Author Interviews, CT Scanning, JAMA, Lung Cancer, NIH / 16.05.2016
Lung Cancer Risk Calculator Improves CT Screening Efficiency and May Save Lives
MedicalResearch.com Interview with:
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Dr. Hormuzd Katki[/caption]
Hormuzd A. Katki, PhD
Division of Cancer Epidemiology and Genetics
National Cancer Institute
National Institutes of Health Department of Health and Human Services,
Bethesda, Maryland
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Katki: The National Lung Screening Trial (NLST) showed that 3 annual CT screens reduced lung cancer death by 20% in a subgroup of high-risk smokers. However, selecting smokers for screening based on their individual lung cancer risk might improve the effectiveness and efficiency of screening. We developed and validated new lung cancer risk tools, and used them to project the potential impact of different selection strategies for CT lung cancer screening.
We found that risk-based selection might substantially increase the number of prevented lung cancer deaths versus current subgroup-based guidelines. Risk-based screening might also improve the effectiveness of screening, as measured by reducing the number needed to screening to prevent 1 death. Risk-based screening might also improve the efficiency of screening, as measured by reducing the number of false-positive CT screens per prevented death.
Dr. Hormuzd Katki[/caption]
Hormuzd A. Katki, PhD
Division of Cancer Epidemiology and Genetics
National Cancer Institute
National Institutes of Health Department of Health and Human Services,
Bethesda, Maryland
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Katki: The National Lung Screening Trial (NLST) showed that 3 annual CT screens reduced lung cancer death by 20% in a subgroup of high-risk smokers. However, selecting smokers for screening based on their individual lung cancer risk might improve the effectiveness and efficiency of screening. We developed and validated new lung cancer risk tools, and used them to project the potential impact of different selection strategies for CT lung cancer screening.
We found that risk-based selection might substantially increase the number of prevented lung cancer deaths versus current subgroup-based guidelines. Risk-based screening might also improve the effectiveness of screening, as measured by reducing the number needed to screening to prevent 1 death. Risk-based screening might also improve the efficiency of screening, as measured by reducing the number of false-positive CT screens per prevented death.
Dr. Geoffrey Liu[/caption]
Dr. Geoffrey Liu, MD MSC
Princess Margaret Hospital/Ontario Cancer Institute
University of Toronto
Toronto, Ontario
Canada
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Liu: Cetuximab is a monoclonal antibody therapy used in metastatic colorectal cancer patients when other chemotherapy options have been exhausted. Currently, the only useful biomarker to determine whether metastatic colorectal cancer patients will benefit from the drug, cetuximab, is whether patients carry a RAS mutation in their tumours. We evaluated additional biomarkers using samples from a Phase III clinical trial led by the Canadian Cancer Trials Group and the Australasian Gastrointestinal Trials Group. Our study identified a germline, heritable biomarker, a FCGR2A polymorphism, that further identifies an additional subgroup of patients who would benefit most from receiving cetuximab. This is important because the drug does have toxicity and is expensive to use; patients who are found not to likely benefit from this drug can go on quickly to try other agents, including participation in clinical trials.
Dr. Debra Silverman[/caption]
Dr. Debra Silverman Sc.D
Branch Chief and Senior Investigator in the Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology & Genetics
National Cancer Institute
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Silverman: We know that bladder cancer mortality rates have been elevated in northern New England for at least five decades. Incidence patterns in Maine, New Hampshire and Vermont are similar—about 20% higher than those for the United States overall. Elevated rates have been observed in both men and women, suggesting the role of a shared environmental etiologic factor.
