Cancer Research
12 Jan Nanomedicine Platform Uses Fluorescence Imaging To Seek and Destroy Cancer Cells
MedicalResearch.com Interview with:
Oleh Taratula, Ph. D.
Assistant Professor of Pharmaceutics
Department of Pharmaceutical Sciences
College of Pharmacy Oregon State University
Corvallis, OR 97331-3507
Medical Research: What is the background for this study? What are the main findings?
Dr. Taratula: Our research group is focused on the development of novel nanotechnology-based approaches to treat different cancers, including ovarian cancer. For many cancers, surgery is a first choice of treatment. For example, only optimal surgical resection of most abdominal metastases can significantly reduce ovarian cancer recurrence and, therefore, improve patient survival. However, it is challenging to remove most of the cancer tumors and residual cancer cells eventually may lead to cancer relapse. Therefore, our aim is to develop a nanomedicine platform, which could help surgeons achieve maximal tumor resection, using the intraoperative guidance with real-time near infrared (NIR) fluorescence signal. Moreover, we expect that the same nanoplatform could further enhance surgical outcomes by combinatorial phototherapy to be performed intraoperatively after tumor resection to eradicate unresected cancer cells.
Our data published in Nanoscale is the first step towards our main goal. At this point, by utilizing naphthalocyanine, we have developed a single-agent-based nanomedicine platform capable of both NIR fluorescence imaging and combinatorial phototherapy. Naphthalocyanine is a commercially available compound, but its potential clinical application is limited by low water solubility and aggregation. Especially, aggregation diminishes the imaging ability and phototherapeutic efficacy of this compound. To address these shortcomings, we discovered that the loading of naphthalocyanine into the dendrimers significantly enhances water solubility, prevents aggregation and preserves imaging and therapeutic abilities. Our data demonstrated that naphthalocyanine-based nanoplatform can generate a NIR fluorescence signal in the cancer tumors, required for elimination of autofluorescence from healthy tissue and body fluids. Furthermore, our results also indicated that the developed nanoplatform is an efficient therapeutic agent which, upon exposure to NIR light, destroys chemotherapy-resistant ovarian cancer tumors by producing both heat and toxic reactive oxygen species.
Finally, many organic fluorophores, including naphthalocyanine, can undergo photobleaching under exposure to light, which could be misinterpreted as a lack of fluorescence signal during the surgery. We demonstrated that the dendrimer encapsulated naphthalocyanine exhibits extremely high photostability and could overcome the above mentioned issue.
12 Jan Socioeconomic Status Affects Long Term Childhood Leukemia Survival
MedicalResearch.com Interview with:
Professor Eleni Petridou
Preventive Medicine & Epidemiology, Department of Hygiene
Epidemiology and Medical Statistics,
Athens University Medical School Athens Greece
Medical Research: What is the background for this study? What are the main findings?
Prof. Petridou: Impressive gains in survival from childhood leukemia have been achieved during the last decades mainly on account of advancements in treatment of the disease. Yet, these big improvements do not seem to be equally shared by all sick children. Disparities in the survival of children suffering leukemia who live in high versus low-income countries, as well as among different racial groups pointed to socio-economic status (SES) of the family as a factor that might adversely affect the outcome. SES, however, is a multifaceted variable comprising economic, social and professional components, which cannot be easily assessed. Therefore, an array of area of residence- and individual family- based proxy indices have been used in order to investigate the association between SES and overall or event-free survival from childhood leukemia. We have intensively searched for published articles around the globe and also analyzed primary data kindly provided by the US National Cancer Institute Surveillance, Epidemiology and End Results Program (SEER) for the period 1973-2010 as well as the Nationwide Registry for Childhood Hematological Malignancies (NARECHEM) in Greece for the period 1996-2011. This study is the first meta-analysis summing up the findings of 29 individual studies and quantifying the adverse effect in the survival due to SES differentials among 60 000 afflicted children. According to the findings, lower socio-economic status children suffering, at least, the more common Acute Lymphoblastic Leukemia (ALL) type have nearly two fold higher death rates compared to those of high socio-economic status. Of note, the SEER data show that the survival gap was wider in the USA with increased risk of death from ALL in the lower SES children (by 20-82%) and widening during the last 40 years time period.
