for advanced breast cancer. In addition to anti-estrogen therapy with selective estrogen receptor modulators, aromatase inhibitors, and/or selective estrogen receptor degraders, combinations with cyclin dependent kinase (CDK) 4/6 inhibitors have led to substantial progression free survival (PFS) improvements in the first and second line settings. While the PI3K/AKT/mTOR pathway is known to be an important growth pathway in HR positive breast cancer, PI3K inhibitors have been disappointing due to modest effect sizes and significant toxicity. The mTOR inhibitor everolimus significantly improves progression free survival when added to ET, and recent studies have improved supportive care allowing less toxicity. While these combination targeted therapies improve outcomes and often delay initiation of chemotherapy, long term overall survival data are lacking and data for the ideal strategy for sequencing these agents remains unclear. Ongoing research evaluating potential biomarkers and mechanisms of resistance is anticipated to continue to improve outcomes for patients with HR positive metastatic breast cancer. In this review, we will discuss management and ongoing challenges in the treatment of advanced HR positive, HER2 negative breast cancer, highlighting single agent and combination endocrine therapies, targeted therapies including palbociclib, ribociclib, abemaciclib, and everolimus, and sequencing of therapies in the clinic.Item Identifying therapeutic targets in gastric cancer: the current status and future direction(Oxford University Press, 2016-01) Yu, Beiqin; Xie, Jingwu; Department of Pediatrics, IU School of MedicineGastric cancer is the third leading cause of cancer-related death worldwide. Our basic understanding of gastric cancer biology falls behind that of many other cancer types. Current standard treatment options for gastric cancer have not changed for the last 20 years. Thus, there is an urgent need to establish novel strategies to treat this deadly cancer. Successful clinical trials with Gleevec in CML and gastrointestinal stromal tumors have set up an example for targeted therapy of cancer. In this review, we will summarize major progress in classification, therapeutic options of gastric cancer. We will also discuss molecular mechanisms for drug resistance in gastric cancer. In addition, we will attempt to propose potential future directions in gastric cancer biology and drug targets.Item The Impact of Genomic Profiling for Novel Cancer Therapy--Recent Progress in Non-Small Cell Lung Cancer(Elsevier, 2016-01-20) Xie, Jingwu; Zhang, Xiaoli; Department of Pediatrics, IU School of MedicineThere is high expectation for significant improvements in cancer patient care after completion of the human genome project in 2003. Through pains-taking analyses of genomic profiles in cancer patients, a number of targetable gene alterations have been discovered, with some leading to novel therapies, such as activating mutations of EGFR, BRAF and ALK gene fusions. As a result, clinical management of cancer through targeted therapy has finally become a reality for a subset of cancers, such as lung adenocarcinomas and melanomas. In this review, we summarize how gene mutation discovery leads to new treatment strategies using non-small cell lung cancer (NSCLC) as an example. We also discuss possible future implications of cancer genome analyses.Item Molecular pathology of urogenital tumors : Recommendations from the 2019 International Society of Urological Pathology (ISUP) Consensus Conference(SpringerLink, 2021-05) Hommerding, Oliver; Allory, Yves; Argani, Pedram; Bismar, Tarek A.; Bubendorf, Lukas; Canete-Portillo, Sofía; Chaux, Alcides; Chen, Ying-Bei; Cheng, Liang; Cubilla, Antonio L.; Egevad, Lars; Gill, Anthony J.; Grignon, David J.; Hartmann, Arndt; Hes, Ondrej; Idrees, Muhammad T.; Kao, Chia-Sui; Knowles, Margaret A.; Looijenga, Leendert H.J.; Lotan, Tamara L.; Pritchard, Colin C.; Rubin, Mark A.; Tomlins, Scott A.; Van der Kwast, Theodorus H.; Velazquez, Elsa F.; Warrick, Joshua I.; Williamson, Sean R.; Kristiansen, Glen; Pathology and Laboratory Medicine, School of MedicineComprehensive understanding of molecular principles in cancer and the diversification of oncological therapy promise individual therapeutic concepts, which have not yet found their way into urogenital cancer therapy. In March 2019 