70-Gene Signature Changes 50% of Breast Cancer Chemotherapy Advice

MedicalResearch.com Interview with:
Anne Kuijer, MD

Departments of Surgery and Radiology
University Medical Center Utrecht and
Thijs van Dalen, PhD
Department of Surgery
Netherlands Cancer Institute, Amsterdam

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: In recent years it has become evident that clinicopathological factors fail to accurately determine prognosis in hormone receptor positive early stage breast cancer patients at intermediate risk of developing metastases. Gene-expression profiles, such as the 70-gene signature (MammaPrint) are therefore increasingly used for chemotherapy decision-making. In the current multicentre study we assessed the impact of 70-gene signature use on chemotherapy decisions in these patients. We demonstrated that, without the use of the 70-gene signature, half of patients was advised chemotherapy, which reflects the current controversy regarding chemotherapy benefit. Use of the 70-gene signature changed the chemotherapy advice in half of all patients and adherence to the 70-gene signature result was high.

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Gene “Decorations” Can Serve as Blood Biomarkers To Detect Cancer

MedicalResearch.com Interview with:

Kun Zhang, PhD Professor UCSD Department of Bioengineering La Jolla, CA 92093-0412

Dr. Kun Zhang

Kun Zhang, PhD
Professor
UCSD Department of Bioengineering
La Jolla, CA 92093-0412

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: We have been interested in a type of chemical modification on the DNA, called CpG methylation, for years. This is like a decoration of DNA molecules that is specific to the cell type or tissue type. We were particularly interested in studying how such decoration spread along the DNA molecules. In this study, we did a very comprehensive search of the entire human genome for various human cell types and tissue types, and found close to 150,000 regions (called MHB in this study) in which adjacent CpG share the same decoration. We then went on to find out how many of such regions are unique to each normal cell/tissue type, and how many are specific to cancers. Then we took some of these highly informative regions as “biomarkers”, and showed that we can detect the absence or presence of cancer, and, in the latter case, where the tumor grow, in a patient’s blood.

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Sleep Duration and Exhaled Nitric Oxide in Asthma and Health Adults

MedicalResearch.com Interview with:
Rauno Joks, MD

Associate Professor of Clinical Medicine
Chief, Division of Allergy & Immunology
Program Director, Allergy &Immunology Fellowship
SUNY Downstate Medical Center

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: There are circadian and circannular patterns to many diseases, including allergy and asthma. Humans spend roughly one-third of their lifetimes asleep. Your immune system never sleeps, but shifts its activity when you sleep.

It is known that asthma disease activity can be worse at night – the reasons for this are complex, and may involve changes in allergic responses.

We found, in a preliminary study of both adults with and without asthma, that longer duration of nighttime sleep was associated with lower levels of exhaled nitric oxide, a biomarker which is elevated in exhaled breath of those with allergic asthma. This may carry over into the afternoon as well, but the sample size was too small to fully conclude that.

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Genetic Variant of p53 Gene May Explain Increased Breast Cancer Risk in African American Women

MedicalResearch.com Interview with:

Maureen E. Murphy, Ph.D. Professor and Program Leader, Molecular and Cellular Oncogenesis Program Associate Vice President for Faculty Affairs Associate Director for Education and Career Development The Wistar Institute Philadelphia, PA 19104

Dr. Murphy

Maureen E. Murphy, Ph.D.
Professor and Program Leader, Molecular and Cellular Oncogenesis Program
Associate Vice President for Faculty Affairs
Associate Director for Education and Career Development
The Wistar Institute
Philadelphia, PA 19104

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: The Murphy group discovered a coding-region variant of the p53 tumor suppressor gene, called Pro47Ser, that exists in individuals of African descent. In previous studies this group reported that this amino acid change reduces the ability of p53 to function as a tumor suppressor.