11 Jan Novel Gene Is Potential Therapeutic Target for Triple Negative Breast Cancer
MedicalResearch.com Interview with: Dr. Pentao Liu PhD and Dr. Walid Khaled PhD Wellcome Trust Sanger Institute Cambridgeshire United Kingdom Medical Research: What is the background for this study? What are the main findings? Dr. Pentao Liu: The significance of this research is that it aims to tackle the worst type of breast cancer. Triple Negative Breast Cancer (TNBC) has the poorest patient survival rate compared to other forms of breast cancer. At present there are no targeted therapies available for TNBC, leaving the non-specific chemotherapy as the only treatment option. In this study we identify a new key gene in Triple Negative Breast Cancer which could potentially be inhibited for the targeted treatment of TNBC. In this study we report the identification of a novel gene for Triple Negative Breast Cancer. By analyzing genomics data from 3,000 patients we find BCL11A to be highly expressed in TNBC. We then demonstrate experimentally that upregulation of BCL11A drives tumour development while its downregulation leads to reduction in tumour size. In the experimental mouse model, inactivation of this gene completely abolishes breast tumour development.11 Jan Risk-Benefits of Tamoxifen for Breast Cancer Prevention
MedicalResearch.com Interview with:
Hazel B. Nichols, PhD
Assistant Professor, Department of Epidemiology
University of North Carolina
Gillings School of Global Public Health
MedicalResearch:What is the background for this study?
Dr. Nichols: Tamoxifen, a drug that is often used to treat breast cancer, has also been approved to prevent breast cancer in women who may be at high risk for developing the disease. Taking tamoxifen for 5 years can lower breast cancer risk by up to 48%. The United States Federal Drug Administration (FDA) approved tamoxifen for breast cancer prevention more than 15 years ago (in 1998) for women ages 35 and older who are at high risk of breast cancer and who are at low risk for serious side effects.
National estimates show that <1% of women who are eligible to use tamoxifen actually use it for breast cancer prevention. While tamoxifen lowers breast cancer risk it does cause hot flashes and may lead to serious side effects such as cataract, stroke, and uterine cancer. Women who start taking may also stop taking it before the recommended 5-years due to side effects.
We used a tool developed by scientists at the National Cancer Institute (NCI) to calculate whether the benefits of tamoxifen outweighed the risks for women in the Sister Study, a study of more than 50,000 U.S. and Puerto Rican women with a family history of breast cancer. The tool uses information on a woman’s age, race, breast cancer risk, menopausal status, and whether she had a hysterectomy (surgical removal of the uterus) to estimate whether there is no, moderate or strong evidence that the benefits of tamoxifen will outweigh the risks.
10 Jan Tumor Marker E2F4 Linked to Breast Cancer Survival
MedicalResearch.com Interview with:
Dr. Chao Cheng PhD
Department of Genetics
Geisel School of Medicine at Dartmouth
Hanover 03755, NH
MedicalResearch: What is the background for this study? What are the main findings?
Dr. Chao Cheng: Cancer survival prognosis—“How long do I have, Dr.?” is a topic of great importance to cancer patients and their families. While clinical and pathological variables, such as cancer type, stage, grade, and patient demographics, have long been used to predict survival outcomes, only recently have molecular signatures become incorporated into survival prediction. A molecular approach holds great promise for improving prediction accuracy and additionally elucidating mechanisms of disease, however it is fraught with difficulty due to assay “noise” and “big data” statistical issues, such as the multiple comparisons problem
In this study, we began by analyzing transcription factor binding profiles across available cell lines. By restricting our analysis to transcription factors, DNA expression regulators known to be involved in tumor genesis, we reasoned that we could avoid many of the “big data” issues and achieve results that would make mechanistic and biological sense. We first employed a statistical method we described previously to calculate which genes were the major downstream targets of our transcription factors. With these targets identified, we then analyzed gene expression data using a bioinformatics method to infer the relative activity of each transcription factor based upon the overall expression levels of their gene targets. From here, we incorporated cancer survival data and examined how each transcription factor’s regulatory activity did, or did not, correlate with survival.
The most prognostic transcription factor was E2F4, a member of the E2F family and a known regulator of the cell cycle. We therefore restricted our analysis to E2F4 and examined how its activity level impacted survival in breast cancer patients.
We found that tumors with high E2F4 regulatory activity as compared to low E2F4 regulatory activity had much worse survival outcomes. These results were stable even after controlling for tumor stage, grade, patient age, and treatment, and were based on data from over 1900 patients across eight independent datasets. These results demonstrate that E2F4 is an independent and enhancing predictor of survival above the currently examined variables.