the International Society of Urogenital Pathology (ISUP) therefore held a consensus conference on recommendations for molecular diagnostics of genitourinary tumors, which were published in five separate manuscripts and are summarized in this article.In preparation for the conference, a comprehensive survey of current practices for molecular testing of urogenital tumors was carried out by members of the ISUP. At the conference, the results and the corresponding background information were presented by five working groups and recommendations for action for diagnostics were developed. An agreement between 66% of the conference participants was defined as consensus.Item Pancreatic acinar cell carcinoma: A review on molecular profiling of patient tumors(Baishideng Publishing Group, 2017-12-07) Al-Hader, Ahmad; Al-Rohil, Rami N; Han, Haiyong; Von Hoff, Daniel; Medicine, School of MedicinePancreatic carcinomas with acinar differentiation are rare, accounting for 1%-2% of adult pancreatic tumors; they include pancreatic acinar cell carcinoma (PACC), pancreatoblastoma, and carcinomas of mixed differentiation. Patients with PACC have a prognosis better than pancreatic ductal adenocarcinomas but worse than pancreatic neuroendocrine tumors. Reports of overall survival range from 18 to 47 mo. A literature review on PACCs included comprehensive genomic profiling and whole exome sequencing on a series of more than 70 patients as well as other diagnostic studies including immunohistochemistry. Surgical resection of PACC is the preferred treatment for localized and resectable tumors. The efficacy of adjuvant treatment is unclear. Metastatic PACCs are generally not curable and treated with systemic chemotherapy. They are moderately responsive to chemotherapy with different regimens showing various degrees of response in case reports/series. Most of these regimens were developed to treat patients with pancreatic ductal adenocarcinomas or colorectal adenocarcinomas. Review of PACC’s molecular profiling showed a number of gene alterations such as: SMAD4, BRAF, BRCA2, TP53, RB1, MEN1, JAK-1, BRCA-1, BRCA-2, and DNA mismatch repair abnormalities. PACCs had multiple somatic mutations with some targetable with available drugs. Therefore, molecular profiling of PACC should be an option for patients with refractory PACC.Item A phase II evaluation of cediranib in the treatment of recurrent or persistent endometrial cancer: An NRG Oncology/Gynecologic Oncology Group study(Elsevier, 2015-09) Bender, David; Sill, Michael W.; Lankes, Heather A.; Reyes, Henry D.; Darus, Christopher J.; Delmore, James E.; Rotmensch, Jacob; Gray, Heidi J.; Mannel, Robert S.; Schilder, Jeanne M.; Hunter, Mark I.; Samuelson, Megan I.; Leslie, Kimberly K.; McCourt, Carolyn K.; Department of Obstetrics and Gynecology, IU School of MedicinePURPOSE: Cediranib is a multi-tyrosine kinase inhibitor targeting vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF) receptors. This phase II study was conducted to assess activity and tolerability of single-agent cediranib in recurrent/persistent endometrial cancer. PATIENTS AND METHODS: Eligible patients had recurrent or persistent endometrial cancer after receiving one or two prior cytotoxic regimens, measurable disease, and Gynecologic Oncology Group (GOG) performance status of ≤2 (≤1 if two prior cytotoxic regimens given). Cediranib 30mg orally daily for a 28daycycle was administered until disease progression or prohibitive toxicity. Microvessel density (MVD) was measured in tumor tissue from initial hysterectomy specimens and correlated with clinical outcome. Primary endpoints were tumor response and surviving progression-free for six months without subsequent therapy (6-month event-free survival [EFS]). RESULTS: Of 53 patients enrolled, 48 were evaluable for cediranib efficacy and toxicity. Median age was 65.5 years, 52% of patients had received prior radiation, and 73% of patients received only one prior chemotherapy regimen. A partial response was observed in 12.5%. Fourteen patients (29%) had six-month EFS. Median progression-free survival (PFS) was 3.65 months and median overall survival (OS) 12.5 months. No grade 4 or 5 toxicities were observed. A trend towards improved PFS was found in patients whose tumors expressed high MVD. CONCLUSION: Cediranib as a monotherapy treatment for recurrent or persistent