In this study, African American women from two different large cohorts were assessed for the incidence of the Pro47Ser variant in pre-menopausal breast cancer. A modest but statistically significant association was found between Pro47Ser and pre-menopausal breast cancer.

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Genetic Defect in DNA Repair Enzyme Linked to Prostate Cancer

MedicalResearch.com Interview with:
G. Andrés Cisneros, Ph.D.

Associate Professor
Department of Chemistry Center for Advanced Scientific Computing and Modeling, University of North Texas

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: The accurate maintenance of DNA is crucial, if DNA damage is not addressed it can lead to various diseases including cancer. Therefore, the question arises about what happens if enzymes in charge of DNA repair are themselves mutated. We previously developed a method to perform targeted searches for cancer-related SNPs on genes of interest called HyDn-SNP-S. This method was applied to find prostate-cancer SNPs on DNA dealkylases in the ALKB family of enzymes.

Our results uncovered a particular mutation on ALKBH7, R191Q, that is significantly associated with prostate cancer. Subsequent computer simulations and experiments indicate that this cancer mutation results in a decreased ability of ALKBH7 to bind its co-factor, thus impeding its ability to perform its native function.

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5-alpha reductase inhibitors For BPH Linked to Higher, Not Lower, PSA Levels

MedicalResearch.com Interview with:
Teemu J Murtola, MD, PhD, adjunct professor
University of Tampere, Faculty of Medicine and Life Sciences
Tampere University Hospital, Department of Urology
Tampere, Finland

MedicalResearch.com: What is the background for this study?

Response: A previous study called Prostate Cancer Prevention Trial
(PCPT) showed that finasteride, which belongs to a drug group called
5alpha-reductase inhibitors lowers serum PSA and increases sensitivity
of PSA to detect high-grade prostate cancer in men who had little or
no symptoms of the lower urinary tract. We postulated that this effect
would increase the accuracy and benefits of PSA-based prostate cancer
screening.

Finnish Randomized Study of Screening for Prostate Cancer was a large
trial of over 80,000 men randomized either to be screened for prostate
cancer with a PSA test at 4-year intervals or to be followed for
prostate cancer incidence and mortality via national registries. Three
consecutive screening rounds were commenced between 1996-2008. In the
current study we compared the effects of PSA-based screening on
prostate cancer risk and mortality separately among men who were using
5alpha-reductase inhibitors finasteride or dutasteride and among men
who were not.

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Genomic Testing Can Improve Confidence in Prostate Cancer Treatment Strategy

MedicalResearch.com Interview with:

Dr. John L. Gore, MD Associate Professor Adjunct Associate Professor-Surgery Department of Urology University of Washington

Dr. John Gore

Dr. John L. Gore, MD
Associate Professor
Adjunct Associate Professor-Surgery
Department of Urology
University of Washington

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: The rationale for our study derives from the uncertainty that both patients and clinicians confront when trying to make decisions about adjuvant therapy for prostate cancers found to have aggressive pathologic features at the time of radical prostatectomy. There is level 1 evidence in support of adjuvant radiation therapy in this setting, but several factors restrain providers from recommending adjuvant radiation. We found that interjecting a genomic test that predicts the risk of clinical metastases 5 years after surgery impacts the treatment recommended and helps men and clinicians feel more confident in the decision they are making or recommending.

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21-Gene Expression Assay May Clarify Need For Chemotherapy in Early Breast Cancer

MedicalResearch.com Interview with:

Carlos H. Barcenas M.D., M.Sc. Assistant Professor Department of Breast Medical Oncology MD Anderson Cancer Center

Dr. Carlos Barcenas

Carlos H. Barcenas M.D., M.Sc.
Assistant Professor
Department of Breast Medical Oncology
MD Anderson Cancer Center