10 Jan Vaccine Boosts Response To Prostate Cancer Therapy
MedicalResearch.com Interview with:
Dr. Robert S. DiPaola
Director, Rutgers Cancer Institute of New Jersey
New Brunswick, NJ 08901
Medical Research: What is the background for this study? What are the main findings?
Dr. DiPaola: Despite significant recent improvements in the treatment of advanced castration-resistant prostate cancer, there remains a need for a standard therapy for those patients who have an early relapse with PSA progression after local therapy. Immune therapy with poxvirus vaccines are optimal, because they can induce potent immune responses by mimicking natural infection, have great flexibility regarding antigen composition and are easily administered.
ECOG-ACRIN Cancer Research Group investigators conducted a Phase II clinical trial examining adult patients from member institutions with advanced prostate cancer (as evidenced by two rising prostate-specific antigen or PSA values and no visible metastasis) who had prior surgery or radiation. We explored two different experimental treatment options.
In step one, patients were treated with PROSTVAC-V/TRICOM and PROSTVAC-F/TRICOM. PROSTVAC-V is derived from a vaccinia virus that was used for many years to vaccinate against smallpox. This virus is modified to produce a PSA protein that helps focus the body’s immune response to the PSA in the prostate tumor. In addition, it is modified to produce three other proteins that help increase an immune cell’s ability to destroy its target (TRICOM). PROSTVAC-F is made from the fowlpox virus, which is found in birds and not known to cause any human disease. It contains the same genetic material as PROSTAC-V, but is given multiple times to further boost the body’s immune system.
Patients in the study were given one cycle of PROSTVAC-V/TRICOM followed by PROSTVAC-F/TRICOM for subsequent cycles in combination with a drug known as GM-CSF. GM-CSF is a protein normally made by the body to increase the amount of certain white blood cells and make them more active. When in drug form, it is used to boost the body’s immune system to fight off disease. After six months from first treatment, 25 of 40 eligible patients (63 percent) were found to have no disease progression and experienced minimal toxicity. The rate of rise of PSA also decreased. The second part of the study included the addition of hormone therapy (androgen ablation) to the PROSTVAC-VF/TRICOM combination. In the 27 patients eligible for this step, 20 patients (74 percent) experienced a significant response at seven months.
07 Jan Screening Mammography Drops After Age 70 But Invasive Breast Cancer Does Not
MedicalResearch.com Interview with: Pamela Vacek, PhD Research Assistant Professor Department of Pathology Medical Biostatistics Unit, College of Medicine University of Vermont, Burlingon, Vermont Medical Research: What is the background for this study? What are the main findings? Dr. Vacek: Clinical trials to evaluate the effectiveness of screening mammography have focused primarily on women under age 70 and, consequently, its benefit for older women is uncertain. However, many believe that the benefit of screening mammography diminishes as women age and acquire other health problems, because they are less likely to live long enough for any detected breast cancer to have a clinical impact. To gain insight into this, we followed approximately 20,000 women aged 70 and older for an average of 10 years to examine their mammography use, cancer detection and survival. We found that screening mammography use declined steadily (9% per year) after age 70, but this was not accompanied by decline in the incidence of invasive breast cancer. Hence, as the women aged breast cancer was more likely to be detected clinically than by screening. The clinically detected tumors were significantly larger and of more advance stage and were associated with poorer overall survival, for all but the oldest and most infirm women. We also found that the use of breast conserving surgery as the only treatment for early stage cancer increased markedly with age and was associated with shorter survival compared to women receiving radiation or mastectomy.07 Jan Study Aims To Determine Why Patients Drop Out of Colon Cancer Screening
MedicalResearch.com Interview with:
Dr Siu Hing Lo
Research Associate in Health Psychology UCL
Research Department of Epidemiology and Public
Medical Research: What is the background for this study? What are the main findings?
Dr. Lo: Most types of population-based cancer screening – such as the Faecal Occult Blood (FOB) test – require repeat participation to be effective. The Faecal Occult Blood test is a stool test that typically needs to be self-completed every two years. This study investigated predictors of repeat participation in the NHS Bowel Cancer Screening Programme (BCSP). Late kit return, a definitive abnormal [FOB test] result and failure to comply with a follow-up colonoscopy in a previous screening episode were consistently and independently associated with lower repeat uptake.
