Cancer Treatment Reviews

Emerging therapeutic targets for patients with advanced prostate cancer Publication date: June 2019 Source: Cancer Treatment Reviews, Volume 76 Author(s): Fred Saad, Neal Shore, Tian Zhang, Shikhar Sharma, Helen K. Cho, Ira A. Jacobs Abstract Although recent advances in the treatment of castration-resistant prostate cancer (CRPC) have significantly improved patient outcomes, advanced prostate cancer is still associated with substantial morbidity and mortality, particularly in patients who develop resistance after multiple lines of therapy. Various cell signaling, DNA repair, and epigenetic enzymatic pathways are being targeted with small-molecule inhibitors in order to identify treatment strategies for patients with CRPC. In this review, we discuss novel targets and agents, studied preclinically and now being validated in clinical trials, including poly ADP-ribose polymerase (PARP), enhancer of zeste homologue 2 (EZH2), hedgehog pathway, MDM2/p53, and tyrosine kinase inhibitors. Further, we outline current approaches for novel prostate cancer vaccines such as DCVAC/PCa, PROSTVAC-V/F, MVI-816, CV9104, and PF-06753512. This wide spectrum of potential treatment strategies holds promise for additional improvements in the treatment of patients with CRPC, as these novel agents are aimed at targets known to be associated with growth and malignant progression of prostate cancer. If primary study endpoints are met, findings from ongoing phase III trials of well-tolerated and active combinations may provide new effective treatment options for advanced prostate cancer and thereby contribute to enhanced disease control in CRPC patients.

Genomic profiling in pancreatic ductal adenocarcinoma and a pathway towards therapy individualization: A scoping review Publication date: May 2019 Source: Cancer Treatment Reviews, Volume 75 Author(s): Ritu R. Singh, Johanna Goldberg, Anna M. Varghese, Kenneth H. Yu, Wungki Park, Eileen M. O'Reilly Abstract Context Pancreatic cancer (PDAC) is one of the most challenging cancers to treat with modest recent improvements in survival from new systemic therapies. There is growing interest in individualized therapy underpinned by somatic and germline genomic alterations. Objective A systematic review of data on therapies targeting somatic and germline alterations, and their downstream pathways in PDAC. Method A systematic literature search was conducted using PRISMA guidelines to include relevant results published after January 1, 2008. Results A total of 71 relevant studies were included. We identified 36 studies targeting the KRAS-pathway, the most common being with MEK-inhibitor therapy. Twenty-two studies were identified that evaluated platinum-based chemotherapy and PARP inhibitors in patients with deleterious mutations in DNA damage repair genes and have shown encouraging results. Immunotherapy has demonstrated activity in patients with mismatch repair deficiency/microsatellite instability. Conclusion Evidence from translational and clinical research presents an exciting platform for genomic targeted therapy in PDAC. Validity for targeting BRCA with platinum and PARP inhibitors and microsatellite instability with immune therapy has been established, nonetheless, evidence for targeting the common driver oncogenes is lacking and much work is needed. Of importance is identifying the subgroup of KRAS -wild type PDAC (approximately 5%) where there is enrichment for targetable opportunities.