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Over the last decade we have realized that we were over-treating many early stage breast cancer patients. In addition to the chemotherapy’s obvious side effects, there are also long term complications for breast cancer survivors. Since 2005, we are using a 21-gene-expression assay that predicts the risk of distant recurrence among early stage breast cancer patients. In 2015, initial results from the international clinical trial, TAILORx, found that women with hormone receptor positive, HER2 and lymph node negative early stage disease that had a low recurrence score (RS) of 0-10 from this assay could have chemotherapy omitted altogether. While these findings changed care for women with a low RS, questions remain regarding the management of women with an intermediate RS, defined by this trial as a RS of 11-25. For our retrospective, single-institution study we identified 1,424 stage I and II breast cancer patients with hormone receptor positive, HER2 and lymph node negative treated between 2005 and 2011 who underwent the 21-gene expression assay. The RS distribution was: 297 (21 percent) scored 0–10; 894 (63 percent) scored 11-25; and 233 (16 percent) scored >25.

Of those groups, 1.7, 15 and 73.4 percent received chemotherapy, respectively. With a median follow up of 58 months, those with a RS of 11-25 had an invasive disease-free survival (IDFS) rate at five years of 92.6 percent, regardless if patients received chemotherapy or not. Among those patients who did not receive chemotherapy, the estimated rates of IDFS and overall survival was 93 percent and 98 percent, respectively, which was comparable to those who did receive chemotherapy.

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New ‘Blood Biopsies’ with Experimental Device to Speed Cancer Diagnosis and Predict Disease Spread

MedicalResearch.com Interview with:

Edwin Posadas, MD, FACP, KM Director, Translational Oncology Program Medical Director, Urologic Oncology Program Samuel Oschin Comprehensive Cancer Institute

Dr. Edwin Posadas

Edwin Posadas, MD, FACP, KM
Director, Translational Oncology Program
Medical Director, Urologic Oncology Program
Samuel Oschin Comprehensive Cancer Institute
Clinical Chief, Division of Hematology/Oncology
Associate Professor, Department of Medicine
Cedars-Sinai

MedicalResearch.com: What is the background for this study? What are the main findings of your work so far?

Response: The technology we are using is called a NanoVelcro assay. This is a nanotechnology that can be used to isolate rare cells and cell-like particles in the blood stream. We have focused the use of the NanoVelcro on isolating circulating tumor cells (or CTCs). This technology is about 10 times more sensitive than that currently used in clinics. More importantly, because of some modification in our approach, we can now not only capture CTCs, but also examine them under the microscope and even analyze them using advanced molecular techniques. In this way, we take a classic and modern approach to our work.

We firmly believe that there is much to be learned by studying the shapes of these CTCs. We in the cancer field have long known that shape and cellular function are intimately related. In fact, a young pathologist in our group readily recognized that patients with the most aggressive cancers had CTCs with small nuclei, which we verified in a larger study. We are now exploring the importance of these shape variations in CTCs by coupling this classic microscopy-driven approach with RNA characterizations, giving us insight into the molecular nature of the CTC. My collaborator, UCLA Professor Hsian-Rong Tseng, PhD, is a brilliant engineer who has found ways of altering the system to allow us to capture and release live cells for analysis. By using this system, we believe that one day we may be able to avoid performing invasive tissue biopsies to study a cancer.

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New Blood Test May Screen For ATTR Cardiac Amyloidosis

MedicalResearch.com Interview with:

Frederick L. Ruberg, MD Director, Cardiovascular Medicine Fellowship Training Program Director, Pilot Grants Program, Boston University Clinical and Translational Science Institute Director, Advanced Cardiac Imaging Program Section of Cardiovascular Medicine, Department of Medicine Department of Radiology Boston Medical Center

Dr. Frederick Ruberg

Frederick L. Ruberg, MD
Director, Cardiovascular Medicine Fellowship Training Program
Director, Pilot Grants Program, Boston University Clinical and Translational Science Institute
Director, Advanced Cardiac Imaging Program
Section of Cardiovascular Medicine
Department of Medicine
Department of Radiology
Boston Medical Center 