05 Jan Adenocarcinoma of Lung May Spread Through Airways
MedicalResearch.com Interview with:
Joao R. Inacio, MD
Cardiothoracic Radiologist Director Visiting Professor Program
Assistant Professor of Radiology, University of Ottawa
Medical Imaging, The Ottawa Hospital Ottawa, ON
Medical Research: What is the background for this study? What are the main findings?
Dr. Inacio: Lung cancer is the most common and most lethal cancer worldwide. Its prognosis remains poor with a 5-year survival rate of 6–18%. Adenocarcinoma has surpassed squamous cell carcinoma as the leading histologic type. The presence of metastases carries the worst prognosis in lung cancer and is the most important in determining staging and management. Hematogenous spread (i.e., carried by blood) is the most common mechanism of intrapulmonary metastasis. Cumulative evidence suggests that intrapulmonary aerogenous spread may exist and is under recognized.
Deriving from our clinical experience, we performed a literature review that supports the hypothesis that lung cancer, particularly adenocarcinoma, may spread through the airways. With aerogenous metastases, it has been postulated that cancer cells growing along the alveolar septa at the primary site detach from the basal membrane, spread through the airways and re-attach and grow along alveolar septa away from the primary focus.
Radiology-pathology correlation studies, using Chest Computed Tomography (CT), have documented the radiological evolution from focal adenocarcinoma to multifocal airspace disease and demonstrated cytologic and histologic findings supportive of aerogenous spread.
03 Jan Risk of Breast Cancer in Women With Atypical Hyperplasia Better Defined
MedicalResearch.com Interview with:
Dr. Lynn C. Hartmann MD
Professor of Oncology, Mayo Clinic
Associate Director for Education of the Mayo Clinic Cancer Center.
Medical Research: What is the background for this study? What are the main findings?
Dr. Hartmann: Women with atypical hyperplasia of the breast – which is defined via breast biopsy that was done to evaluate findings on a mammogram or a palpable concern – have been considered a “high risk” group of women, but the extent of their risk has not been clearly defined. As a consequence, practice guidelines for high-risk women (eg for screening MRI) do not include them. Mayo Clinic has developed a cohort of women with atypical hyperplasia who have been followed long-term for later breast cancers and we show that their risk of developing breast cancer is about 30% at 25 years of follow-up. This same level of risk was confirmed in the other large cohort of women with atypical hyperplasia, based at Vanderbilt University (Nashville Breast Cohort). This level of risk meets the current criterion for screening MRI and should also encourage the use of anti-estrogen drugs, such as tamoxifen, which have already been shown to be efficacious in this population of women.
03 Jan Non-Small Cell Lung Cancer: Stereotactic Radiation Plus Chemo Improved Survival
Posted at 11:41h
in Author Interviews, Journal Clinical Oncology, Lung Cancer, Radiation Therapy, UT Southwestern
[caption id="attachment_10398" align="alignleft" width="200"]
Dr. Puneeth Iyengar (left) and Dr. Robert Timmerman[/caption]
MedicalResearch.com Interview with:
Dr. Puneeth Iyengar, MD, PhD.
Assistant Professor Director of Clinical Research
Dept of Radiation Oncology Co-leader, Thoracic Disease Oriented Team Harold Simmons Cancer Center
UT Southwestern Medical Center Dallas, TX
Medical Research: What is the background for this study? What are the main findings?
Response: Stage IV Non-small cell lung cancer (NSCLC) remains a disease of limited survival, in the range of one year for a majority of patients who historically have gone on to receive systemic therapy only. Disease in this patient population most often recurs in the sites of original gross disease. With greater understanding of the biology and patterns of failure that occur in stage IV NSCLC, it is becomingly increasingly obvious that there are subsets of patients, those with limited sites of metastatic disease, who may benefit with more aggressive local therapy in addition to systemic agents to effectuate longer progression free survival (PFS) and potentially overall survival (OS). Since failures of treatment occur most commonly in original gross deposits, local non-invasive therapy in the form of stereotactic body radiation therapy (SBRT) may offer a means to curtail the recurrences, perhaps as a way to shift the time to and patterns of failure.