A unique feature of northern New England is that a high proportion of the population uses private wells as their primary source of drinking water. The well water may contain low-to-moderate levels of arsenic. There are two possible sources of this arsenic contamination:
Dr. Mathias Buttmann[/caption]
PD Dr. Mathias Buttmann
Senior Consultant Neurologist and Head of the Multiple Sclerosis Outpatient Clinic
University of Wuerzburg
Wuerzburg, Germany
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Buttmann: The synthetic anthracenedione mitoxantrone is approved for disease-modifying treatment of patients with aggressive forms of relapsing or secondary progressive multiple sclerosis (MS). It has been known for years that this DNA-intercalating agent increases the risk of acute myeloid leukemia. We performed a retrospective cohort study to investigate whether mitoxantrone also increases the risk for other types of malignancies. We included all 677 mitoxantrone-treated multiple sclerosis patients who were seen at our large German academic MS centre between 1994 and 2007 and collected follow-up information on the occurrence of malignancies, death and causes of death as of 2011. Follow-up was complete in 676 patients. The median age at mitoxantrone initiation was 41 years and the median follow-up duration was 8.7 years. We identified 37 patients with a malignancy after mitoxantrone initiation, among them 4 cases of acute myeloic leukemia and 7 cases of colorectal cancer.
Compared to the general population matched for sex, age and year of occurrence, we calculated an 1.5-fold increased incidence of any type of malignancy, a tenfold increased incidence of acute myeloic leukemia and a threefold increased incidence of colorectal cancer, while the incidence of other types of malignancies was not increased. Higher age at mitoxantrone initiation but neither higher cumulative mitoxantrone dose nor treatment with other immuosuppressive agents was identified as a malignancy risk factor. Fifty-five patients had died, among them 12 from a malignancy. Our study confirmed previous reports on an increased incidence of acute myeloic leukemia after mitoxantrone treatment and newly described an association between mitoxantrone therapy and an increased incidence of colorectal cancer.
Dr. Katarina Truvé[/caption]
Katarina Truvé PhD
Swedish University of Agricultural Sciences and
Kerstin Lindblad-Toh
Uppsala University
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Truvé: Gliomas are malignant brain tumors that are rarely curable. These tumors occur with similar frequencies in both dogs and humans. Gliomas in dogs are strikingly similar at the biological and imaging level to human tumor counterparts. Some dog breeds such as Boxer and Bulldog are at considerably higher risk of developing glioma. Since these breeds at high risk are recently related, they are most likely carrying shared genetic risk factors. Our goal was therefore to use the dog genome to locate genes that may be involved in the development of glioma in both dogs and humans. We found a strongly associated locus and identified three candidate genes, DENR, P2RX7 and CAMKK2 in the genomic region. We have shown that CAMKK2 is lower expressed in glioma tumors than normal tissue in both dogs and human, and it has been reported that the associated canine mutation in P2RX7 results in a decrease in receptor function.
Dr. Maryam Farvid[/caption]
MedicalResearch.com Interview with:
Maryam Farvid, Ph.D.
Visiting Scientist
Department of Global Health and Population
Harvard T.H. Chan School of Public Health
MedicalResearch: What is the background for this study? What are the main findings?
Dr. Farvid: Breast cancer is one of the most frequently diagnosed cancers and is the second leading cause of cancer deaths among women in the United States. While we know many breast cancer risk factors, few of them are easily modified. Further, evidence suggests that exposure to carcinogens and anti-carcinogens in early life may play an important role. According to this study, what women eat as teens or young adults could affect their breast cancer risk in the future. Teenage girls who eat a lot of fruits may have a lower risk of breast cancer later in life. The risk of breast cancer among women who reported the highest amount of 
Dr. Jonathan Shoag[/caption]
Jonathan Shoag MD
Urology Resident at
Cornell Department of Urology and
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Dr. Jim Hu[/caption]
Dr. Jim C. Hu MD
Ronald Lynch Professor of Urologic Oncology
Professor of Urology
Director, Lefrak Center for Robotic Surgery
Attending Urologist, New York-Presbyterian Hospital (Cornell campus)
MedicalResearch.com: What is the background for this study?
Response: Prostate Specific Antigen (PSA) is a blood test that is used to detect prostate cancers and to follow a cancer’s response to treatment. PSA was widely implemented as a screening tool for prostate cancer in the early 1990s, and became a routine test during an annual physical for men over 40. Doctors started using it because values above a “normal” threshold were associated with a greater risk of prostate cancer. Following the adoption of PSA screening in the early 1990s, there has been a large increase in the number of men diagnosed with cancer, and a decrease of approximately 50% in the rate of prostate cancer death.