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: ATTR cardiac amyloidosis is an under-recognized cause of congestive heart failure in older adults that results from the deposition of misfolded TTR protein in the heart. One cause of ATTR cardiac amyloidosis is a genetic abnormality, inherited from an affected patient’s parent, that causes the protein TTR to misfold. The most common genetically inherited cause of ATTR amyloidosis in the US is called Val122Ile (V122I), named for the specific mutation in the TTR gene, that is seen in approximately 3.5% of US African Americans. ATTR cardiac amyloidosis was once an untreatable disease, but now new drugs are in different stages of clinical trial testing. Thus, recognition is important to get patients on the right treatments.

One of the principal reasons why the disease is under-recognized is that doctors don’t have proven and available diagnostic tests that can be applied in the outpatient clinic. This study demonstrated that a new point-of-care diagnostic test, using measurement of a blood protein called retinol binding protein 4 (RBP4) and other standard of care test information, can accurately diagnose ATTR cardiac amyloidosis. We demonstrated the validity of this test in two separate cohorts of patients with proven ATTR cardiac amyloidosis due to the Val122Ile mutation and control patients with heart failure but without amyloidosis.

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Hair Cortisol in the Evaluation of Cushing Syndrome

MedicalResearch.com Interview with:
Mihail Zilbermint, M.D.
Endocrinologist, Office of the Scientific Director

Mihail Zilbermint, M.D. Endocrinologist, Office of the Scientific Director Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health

Eunice Kennedy Shriver
National Institute of Child Health and Human Development
National Institutes of Health 

MedicalResearch.com: What is the background for this study?

Response: Diagnosing Cushing Syndrome is often difficult and challenging.  Diagnosing hypercortisolemia, could require the use of a combination of any of these tests: 24-hour free urine cortisol monitoring, an overnight dexamethasone suppression test, and measurement of late night salivary cortisol.  Cortisol levels may change daily, requiring that testing be repeated.  Undiagnosed and untreated Cushing Syndrome greatly increases morbidity and mortality risk.

Cortisol levels can be detected in hair samples.  Much like hemoglobin A1C is a long-term indicator of blood glucose levels, efforts have been made to determine if hair cortisol could serve as a long-term measure of the body’s glucocorticoid levels.  We sought to compare the results of cortisol levels for Cushing Syndrome patients with data from data on cortisol in hair segments, to gain further information on the role of sampling hair cortisol as an initial or supportive method for diagnosing Cushing Syndrome.

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Gene Variant That Controls Tumor Metabolism Linked To Breast Cancer Risk

MedicalResearch.com Interview with:

Ulrich Pfeffer, PhD Head of the Functional Genomics lab IRCCS AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro Genova, Italy

Dr. Ulrich Pfeffer

Ulrich Pfeffer, PhD
Head of the Functional Genomics lab

IRCCS AOU San Martino – IST Istituto Nazionale per la Ricerca sul Cancro
Genova, Italy

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: In recent years our knowledge on genetic variants that are associated with the risk to develop breast cancer has grown substantially. In addition to the two breast cancer genes, BRCA1 and BRCA2 we know approximately 100 other genes that are present in the population in two variants. In the presence of a single of these variants the breast cancer risk is slightly increased and several variants together determine a significant increase in risk. We also know that certain variants are associated with specific subtypes of breast cancer such as the estrogen receptor positive breast cancer.

We show in our work for the first time that some of these variants are more frequent in breast cancers that carry a specific somatic, non-inherited, mutation. In particular, we show this for the most frequent somatic mutation in breast cancer, PIK3CA, a gene involved in the control of tumor metabolism and many other aspects, a fundamental gene. The knowledge of this association tells us a lot on cancer biology. But most important, it might help to design specific prevention strategies. Since when you carry a germline allele that is associated with a specific somatic mutation you know your risk of a specific molecular type of breast cancer and eventually you can do something specific to prevent it.

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