To address these concepts, a multi institutional single arm phase II study was conducted at UT Southwestern Medical Center in Dallas and University of Colorado Medical Center. Twenty-four patients with limited metastatic NSCLC (fewer than or equal to six sites of disease including the primary) who had progressed through at least one systemic therapy regimen were treated with SBRT to all sites of gross disease and the EGFR inhibitor erlotinib with progression free survival the primary end point. The results of the study were very significant, with a PFS in this study cohort of 14.7 months, compared to historical ranges of 2-4 months, and an OS of 20.4 months, compared to historical ranges of 6-9 months for this same patient population. The SBRT treatments were found to be very safe and efficacious – only 3 out of 47 measurable lesions irradiated recurred with a concomitant shift in failure patterns from local to distant sites. As importantly, EGFR status was evaluated in 13 patient tumors, with none harboring the most common mutations. One could, therefore, predict that with a mutation enriched population, the combination of EGFR inhibitor and SBRT may have offered even greater PFS and OS benefits. Our observations also suggest that the SBRT treatments probably contributed the most to the dramatic PFS and OS outcomes.
These findings were published in the Journal of Clinical Oncology in the December 1, 2014 print issue with an accompanying editorial.
31 Dec Study Links Red Meat To Inflammation and Tumor Formation
MedicalResearch.com Interview with:
Dr. Annie Samraj MD
Postdoc Fellow
Varki Lab and
Ajit V
arki MD
Distinguished Professor of Medicine and Cellular & Molecular Medicine , Co-Director, Center for Academic Research and Training in Anthropogeny, Co-Director, Glycobiology Research and Training Center
University of California, San Diego, La Jolla, CA
Medical Research: What is the background for this study? What are the main findings?
Dr. Varki: For the past decade, there has been increasing evidence that people who consume red meat (beef, pork, lamb) are at a higher risk for certain kinds of cancers. Although red meat is a high quality source of protein, iron and vitamins, too much consumption may be harmful to humans. While there are other hypotheses under consideration, we focused on a non-human sugar molecule called Neu5Gc in red meat that could explain the link to cancer risk.
We extensively studied various foods and concluded that red meat (particularly beef) is rich in Neu5Gc. In contrast poultry, fish steaks and hen eggs have little or no Neu5Gc. From previous studies, we knew that animal-derived Neu5Gc could be incorporated into human tissues. In this study, we hypothesized that eating red meat could lead to inflammation if the body’s immune system targets the foreign Neu5Gc. Chronic inflammation is also known to instigate or promote tumor progression.
To test this hypothesis, we used mice engineered to be similar to humans in that they lacked Neu5Gc, and also produced antibodies against it. When these mice were fed Neu5Gc, they developed systemic inflammation. Tumor formation increased fivefold and Neu5Gc accumulated in the tumors, proving the hypothesis. None of the various control groups of mice showed this effect.
30 Dec Potential Drug Combination With Viagra May Enhance Cancer and Infection Treatments
MedicalResearch.com Interview with:
Paul Dent PhD
Massey Cancer Center,
Departments of Biochemistry and Molecular Biology
Virginia Commonwealth University, Richmond, VA 23298
Medical Research: What is the background for this study? What are the main findings?
Dr. Dent: I have worked on understanding how the drug OSU-03012 (AR-12) kills cancer cells since 2005.
The drug was originally advertised as an inhibitor of PDK1 in the PI3 kinase pathway. We found that PDK1 inhibition could not be the major way in which the drug worked. We found that the drug killed brain cancer cells through endoplasmic reticulum stress signaling. And in 2012 we published that OSU-03012 destabilized the chaperone protein GRP78, without significantly altering its transcription. Loss of GRP78 was responsible for the prolonged intense endoplasmic reticulum stress signal, that was toxic. In 2014 we published that OSU-03012 + Viagra / Cialis synergized to kill brain cancer cells. We hypothesized that Viagra / Cialis might enhance the anti-GRP78 effect of OSU-03012; and this was proven to be true.
We discovered that the OSU-03012 + Viagra combination, but not OSU-03012 alone, reduced expression of other chaperone proteins, such as HSP70, GRP94. In mice, the combination was not toxic to "normal" tissues, but was toxic to tumor cells.
In human patients the drug was found to be safe in a phase I trial, with plasma levels of up to 8 microM, and patients on trial for up to 9 months.