Short-duration versus 1-year adjuvant trastuzumab in early HER2 positive breast cancer: A meta-analysis of randomized controlled trials Publication date: May 2019 Source: Cancer Treatment Reviews, Volume 75 Author(s): Lujia Chen, Wenqi Zhou, Xiaolei Hu, Man Yi, Changsheng Ye, Guangyu Yao Abstract Background One year of adjuvant trastuzumab treatment is the standard of care for early stage human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients; however, controversy remains regarding the optimal schedule of trastuzumab because the selection of the 1-year schedule was arbitrary. After the remarkable results of the PERSEPHONE trial as well as the updated final results of the PHARE trial, we performed an updated meta-analysis to reassess the efficacy and safety of shorter durations of trastuzumab. Methods A literature search of databases was conducted to identify randomized controlled trials reporting the efficacy and cardiotoxicity of shorter-duration and standard 1-year trastuzumab treatment. The hazard ratios (HRs) of disease-free survival (DFS) and overall survival (OS), and the odds ratios (ORs) of cardiac events were also estimated and pooled. Results Six studies were eligible, including a total of 11,496 patients. Both DFS (HR = 1.13; 95% confidence interval [CI] = 1.03–1.25; p = 0.01) and OS (HR = 1.16; 95% CI = 1.01–1.32; p = 0.03) were significantly improved with conventional 1-year trastuzumab treatment compared with shorter treatments. The more pronounced survival benefits observed in patients with negative estrogen receptor (ER) tumor and nodal involvement should be interpreted cautiously because of the lack of interaction between the survival benefit and ER, as well as the nodal status (interaction test, ER status: p = 0.26; nodal status: p = 0.60). One year of trastuzumab treatment resulted in a substantial DFS benefit compared with shorter schedules when administered concurrently with chemotherapy (HR = 1.22; 95% CI = 1.09–1.38; p = 0.0008; p = 0.02 for the interaction test). Patients in the shorter duration group experienced significantly fewer cardiac events (OR = 0.52; 95% CI = 0.43–0.62; p < 0.00001). Conclusions Though correlated with an increasing risk of cardiotoxicity, 1 year of adjuvant trastuzumab treatment conferred substantial survival benefits and should remain as the preferred treatment for early stage HER2-positive breast cancer. Shorter durations of trastuzumab may serve as an alternative choice for patients with cardiac disease and those at lower risk of recurrence.

Personalizing therapy for older adults with acute myeloid leukemia: Role of geriatric assessment and genetic profiling Publication date: May 2019 Source: Cancer Treatment Reviews, Volume 75 Author(s): Vijaya Raj Bhatt Abstract Acute myeloid leukemia (AML) presents therapeutic challenges in older adults because of high-risk leukemia biology conferring chemoresistance, and poor functional status resulting in increased therapy-related toxicities. Recent FDA approval of 8 new drugs for AML has increased therapeutic armamentarium and also provides effective low-intensity treatment options. Rational therapy selection strategies that consider individual's risk of therapy-related toxicities and probability of disease control can maximize benefits of available treatments. Studies have demonstrated that fitness level, measured by geriatric assessment can predict therapy-related toxicities, whereas cytogenetic and mutation results correlate with the probability of responses to standard chemotherapy. We are approaching an era when we move from "one size fits all" approach to personalized therapy selection based on geriatric assessment, genetic and molecular profiling.

Aggressive variants of prostate cancer – Are we ready to apply specific treatment right now? Publication date: May 2019 Source: Cancer Treatment Reviews, Volume 75 Author(s): Igor Tsaur, Isabel Heidegger, Alexander Kretschmer, Hendrik Borgmann, Giorgio Gandaglia, Alberto Briganti, Pieter de Visschere, Romain Mathieu, Massimo Valerio, Roderick van den Bergh, Piet Ost, Cristian Mirvald, Derya Tilki, Guillaume Ploussard, Cristian Surcel, On behalf of the EAU-YAU Prostate Cancer Working Party Abstract Recently, adoption of novel drugs for systemic treatment of metastatic prostate cancer has led to a striking improvement of response rate and survival in both hormone-sensitive and castration-resistant disease. In most cases, prostate cancer essentially depends on androgen receptor signaling axis, even in castration-resistant setting, and hence may be targeted by second generation hormonal therapy. However, a subset of patients bears androgen-independent cancer biology with a short-term response to hormonal treatment, early and extensive visceral metastases, low PSA levels and poor outcomes. Identification and specific management of these rapidly fatal malignancies is of an unmet medical need since their classification and utilized therapeutic regimens vary significantly. Unfortunately, molecular pathways have not been sufficiently elucidated yet in order to provide an effective targeted treatment with a prolonged response. Lack of diagnostic and predictive biomarkers for these cancers makes successful counteractions against them even more sophisticated. In this comprehensive review, we aimed at summarizing the current body of literature reporting on causal molecular machinery as well as diagnostic and therapeutic concepts of aggressive prostate tumors and draw clinically relevant conclusions for the up-to-date sensible disease management.

