Volume Articles

Bridging the Data Gap in Breast Cancer Risk Assessment to Enable Widespread Clinical Implementation across the Multiethnic Landscape of the US

Erika Spaeth^1*, Athena Starlard-Davenport², Richard Allman³

¹Phenogen Sciences Inc, Charlotte, NC 28269, USA

²Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN 38163, USA

³Genetic Technologies, Ltd, Fitzroy, VIC 3065, Australia

Breast cancer remains the second leading cause of cancer death among women and is the most commonly diagnosed cancer in women. Breast cancer risk assessment has been clinically available for nearly 30 years yet is under-utilized in practice for multiple reasons. Incorporation of polygenic risk as well as breast density measurements, promise to increase the accuracy of risk assessment. With that comes the hope that both prevention and screening become more personalized and thus more effective. Incidence rates have been static over the past 15 years and have even increased slightly in African American and Asian/Pacific Islander populations despite the robust data on breast cancer risk reduction measures that exist. Current challenges in reducing breast cancer incidence begin with robust data curation that allows for appropriate risk stratification across our multiethnic population and conclude with the implementation of prevention strategies within our fractured healthcare system.

MicroRNA-181a Suppresses Progestin-Stimulated Breast Cancer Cell Growth

Xue Li¹, Chun Yang², Xiangyan Ruan¹, Stéphane Croteau², Pierre Hardy²*

¹Department of Gynecological Endocrinology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China

²Departments of Medicine, Pediatrics, Pharmacology and Physiology, University of Montreal, Montreal, Quebec, Canada

Despite all our efforts, breast cancer remains a major public health problem threatening women’s health all around the world. The morbidity of breast cancer is rising in most countries and is going to rise further over the next 20 years. Hormone treatment is widely used and it is the most efficient method of reducing menopausal symptoms or preventing abortion and pregnancy. However, multiple studies have demonstrated that hormones, especially synthetic progesterone, remain an indisputable risk factor for breast cancer. MicroRNAs are a group of endogenous small non-coding single strand RNAs which play regulatory roles in the initiation, development, and progression of different types of cancer. Evidence from multiple sources indicates that microRNA-181a exerts anti-breast cancer effects by inducing cancer cell death and preventing tumor invasion, infiltration and metastasis, etc. Our recent studies revealed that microRNA-181a not only suppresses breast cancer MCF-7 cell growth but also abrogates progestin-provoked cell growth. In this review, several interesting aspects of hormone replacement therapy and the role of microRNA-181a during progestin treatment are discussed.

Therapeutic Approaches to Radiation-Induced Fibrosis

Edward J. Macarak, Joel Rosenbloom*

The Joan and Joel Rosenbloom Research Center for Fibrotic Diseases, Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA

Radiation induced fibrosis (RIF) is a common morbidity in patients being treated for cancer with radiation. Off-target effects result in intense inflammatory responses which ultimately results in the generation of extracellular matrix (ECM) producing myofibroblasts which mediate a progressive fibrosis resulting in scarring and organ and tissue dysfunction. Unfortunately, currently, there are no effective therapies to block the excess accumulation of ECM. We have previously reported on the use of trametinib, a MEK inhibitor, to essentially block the formation of abdominal adhesions in a mouse model of cecal abrasion. Using this drug in the mouse model, the complete trans-differentiation of precursor cells into ECM-producing myofibroblasts was blocked. Trametinib is a potentially powerful drug to thwart organ and tissue fibrosis in RIF because it has a potential dual function in that it may block RIF as well as prevent radiation-resistance. Given the intractability of RIF, trametinib should be considered for more extensive testing.

Functional Imaging-guided Radiotherapy for Locally Advanced Non-Small-Cell Lung Cancer: Review

Xiao Wang*, Yin Zhang, Ning Yue, Ke Nie

Department of Radiation Oncology, Rutgers-Cancer Institute of New Jersey, Robert Wood Johnson Medical School, New Brunswick, NJ, USA

In treating locally advanced non-small-cell lung cancer (NSCLC), radio-tolerance of the normal lung often limits the amount of dose that can be delivered to the primary cancer site. Radiation-related pneumonitis (RP) and other normal lung tissue complications have a significant impact on clinical outcome and patient quality of life. How to minimize treatment side effects while achieving desirable local control of lung cancers has been a continuous challenge.