The PLCO trial was a large randomized trial designed and funded by the National Cancer Institute (NCI) to determine the effect of PSA screening on death from prostate cancer. The trial found that men randomized/assigned to prostate cancer screening had the same number of prostate cancer deaths as men in the control group of the trial, arguing that PSA screening does not decrease prostate cancer mortality.
This was a major piece of evidence used by the United States Preventative Services Task Force (USPSTF) to form its 2012 recommendation against PSA screening. The argument was that in spite of the other evidence showing a benefit to PSA testing, including US epidemiologic trends, and another large randomized trial showing PSA screening was effective (the ERSPC), we now had good evidence showing no benefit to PSA testing in the US. Since 2012 we have seen dramatic declines in prostate cancer screening in the US as a result.
Dr. Vikas Gulani[/caption]
Dr. Vikas Gulani MD, PhD
Director, MRI, University Hospitals Case Medical Center
Associate Professor, Radiology
CWRU School of Medicine
Cleveland, OH
MedicalResearch.com: What is the background for this study?
Dr. Gulani: For men that have a suspicion for prostate cancer either via the prostate specific antigen (PSA) test or a digital rectal exam, the current standard of care is to perform a transrectal ultrasound (TRUS) guided biopsy to detect cancer. The problem with TRUS biopsy is that most tumors are not visible on ultrasound and hence many significant cancers are missed. At the same time this strategy detects a high number of low risk, indolent cancers, and leads to overtreatment of disease that would be better left untreated.
Diagnostic MRI and MRI-guided biopsy (cognitive, ultrasound-MR fusion, or in-gantry) have been shown to be effective in detecting clinically significant prostate cancer. However, despite these advantages there is reluctance to incorporate MRI into standard practice because it is perceived to be expensive. Our goal was to determine if this presumption is true, and evaluate the cost-effectiveness of the MRI-guided techniques most commonly used.
MedicalResearch.com: What are the main findings?
Dr. Gulani: We found that every MRI strategy we evaluated was cost-effective compared to standard biopsy. Cognitive MRI guided biopsy – where the operator performs an ultrasound biopsy based on knowledge of lesion location from the MRI – was the most cost-effective strategy compared to standard biopsy. In-gantry MRI yielded the highest net health benefits as measured in quality adjusted life years.
Dr. Han Liang[/caption]
Dr. Han Liang PhD
Associate Professor and Deputy Department Chair, Department of Bioinformatics and Computational Biology
The University of Texas MD Anderson Cancer Center
Faculty Member, Baylor College of Medicine
Houston, TX
MedicalResearch: What is the background for this study? What are the main findings?
Dr. Liang: An individual’s sex has been long recognized as a key factor affecting the risk of cancer development and management. However, previous studies on the sex effect have been limited to individual genes, single molecular data types, and single cancer lineages.
We performed a comprehensive analysis of molecular differences between male and female patients in a diversity of cancer types and revealed two sex-effect groups.
One group contains a small number of sex-affected genes, whereas the other shows much more extensive sex-biased molecular signatures. More than half of clinically actionable genes (e.g., therapeutic targets or biomarkers) show sex-biased signatures.
Jayant S Vaidya MBBS MS DNB FRCS PhD
Professor of Surgery and Oncology,
Scientific Director, Clinical Trials Group,
Division of Surgery and Interventional Science,
University College London
Whittington Health - Clinical Lead for Breast Cancer
Royal Free Hospital
University College London Hospital
MedicalResearch.com: What is the background for this study? What are the main findings?
Prof. Vaidya: TARGIT-A randomised clinical trial (
Dr. Corrine Leach[/caption]
Corinne Leach, MPH, MS, PHD
Strategic Director, Cancer and Aging Research
American Cancer Society, Inc.
Atlanta, GA 30303
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Leach: Using linked data from cancer registries and the Medicare Health Outcomes Survey, we prospectively examined the short-term impact of cancer on the functioning, development of and worsening of age-related health conditions among 921 older adults who developed cancer compared to 4,605 propensity score matched controls. We found that cancer groups demonstrated greater declines in activities of daily living and physical functioning compared to controls with the greatest change for lung cancer patients. Having a cancer diagnosis increased risk for depression but did not increase the odds of developing arthritis in the hand/hip, incontinence (except for prostate cancer), or vision/hearing problems. Having a cancer diagnosis also did not exacerbate the severity of arthritis or foot neuropathy.