30 Dec Racial Disparities in Colon Cancer Survival Persist
Posted at 01:41h
in Annals Internal Medicine, Author Interviews, Colon Cancer, Race/Ethnic Diversity, University of Pennsylvania
MedicalResearch.com Interview with:
Jeffrey H. Silber, M.D., Ph.D.
The Nancy Abramson Wolfson Endowed Chair in Health Services Research Director, Center for Outcomes Research
The Children's Hospital of Philadelphia
Professor of Pediatrics, Anesthesiology & Critical Care
The Perelman School of Medicine
Professor of Health Care Management, The Wharton School
The University of Pennsylvania Philadelphia, PA 19104
Medical Research: What is the background for this study? What are the main findings?
Response: Differences in colon cancer survival by race is a well recognized problem among Medicare beneficiaries. We wanted to determine to what extent the racial disparity in survival is due to a racial disparity in presentation characteristics at diagnosis (such as advanced stage and the presence of chronic diseases) versus a disparity in subsequent treatment by surgeons and oncologists.
To answer this question, we compared black colon cancer patients to three matched white groups:
(1) “Demographics” match controlling age, sex, diagnosis year, and Survey, Epidemiology, and End Results (SEER) site;
(2) “Presentation” match controlling demographics plus comorbidities and tumor characteristics including stage and grade; and
(3) “Treatment” match including presentation variables plus details of surgery, radiation and chemotherapy.
We studied Medicare patients 65 years of age and older diagnosed between 1991-2005 in the SEER-Medicare database. There were 7,677 black patients and 3 sets of 7,677 matched white controls.
We found that difference in 5-year survival (black-white) was 9.9% in the demographics match. This disparity remained unchanged between 1991-2005. After matching on presentation characteristics, this difference fell to 4.9%. Finally, after additionally matching on treatment, this same difference hardly changed, moving to only 4.3%. So the disparity in survival attributed to treatment differences comprised only an absolute 0.6% of the overall 9.9% survival disparity.
29 Dec Endoscopic Imaging System Sees and Treats Tumors
MedicalResearch.com Interview with:
Ulas Sunar, Ph.D.
Research Assistant Prof.
Dept of Biomedical Engineering
SUNY-University at Buffalo
Medical Research: What is the background for this device? What are the main implications?
Dr. Sunar: Most of ovarian cancer cases are not diagnosed until after the disease has spread in the abdominal cavity. A major challenge is to detect and remove dozens or hundreds of metastatic tumor nodules within the abdominal cavity. Fluorescence endoscopy can utilize the high sensitivity and specificity of fluorescence contrast and high resolution of endoscopic imaging.
We are developing a clinically-relevant, fiber-based endoscopy system that allows both accurate fluorescence imaging and for projecting adaptive-shaped light for light-induced chemodrug delivery. The system can provide high contrast for improved demarcation and trigger drug release to destroy micrometastases. The system utilizes a highly sensitive camera and structured light illumination scheme with a projector for accurate fluorescence imaging of drug distribution, as well as allows light-triggered drug release and adaptive light delivery for optimized treatment of micrometastases. We expect that our novel illumination and drug release strategy will permit lower doxorubicin doses to be administered while simultaneously achieving more specific drug delivery in order to destroy the micrometastases and improve survival rates.
29 Dec Triple Negative Breast Cancer: Presurgery Chemotherapy Benefits
MedicalResearch.com Interview with:
William M. Sikov, MD
Associate Chief of Clinical Research Program in Women's Oncology
Women & Infants Rhode Island
Associate professor of Medicine
The Warren Alpert Medical School of Brown University
Medical Research: What is the background for this study? What are the main findings?
Dr. Sikov: The data presented at San Antonio this year are the first results from correlative studies performed on pretreatment tissue samples from patients treated on CALGB 40603, a 2 x 2 factorial randomized phase II study which tested the addition of carboplatin or bevacizumab to a standard neoadjuvant chemotherapy regimen consisting of weekly paclitaxel followed by dose-dense AC in patients with stage II-III triple breast cancer. Last year at San Antonio (and subsequently published in the JCO) we presented the primary endpoint of the study - pathologic complete response (pCR) - and reported that the addition of either carboplatin or bevacizumab significantly increased pCR rates compared to the control regimen. This year we reported results of a preplanned analysis which assessed the impact of intrinsic subtype (based on mRNA expression analysis) - especially the basal-like subtype - on the impact of the two agents on pCR rates. We also reported the effects of a number of previously published mRNA expression signatures on pCR rates and the benefits of adding carboplatin or bevacizumab.