endometrial cancer is well tolerated and met protocol set objectives for sufficient activity to warrant further investigation. MVD may be a useful biomarker for activity.Item Precision Genomic Practice in Oncology: Pharmacist Role and Experience in an Ambulatory Care Clinic(MDPI, 2020-03) Raheem, Farah; Kim, Pauline; Grove, Meagan; Kiel, Patrick J.; Medicine, School of MedicineRecent advancements in molecular testing, the availability of cost-effective technology, and novel approaches to clinical trial design have facilitated the implementation of tumor genome sequencing into standard of care oncology practices. Current models of precision oncology practice include specialized clinics or consultation services based on a molecular tumor board (MTB) approach. MTBs are comprised of interprofessional teams of clinicians and scientists who evaluate tumors at the molecular level to guide patient-specific targeted therapy. The practice of precision oncology utilizing MTB-based models is an emerging approach, transforming precision genomics from a novel concept into clinical practice. This rapid shift in practice from cytotoxic therapy to targeted medicine poses challenges, yet brings exciting opportunities to clinical pharmacists practicing in hematology and oncology. Only a few precision genomics programs in the United States have a strong pharmacy presence with oncology pharmacists serving in leadership roles in research, interpreting genomic sequencing, making treatment recommendations, and facilitating off-label drug procurement. This article describes the experience of the precision medicine clinic at the Indiana University Health Simon Cancer Center, with emphasis on the role of the pharmacist in the precision oncology initiative.Item Randomized phase II trial of bevacizumab plus everolimus versus bevacizumab alone for recurrent or persistent ovarian, fallopian tube or peritoneal carcinoma: An NRG oncology/gynecologic oncology group study(Elsevier, 2018-11) Tew, William P.; Sill, Michael W.; Walker, Joan L.; Secord, Angeles Alvarez; Bonebrake, Albert J.; Schilder, Jeanne M.; Stuckey, Ashley; Rice, Laurel; Tewari, Krishnansu S.; Aghajanian, Carol A.; Obstetrics and Gynecology, School of MedicinePURPOSE: Bevacizumab (BV) monotherapy leads to compensatory upregulation of multiple signaling pathways, resulting in mTOR activation. We evaluated combining BV and everolimus (EV), an mTOR kinase inhibitor, to circumvent BV-resistance in women with recurrent or persistent ovarian, fallopian tube or primary peritoneal cancer (OC). PATIENTS AND METHODS: Eligible OC patients had measurable (RECIST1.1) or detectable disease, 1-3 prior regimens, performance status (PS) 0-2, and no prior m-TOR inhibitor. All patients received BV 10 mg/kg IV every 2wks. Patients were randomized (1:1) to oral EV (10 mg daily) or placebo stratified by platinum-free interval (PFI), measurable disease and prior BV. Primary endpoint was progression-free survival (PFS); secondary endpoints included safety and response. RESULTS: 150 patients were randomized to BV with (n = 75) and without (n = 75) EV. Arms were well-balanced for age (median 63: range 28-92), PS (0: 73%, 1-2: 27%), prior regimens (1: 37%, 2: 47%, 3: 16%), prior BV (11%), PFI (<6mos: 65%) and measurable disease (81%). The BV + EV vs BV median PFS was 5.9 vs 4.5 months (hazard ratio [HR] 0.95 (95% CI, 0.66-1.37, p = 0.39)). Median OS was 16.6 vs 17.3 months (HR 1.16 (95% CI, 0.72-1.87, p = 0.55). Objective measurable responses were higher with BV + EV (22% vs 12%). Study removal due to toxicity was higher with BV + EV (29% vs 12%). Toxicity (≥grade 3) from BV + EV were "other GI (mucositis)" (23 vs 1%) and "metabolic/nutrition" (19 vs. 7%); common ≥ grade 2 toxicities with BV + EV were cytopenia, nausea, fatigue and rash. CONCLUSION: The combination regimen (BV + EV) did not significantly reduce the hazard of progression or death relative to BV and was associated with higher rates of adverse events and study discontinuation when compared to BV alone.Item Real-World Data on Cabozantinib in Previously Treated Patients with Metastatic Renal Cell Carcinoma: Focus on Sequences and Prognostic Factor(MDPI, 2019) Santoni, Matteo; Heng, Daniel Y.; Bracarda, Sergio; Procopio, Giuseppe; Milella, Michele; Porta, Camillo; Matrana, Marc R.; Cartenì, Giacomo; Crabb, Simon J.; De