Dr. Josefin Segelman[/caption]
Josefin Segelman MD, PhD
Senior consultant colorectal surgeon
Department of Molecular Medicine and Surgery
Karolinska Institutet
Ersta Hospital
Stockholm Sweden
MedicalResearch.com: What is the background for this study?
Dr. Segelman: Hormonal factors influence the development of colorectal cancer. Observational studies and clinical trials have reported a protective effect of hormone replacement therapy and oral contraceptives. Oophorectomy alters endogenous levels of sex hormones, but the effect on colorectal cancer risk is unclear. Removal of the ovaries alters levels of sex hormones in both pre- and postmenopausal women. In premenopausal women, bilateral oophorectomy is followed by surgical menopause as the endogenous estrogen levels drop. Both before and after natural menopause, bilateral oophorectomy promptly decreases endogenous androgen levels by half as the ovaries and adrenals are equally important for androgen production.
MedicalResearch.com: What are the main findings?
Dr. Segelman: The present nationwide cohort study explored the association between removal of the ovaries for benign indications and subsequent risk of colorectal cancer. Among 195 973 women who underwent the procedure from 1965 – 2011, there was a 30% increased risk of colorectal cancer compared with the general population. After adjustment for various factors, women who underwent bilateral oophorectomy had a higher risk of rectal cancer than those who had unilateral oophorectomy (HR 2.28, 95% CI 1.33-3.91).
Dr. Reina Haque[/caption]
Reina Haque, PhD MPH
Research scientist
Kaiser Permanente Southern California Department of Research & Evaluation
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Haque: The study fills an important knowledge gap about the long-term association of aromatase inhibitors on cardiovascular disease risk in breast cancer survivors.
This was a retrospective cohort study that included a cohort of 13,273 postmenopausal breast cancer survivors who were diagnosed with breast cancer, either estrogen or progesterone receptor positive, from 1991 to 2010. The patients were followed through 2011, or a maximum of 21 years. The study participants were divided into four groups based on the drugs they received: 31.7 percent were treated only with tamoxifen; 28.6 percent only with aromatase inhibitors; 20.2 percent used both; and 19.4 percent did not use any of these drugs. These oral drugs are used to combat breast cancer recurrence, but may have long-term side effects on other organs.
The study determined that the risk of cardiac ischemia (which can lead to a heart attack) and stroke were not elevated in patients who only took aromatase inhibitors compared to those who only took tamoxifen. These results provide reassurance that aromatase inhibitors may not increase risk of the potentially fatal cardiovascular outcomes compared to tamoxifen.
Dr. Orit Markowitz[/caption]
Orit Markowitz, MD, FAAD
Director of Pigmented Lesions and Skin Cancer
Assistant Professor of Dermatology
Mount Sinai Medical Center, NY, NY
Director of Pigmented lesions clinic
Brooklyn VA, Brooklyn, NY
Adjunct Professor, Dermatology
SUNY Downstate Medical Center, Brooklyn, NY
Chief of Dermatology
Queens General Hospital, Jamaica, NY
MedicalResearch.com: How common is skin cancer? Is the incidence rising in US adults? Who is most at risk?
Dr. Markowitz: The annual incidence of skin cancer is more than breast, colon, lung, and prostate cancer combined. Of the 7 most common skin cancers in the US melanoma is the only one whose incidence is increasing. The highest risk group for skin cancer are fair skin, adults with a history of sun exposure.
Dr. Asal Mohamadi Johnson[/caption]
Asal Mohamadi Johnson, PhD, MPH
Assistant Professor of Epidemiology, Integrative Health Science
Stetson University
DeLand, FL 32723
MedicalResearch.com: What is the background for this study?
Dr. Johnson: Public health research is primarily focused on neighborhood poverty and racial disparities by illustrating differences between white and black individuals or communities. For example, it has been established that African Americans have higher cancer mortality rates and are less likely to receive appropriate treatment that whites. What we wanted to know in this study was the impact of living in segregated areas apart from other area level characteristics such as poverty or education. Instead of solely looking at health disparities between whites and black patients, our study focused on differences in survival among black patients with early stage Non-Small Cell Lung Cancer (NSCLC) living in different levels of neighborhood segregation.