The findings reported were as follows: We had a higher percentage of basal-like cancers than we anticipated when the study was designed (87% vs. 70-80% expected), which we hypothesize is due to improvements in the ways we assess hormone receptor and HER2 status, and thus define triple-negative breast cancer, compared to 10-15 years ago. When we limit our analysis to the subset of patients with basal-like cancers, we continue to see a statistically significant increases in pCR rates with both carboplatin and bevacizumab. However, while the 13% of patients with non-basal-like cancers get essentially the same increase in pCR rates with carboplatin as do the basal-likes, non-basal-likes actually had a reduction in their pCR rates with the addition of bevacizumab - thus, there was a significant interaction between subtype and pCR benefit for bevacizumab but not for carboplatin. Among the mRNA signatures we assessed, higher expression of immune signatures (indicating more tumor-infiltrating lymphocytes) correlated with higher pCR rates, but not greater pCR increments with either carboplatin or bevacizumab. Higher proliferation, lower estrogen, and higher TP53 mutation signaturss also correlated with higher pCR rates overall, and also with greater pCR increments with bevacizumab, but not carboplatin.
28 Dec Increased Risk Of Leukemia After Breast Cancer Treatment
Posted at 18:39h
in Author Interviews, Breast Cancer, Johns Hopkins, Journal Clinical Oncology, Leukemia
MedicalResearch.com Interview with:
Dr. Judy Karp, Dr. Antonio Wolff and Dr. Kala Visvanathan
Breast Cancer Program
Johns Hopkins Sidney Kimmel Comprehensive Cancer Center
Baltimore, MD 21287
Medical Research: What is the background for this study? What are the main findings?
Response: The background for this study was the clinical observation from the Johns Hopkins Leukemia Program that a significant number of women with newly diagnosed acute myeloid leukemia had a personal history for breast and/or ovarian cancers. This observation led to our examination of the large NCCN breast cancer database in a multidisciplinary and multi-institutional study. The overarching finding in our study is that the risk of developing some form of leukemia following chemotherapy with or without radiation therapy, while small, continues to increase over at least 10 years without a plateau and is roughly twice what we thought it to be from previous breast cancer studies.
21 Dec BRCA Screening of Ashkenazi Women Would Be Cost Effective
MedicalResearch.com Interview with: Dr Ranjit Manchanda Consultant Gynaecological Oncologist, St Bartholomew’s Hospital, London, UK Honorary Sr Lecturer, Women’s Cancer, EGA Institute for Women's Health, University College London, UK and Professor Ian Jacobs Vice President, The University of Manchester Dean & Head School of Medicine Faculty of Medical & Human Sciences, Director MAHSC (Manchester Academic Health Science Centre) Medical Research: What is the background for this study? What are the main findings? Dr. Jacobs: Background- Women carrying a BRCA1/2 gene alteration have a very high risk of developing breast and ovarian cancer and men carrying this alteration have an increased risk of prostate and breast cancer. Approximately 45-65% women who have this inherited genetic change will develop breast cancer and 15-35% ovarian cancer. They also have a 50% chance of passing these genes on to their children. At risk individuals can access available options of screening and prevention through the National Health Service (NHS). Some population groups across the world are known to have a higher frequency of BRCA 1/2 gene alterations than others. One example is Ashkenazi Jews who have a 1 in 40 likelihood of having a BRCA1/2 gene alteration. This is 10-20 times higher than in the general non-Jewish population. At present in the UK, genetic testing is available within the NHS to individuals who have a strong family history of cancer. However, many people are not aware of their family history or its significance and do not seek advice. Many other individuals with BRCA1/2 gene alterations do not have a family history at all. The current approach misses a large number of people at risk who could benefit from knowing about their BRCA 1/2 mutation status and the ability to access opportunities for prevention or screening. In order to address this the GCaPPS study has investigated the best method of screening for risk of inherited (familial) cancer by exploring the alternative approach of offering the genetic test to all men and women >18 years in the Ashkenazi Jewish population. It does so by comparing the benefits and disadvantages of: (i) The current system of testing only those with a family history and (ii) The new option of testing everyone in the population. Main Findings: Over half of the BRCA1/BRCA2 carriers detected did not give a strong family history of cancer and would not have been identified by current family history based testing criteria used in the NHS (National Health Service) in the UK and most health systems internationally. Reassuringly population-based genetic testing in Ashkenazi Jews did not adversely affect short term psychological health or quality-of-life. A health economic analysis indicated that population-based screening for BRCA-mutations in Ashkenazi Jewish women ≥30years would be highly cost-effective compared to the traditional family history based approach. Such an approach if implemented could reduce the incidence of and deaths from breast and ovarian cancer as well as reducing cost and save the NHS funds.20 Dec Triple Negative Breast Cancer: Tryptophan Degradation Pathway Promotes Metastatic Phenotypes
Posted at 13:41h
in Breast Cancer
MedicalResearch.com Interview with:
Thomas Rogers
PhD Candidate- Cancer Biology Graduate Program
Laboratory of Jennifer Richer
Department of Pathology
University of Colorado-Anschutz Medical Campus
Laboratory of CU Cancer Center investigator, Jennifer Richer, PhD.