Functional imaging-guided radiotherapy, which can achieve a local boost of primary cancer site or functional avoidance of normal organs, has been increasingly utilized in clinics. Various imaging approaches have been employed to achieve functional imaging guidance and implemented in different treatment regimens. There are several on-going clinical trials aiming to evaluate the clinical outcomes that are utilizing functional imaging-guided photon radiation to spare the high functioning portions of the lungs. The main applications of functional imaging-guided radiotherapy in the management of NSCLC patients will be discussed in this review.

Value of Multiplatform Molecular Profiling (MMP) of Tumors in Clinical Practice

Ofer Purim^1*, Aron Popovtzer², Ron Epelbaum³

¹Oncology Institute, Assuta Ashdod Academic Hospital, Ashdod, Israel

²Institute of Oncology, Davidoff Center, Rabin Medical Center, Petah Tikva, Israel, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

³Department of Oncology, Rambam Health Care Campus, Haifa, Israel

In the last 20 years, cancer treatment has witnessed a paradigm shift with the advent of modern targeted therapies. Still, at present, targeted therapies, despite being very effective, are only relevant for a minority of patients, whereas the majority of patients are still being offered cytotoxic drugs. The goal of this mini-review is to describe the clinical utility of tumor multi-panel molecular profiling (MMP) to guide treatment decisions (primarily chemotherapies but also targeted therapies) in patients with solid tumors and the evidence supporting this approach, focusing on the Caris Molecular Intelligence (CMI) MMP. The evidence suggests that MMP is a practical, implementable tool that can be used to personalize treatment (including that of chemotherapies), increasing the likelihood of response and sparing patients from unnecessary toxicity associated with ineffective therapies. MMP provides the ability to offer therapy to patients in later lines, particularly for those who have already failed multiple lines of therapy and exhausted the standard therapy options (by suggesting therapies which may be used off-label). Furthermore, the evidence indicates that MMP-guided therapy favorably impacts both progression-free survival and overall survival. As the current data consist of mainly retrospective studies, prospective trials are warranted to strengthen the evidence.

Mini Review: Immunohistochemistry Using EGFR-Mutant Specific Antibodies in Non-Small Cell Lung Carcinoma: Accuracy and Reliability

Rania Gaber^1,2,3, Torsten Goldmann^1,3*

¹Pathology of the University of Lübeck and the Research Center Borstel, Site Borstel, Clinical and Experimental Pathology, Borstel, Germany

²Department of Pathology, Faculty of Medicine, Alexandria University, Alexaandria, Egypt

³Airway Research Center North (ARCN), Member of the German Center for Lung Research, Germany

Epidermal growth factor receptor (EGFR) is a predictive biomarker in many solid cancers including non-small cell lung carcinoma (NSCLC). Patients’ responsiveness to therapy is based on the prior determination of EGFR status. Many techniques were used to detect the potential predictive biomarker and considered as gold standards based on molecular genetic techniques as direct sequencing and polymerase chain reaction (PCR). Immunohistochemistry (IHC) using EGFR mutation-specific antibodies were generated as an alternative simple tool to identify EGFR status and its response to tyrosine kinase inhibitors (TKIs). EGFR gene copy number and wild-type EGFR are other parameters which determine the response to TKIs. The aim of this mini-review is to analyze the studies which investigated the IHC EGFR mutation-specific antibodies, in lung adenocarcinoma (ADC), to determine its accuracy and reliability as a pre-selection tool for candidate patients for TKIs therapy as well as the interplay with other EGFR biomarkers which are EGFR gene copy number and the wild-type EGFR in lung NSCLC. The later determine the response to TKIs and their detection methodology is standardized making them good candidates for comparison with the EGFR-mutation.