Dr. Paul Nghiem[/caption]
Paul Nghiem, MD, PhD
Professor & Head, University of Washington Dermatology
George F. Odland Endowed Chair
Affiliate Investigator, Fred Hutchinson Cancer Research Center
Professor, Adjunct, of Pathology and Oral Health Sciences
Clinical Director, Skin Oncology, Seattle Cancer Care Alliance
UW Medical Center at Lake Union
Seattle WA 98109
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Nghiem: Merkel cell carcinoma (MCC) is about 30 times less common than malignant melanoma, but about 3 times more likely to kill a patient than a melanoma. There is no FDA-approved therapy for this cancer & chemotherapy typically only provides about 90 days prior to the cancer progressing. Because of the strong links between MCC and the immune system, including the fact that most MCCs are caused by a virus, there was interest in trying to use immune checkpoint therapy to treat advanced Merkel cell carcinoma. The response to immune stimulation with anti-PD1 therapy was about as frequent as to chemotherapy (56% of patients responded) but importantly, among the responders, 86% remained in ongoing responses at a median of 7.6 months. While still early, this appears to be strikingly more durable than responses to chemotherapy.
Dr. Stephen Freedland[/caption]
Stephen J. Freedland, MD
Associate Director, Faculty Development Samuel Oschin Comprehensive Cancer Institute
Co-Director, Cancer Genetics and Prevention Program
Director, Center for Integrated Research in Cancer and Lifestyle
Professor, Surgery
Warschaw Robertson Law Families Chair in Prostate Cancer
Cedars-Sinai, Los Angeles
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Freedland: PSA is a marker of prostate pathology. While often used to screen for prostate cancer, it is not prostate specific and can be elevated due to inflammation or enlarged prostate or other reasons. Whether it predicts the development of urinary symptoms is not clear. Among men with minimal to no urinary symptoms, we found that the higher the PSA, the greater the risk of future development of urinary symptoms.
MedicalResearch.com: What should clinicians and patients take away from your report?
Dr. Freedland: The readers should know that if a man has an elevated PSA and a negative prostate biopsy, the higher the PSA, the greater the risk of future urinary symptoms. These are men who may need closer follow-up.
Dr. J. William Harbour[/caption]
Dr. Stacie Dusetzina[/caption]
Stacie B. Dusetzina, PhD
Assistant Professor
Division of Pharmaceutical Outcomes and Policy
Eshelman School of Pharmacy
University of North Carolina at Chapel Hill
Chapel Hill, NC
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Dusetzina: Drug prices are of significant policy interest, particularly the prices for so-called “specialty” medications which are used to treat rare and/or complex conditions like cancer. In this study I estimated monthly price for orally-administered cancer treatments that were approved between 2000 and 2014. First I looked at the price of the drug during the year of initial FDA approval and then I looked at annual changes in the price after the year of approval. The main findings are that, even after inflation adjustment, the monthly price paid for orally-administered cancer treatments is increasing rapidly both at the time of approval and in subsequent years.
As an example, if you compare average monthly prices during the first year post-approval for treatments approved between 2000-2010 to those approved after 2010 there was a major increase in launch prices from $5,529 per month to $9,013 per month. Year-to-year changes in price after launch varied a lot by drug ranging from decreases in price of -2.7% per year to increases of 11.4% per year. However, nearly all of the products studied increased in price over time.
Donghao Lu[/caption]
Donghao Lu MD, PhD candidate
Department of Medical Epidemiology & Biostatistics,
Karolinska Institutet
Stockholm
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Lu: Psychiatric comorbidities are common among cancer patients. However, whether or not there is already increased risk of psychiatric disorders during the diagnostic workup leading to a cancer diagnosis was largely unknown.
We found that, among cancer patients, the risks for several common and potentially stress-related mental disorders, including depression, anxiety, substance abuse, somatoform/conversion disorder and stress reaction/adjustment disorder started to increase from ten months before cancer diagnosis, peaked during the first week after diagnosis, compared to cancer-free individuals in Sweden.