Refining adjuvant therapy for non-metastatic colon cancer, new standards and perspectives Publication date: May 2019 Source: Cancer Treatment Reviews, Volume 75 Author(s): Julien Taieb, Thierry André, Edouard Auclin Abstract Colon cancer is the third most frequent cancer in males and the second in females. Approximately 75% are diagnosed at a localized stage. Recurrence occurs in 30% of patients when there is nodal involvement (stage III) due to micrometastatic spreading. To date only chemotherapeutic drugs such as fluoropyrimidines or oxaliplatin have proven effective to kill this residual disease and are currently recommended by scientific societies. To improve patient management in the near future, recent research has focused on new ways of using currently available agents, tools to better define each individual patient prognosis more clearly so as to tailor adjuvant treatment, and molecular profiling to identify specific subgroups of patients with tumors that may benefit from specific therapeutic approaches. In this review, we will focus on current scientific knowledge on adjuvant treatment in localized colon cancer, the duration and timing of adjuvant therapy and the perspectives for better selection of patients who will benefit from adjuvant treatments.

Choosing wisely first line immunotherapy in non-small cell lung cancer (NSCLC): what to add and what to leave out Publication date: May 2019 Source: Cancer Treatment Reviews, Volume 75 Author(s): C. Proto, R. Ferrara, D. Signorelli, G. Lo Russo, G. Galli, M. Imbimbo, A. Prelaj, N. Zilembo, M. Ganzinelli, L.M. Pallavicini, I. De Simone, M.P. Colombo, A. Sica, V. Torri, M.C. Garassino Abstract Immunotherapy has dramatically changed the therapeutic scenario in treatment naïve advanced non-small cell lung cancer (NSCLC). While single agent pembrolizumab has become the standard therapy in patients with PD-L1 expression on tumor cells ≥ 50%, the combination of pembrolizumab or atezolizumab and platinum-based chemotherapy has emerged as an effective first line treatment regardless of PD-L1 expression both in squamous and non-squamous NSCLC without oncogenic drivers. Furthermore, double immune checkpoint inhibition has shown promising results in treatment naïve patients with high tumor mutational burden (TMB). Of note, the presence of both negative PD-L1 expression and low TMB may identify a subgroup of patients who has little benefit from immunotherapy combinations and for whom the best treatment option may still be platinum-based chemotherapy. To date, first-line single agent immune checkpoint blockade has demonstrated limited activity in EGFR mutated NSCLC and the combination of immunotherapy and targeted agents has raised safety concerns in both EGFR and ALK positive NSCLC patients. Finally, in EGFR mutated or ALK rearranged NSCLC, atezolizumab in combination with platinum-based chemotherapy and bevacizumab is emerging as a potential treatment option upon progression to first line tyrosine kinase inhibitors.

Editorial Board Publication date: May 2019 Source: Cancer Treatment Reviews, Volume 75 Author(s):

Management of metastatic bladder cancer Publication date: Available online 15 April 2019 Source: Cancer Treatment Reviews Author(s): Rosa Nadal, Joaquim Bellmunt Abstract Important advances in the understanding of the biology and mechanisms of tumor progression of urothelial carcinoma (UC) have been achieved over the past decade. The treatment landscape for advanced-stage, unresectable or metastatic UC has shifted dramatically over a short period of time, with 5 new therapeutic agents available for clinical use. The use of traditional chemotherapy and new immune checkpoints inhibitors (ICIs) directed at programmed cell-death protein 1 (PD-1) or its ligand has led to unprecedented survival benefits in selected patients with metastatic UC. Data show that anti-PD-1 ICIs are not only improving long-term clinical benefit, but also quality of life for patients in the second-line setting. In the front-line setting, regulatory agencies have restricted the indications of atezolizumab and pembrolizumab (both ICIs) to patients with PD-L1positivity with advanced UC and who are platinum-ineligible. Meanwhile, erdafitinib, a pan-FGFR inhibitor, and enfortumab vedotin, an antibody-drug conjugate, have been granted breakthrough designation by the FDA for the treatment of metastatic UC. Here we review the clinical trial data that have established standard-of-care treatment for advanced-stage UC. In addition, mechanisms of resistance and biomarkers of response to platinum-based chemotherapies and immunotherapies are also discussed, along with the clinical benefits and limitations of these therapies.