Recent Development of Bio-Reducible Polymers for Efficient Gene Delivery System

Sung Wan Kim^1,2*, Joung-Pyo Nam^1,2, Soyoung Kim^1,2, Yong Kiel Sung^1,2,3

Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, Utah 84112, USA

Center for Chemically Controlled Delivery, University of Utah, Salt Lake City, Utah 84112, USA

Department of Chemistry, Dongguk University, Phildong-ro 1 Gil, Chung-gu, Seoul 04620, Korea

The design of a gene delivery system requires a complete understanding of the interaction between targeting cell and delivery systems. The poly(cystaminebis- (acrylamide)-diaminohexane) (poly(CBA-DAH)) has been confirmed as a bio-reducible efficient delivery carrier among the various systems. Poly(ethylenimine) (PEI, 1.8?kDa) was conjugated to poly(CBA-DAH) via a disulfide bond. The PEI conjugated poly(CBA-DAH) (PCDP) was able to bind with pDNA at a very low molecular weight ratio and form the polyplexes with nano-size and positive surface charge. To confirm the transfection efficiency, the plasmid DNA encodes with the luciferase reporter gene and green fluorescent protein reporter gene have made to use a bio-reducible efficient gene delivery. The PCDP polyplexes show 10 times higher gene transfection efficiency than Lipofectamine® polyplexes in bio-mimic in vivo condition. It has been reviewed that the bio-reducible PEI(1.8kDa) conjugated poly(CBA-DAH) is finally concluded as an efficient gene delivery carrier.

Management of Loco-Regional Nasopharyngeal Carcinoma-The Role of Induction Chemotherapy-A Mini-Review

Frank E Mott^1*, Ruth L. Sacks²

¹Thoracic and Head/Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Texas, USA

²University of Texas MD Anderson Cancer Center, Texas, USA

Standard treatment of locally advanced nasopharyngeal carcinoma is patterned after the Intergroup 0099 trial with concurrent cisplatin with radiotherapy, followed by consolidation chemotherapy. This remains the guideline recommended standard. With the wider use of intensity modulated radiotherapy and the incorporation of taxanes in the chemotherapy regimen, many oncologists are increasingly using an induction approach with chemotherapy followed by concurrent chemoradiotherapy. Induction chemotherapy is not considered a standard approach despite studies showing efficacy and tolerability. In this mini-review, we summarize the data from trials and reviews of induction therapy and argue for its recognition as a viable standard option for patients with locally advanced nasopharyngeal carcinoma.

Pyrrole indolin-2-One Based Kinase Inhibitor as Anti-Cancer Agents

Ting-Hsuan Yang^1,2, Ren-Jun Hsu², Wen-Hsin Huang¹, An-Rong Lee¹*

School of Pharmacy, National Defense Medical Center, No. 161, Section 6, Mingchuan East Road, Taipei 11490, Taiwan

Tri-Service General Hospital Biobank, No.325, Sec. 2, Chenggong Rd. Taipei 11490, Taiwan

Cancer cells are characterized by uncontrolled proliferation after escaping from inherent physiological constraints on growth and survival and by destructive invasion of the healthy surrounding tissues. Many kinases involved in signal transduction are overactive in malignant tumor cells. Thus, pharmacotherapeutic interventions targeting kinases responsible for signal transduction of cancer hallmarks have become promising in developing novel anticancer agents. Pyrrole indolin-2-one (or pyrrole oxindole, 1), a lead scaffold of kinase inhibitors, is used for anti-angiogenesis via inhibiting vascular endothelial growth factor receptors (VEGFs) and platelet-derived growth factor receptors (PDGFRs). The kinase selectivity and inhibitory activity of pyrrole indolin-2-one 1 can be significantly influenced through structural modifications. This mini-review provides a detailed overview of structural modification of pyrrole indolin-2-one derivatives for the development of novel kinase inhibitors.