Dr. Stamatia Destounis[/caption]
Stamatia Destounis, MD, FSBI, FACR
Elizabeth Wende Breast Care, LLC,
Clinical Professor of Imaging Sciences
University of Rochester
School of Medicine and Dentistry
Rochester NY 14620
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Destounis: Identification of women who have an increased risk of breast cancer is important, as they are often eligible for additional screening methods, such as breast MRI. One criterion for eligibility for screening breast MRI is >20% lifetime risk of breast cancer, as determined by risk assessment models through genetic counseling.
At my facility, we have incorporated a genetics program. Through the program we are flagging and identifying a large volume of patients who are potentially eligible for additional services. This study was conducted to determine the value of screening MRI in the patient subgroup who have undergone genetic counseling at my facility. In this group we found 50% of patients who were referred for counseling were also recommended to have screening MRI. However, only 21.3% of those recommended actually pursued the exam. Of those patients who did have a screening MRI, 4 were diagnosed with breast cancer, all of which were invasive and node negative. We ultimately had a 10% biopsy rate and 50% cancer detection rate in this subgroup.
Dr. Elizabeth Rafferty[/caption]
Elizabeth A. Rafferty, MD
Department of Radiology,
Massachusetts General Hospital, Boston
Now with L&M Radiology, West Acton,
Massachusetts
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Rafferty: Breast tomosynthesis has been approved for mammographic screening in the United States for just over 5 years, and many single center studies have demonstrated its improved performance for screening outcomes over digital mammography alone. Our previously published multi-center analysis, (JAMA 2014;311(24), the largest study on this topic to date, demonstrated significantly improved cancer detection and reduced recall rates for women undergoing tomosynthesis compared with digital mammography alone. In the current issue of JAMA we evaluate the differential screening performance after implementation of breast tomosynthesis as a function of breast density.
While tomosynthesis continues to be increasingly available, questions remained about which women should be imaged with this technique. In particular, does this technology offer additional benefit for all women, or only for women with dense breasts. The size of the database compiled by the centers participating in this study allowed us to evaluate this important question.
The most critical finding of our study was that the use of tomosynthesis for breast cancer screening significantly improved invasive cancer detection rates while simultaneously significantly reducing recall rates both for women with dense and non-dense breast tissue. Having said that, the magnitude of the benefit was largest for women with heterogeneously dense breast tissue; for this population, tomosynthesis increased the detection of invasive cancers by 50% while simultaneously reducing the recall rate by 14%.
Dr. Reddy[/caption]
E. Premkumar Reddy, Ph.D.
Professor, Department of Oncological Sciences
and Department of Structural and Chemical Biology
Director, Experimental Cancer Therapeutics
Mount Sinai School of Medicine
New York, NY 10029
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Reddy: It is now well established that cancer cells harbor mutations in their genome which are responsible for uncontrolled proliferation. Nearly 30 years ago, we as well as two other groups discovered that RAS genes are often mutated in human cancers. Later studies showed that nearly 25-30% of human cancers contain this mutation and these mutations can be caused by chemical carcinogens such as tobacco smoke. Since then there has been an intense effort to understand the biological functions of RAS and to develop drugs that block the activity of these mutant RAS genes. Although molecular oncologists have made significant headway in understanding these mutations and their impact on cellular signaling, little progress has been made towards developing drugs that systematically target the RAS oncogenes. This lack of progress has led many in the field to label RAS as “undruggable”. However, basic research conducted by scientists in this field has revealed that RAS proteins function as ON-OFF switches to signal cells to grow or not to grow because of their ability to bind to a large number of cellular proteins and transmit this signal to their binding partners. These findings also revealed that mutations in RAS genes leaves them in a permanent “ON” position which continues to transmit growth signals permanently. Since most efforts to develop drugs that bind to RAS proteins and reverse their activity failed, we took a different approach to block these signals. Since transmission of growth signals by RAS genes requires their interaction with cellular proteins, all of which contain a domain called “RAS-Binding Domain (RBD)” we created a drug named “Rigosertib” that binds to these RBDs and block their binding to RAS, thereby interrupting RAS signals. When Rigosertib was tested in animals, it could readily inhibit the growth of human tumors that contain RAS mutations. Our studies also show that Rigosertib is a very safe drug with minimal side-effects.