Giorgi, Ugo; Basso, Umberto; Masini, Cristina; Calabrò, Fabio; Vitale, Maria Giuseppa; Santini, Daniele; Massari, Francesco; Galli, Luca; Fornarini, Giuseppe; Ricotta, Riccardo; Buti, Sebastiano; Zucali, Paolo; Caffo, Orazio; Morelli, Franco; Carrozza, Francesco; Martignetti, Angelo; Gelibter, Alain; Iacovelli, Roberto; Mosca, Alessandra; Atzori, Francesco; Vau, Nuno; Incorvaia, Lorena; Ortega, Cinzia; Scarpelli, Marina; Lopez-Beltran, Antonio; Cheng, Liang; Paolucci, Vittorio; Graham, Jeffrey; Pierce, Erin; Scagliarini, Sarah; Sepe, Pierangela; Verzoni, Elena; Merler, Sara; Rizzo, Mimma; Sorgentoni, Giulia; Conti, Alessandro; Piva, Francesco; Cimadamore, Alessia; Montironi, Rodolfo; Battelli, Nicola; Pathology and Laboratory Medicine, School of MedicineCabozantinib is approved for the treatment of renal cell carcinoma (RCC). However, prognostic factors are still lacking in this context. The aim of this study was to evaluate prognostic factors in RCC patients treated with second- or third-line cabozantinib. A multicenter retrospective real-world study was conducted, involving 32 worldwide centers. A total of 237 patients with histologically confirmed clear-cell and non-clear-cell RCC who received cabozantinib as second- or third-line therapy for metastatic disease were included. We analyzed overall survival (OS), progression-free survival (PFS) and time-to-strategy failure (TTSF) using Kaplan-Meier curves. Cox proportional models were used at univariate and multivariate analyses.The median PFS and OS of cabozantinib were 7.76 months (95% CI 6.51-10.88) and 11.57 months (95% CI 10.90-not reached (NR)) as second-line and 11.38 months (95% CI 5.79-NR) and NR (95% CI 11.51-NR) as third-line therapy. The median TTSF and OS were 11.57 and 15.52 months with the sequence of cabozantinib-nivolumab and 25.64 months and NR with nivolumab-cabozantinib, respectively. The difference between these two sequences was statistically significant only in good-risk patients. In the second-line setting, hemoglobin (Hb) levels (HR= 2.39; 95% CI 1.24-4.60, p = 0.009) and IMDC (International Metastatic Renal Cell Carcinoma Database Consortium) group (HR = 1.72, 95% CI 1.04-2.87, p = 0.037) were associated with PFS while ECOG-PS (HR = 2.33; 95%CI, 1.16-4.69, p = 0.018) and Hb levels (HR = 3.12; 95%CI 1.18-8.26, p = 0.023) correlated with OS at multivariate analysis, while in the third-line setting, only Hb levels (HR = 2.72; 95%CI 1.04-7.09, p = 0.042) were associated with OS. Results are limited by the retrospective nature of the study.This real-world study provides evidence on the presence of prognostic factors in RCC patients receiving cabozantinib.Item The Role of Obesity in Renal Cell Carcinoma Patients: Clinical-Pathological Implications(MDPI, 2019-11-13) Aurilio, Gaetano; Piva, Francesco; Santoni, Matteo; Cimadamore, Alessia; Sorgentoni, Giulia; Lopez-Beltran, Antonio; Cheng, Liang; Battelli, Nicola; Nolè, Franco; Montironi, Rodolfo; Pathology and Laboratory Medicine, School of MedicineObesity is a well-known risk factor for renal cell carcinoma (RCC) development. However, the RCC–obesity link has not been fully addressed when considering a comprehensive scenario starting from pathogenetic aspects through pathological issues up to the outcome of medical treatment. We therefore conducted an electronic PubMed search using keywords “obesity”, “body mass index”, “overweight”, “renal cell carcinoma/kidney cancer”, “medical treatment”, “targeted therapy”, and “immunotherapy/immune checkpoint inhibitors”. The selected data supported a crosstalk between adipose tissue (adipocytes and other white adipose tissue cells) and cancer cells inducing several signaling pathways that finally stimulated angiogenesis, survival, and cellular proliferation. Accurate sampling of renal sinus fat correlated with a prognostic value. Retrospective clinical evidence in metastatic RCC patients with higher body mass index (BMI) and treated with targeted therapies and/or immune checkpoint inhibitors showed advantageous survival outcomes. Therefore, obesity may influence the course of RCC patients, although the interplay between obesity/BMI and RCC warrants a large prospective confirmation. We are therefore still far from determining a clear role of obesity as a prognostic/predictive factor in metastatic RCC patients undergoing targeted therapy and immunotherapy.