Medical Research: What is the background for this study? What are the main findings?
Response:
Background: Survival while detached from a basement membrane is a critical trait of cancer cells progressing through the metastatic cascade. This is particularly important for the triple-negative breast cancer (TNBC) subtype, which lacks estrogen and progesterone receptors and does not have amplification of HER2, and has a peak risk of recurrence within the first three years post-diagnosis. Triple-negative breast cancer also has the highest mortality rate in the first five years as compared to other breast cancer subtypes. We performed global profiling of TNBC cells in adherent versus forced suspension culture conditions after24 hours. These data revealed that triple-negative breast cancer cells surviving in suspension upregulate multiple genes involved in tryptophan catabolism, also known as the kynurenine pathway, including the rate limiting enzyme tryptophan 2,3,-dioxygenase (TDO2) and kynureninase (KYNU). Kynurenine, a key intermediate metabolite of this pathway activates the aryl hydrocarbon receptor (AhR), which was also up-regulated in TNBC cells grown in forced-suspension culture.
Main Findings: Critical enzymes of the kynurenine pathway, TDO2 and KYNU, are upregulated in triple-negative breast cancer cells grown in forced-suspension culture. Furthermore, secreted kynurenine doubles in TNBC cells in forced-suspension culture as measured by high performance liquid chromatography (HPLC). Kynurenine activates the aryl hydrocarbon receptor in triple-negative breast cancer cells grown in forced-suspension culture. Targeting TDO2 and AhR with small molecule inhibitors or short hairpin RNAs decreased survival in suspension, migration/invasion, and proliferation of TNBC cells. Lastly, TDO2 gene expression is higher in invasive ductal breast carcinoma as compared to normal breast tissue and is significantly higher in estrogen receptor negative tumors as compared to estrogen receptor positive tumors. In addition, patients with higher (above-median) TDO2 expression in their primary tumor had significantly shorter overall survival than those with low TDO2.
Conclusions: The kynurenine pathway is activated in TNBC cells in forced suspension and facilitates the invasive/metastatic phenotype of this aggressive breast cancer subtype. Our findings support further investigations into targeting the enzyme TDO2 in TNBC as a novel therapeutic strategy with potential to reduce TNBC mortality rates. Kynurenine is well-known to suppress immune cell function via activation of AhR.
19 Dec NSAIDS May Prevent Some Squamous Cell Skin Cancers
MedicalResearch.com Interview with:
Dr Catherine Olsen | Senior Research Officer
QIMR Berghofer Medical Research Institute
Royal Brisbane Hospital, QLD 4029
Medical Research: What is the background for this study? What are the main findings?
Response: Squamous cell carcinomas (SCCs)are the second most common skin cancer occurring in white skinned populations. They cause significant morbidity as they can invade local structures (often the nose or ears) and they also have the potential to metastasize although most are successfully treated before any spread occurs. They are also very expensive cancers to treat because they are so common, posing a significant burden on health care budgets. NSAIDS have been shown to be protective for other cancers (e.g. colorectal and oesophageal cancer). This prompted use to evaluate all of the available evidence on NSAIDs use and SCC by conducting a systematic review and meta-analysis of the association.
18 Dec Pilots and Cabin Crew Fly With Greater Risk of Melanoma
MedicalResearch.com Interview with:
Martina Sanlorenzo, MD
Department of Dermatology
Mount Zion Cancer Research Center
University of California, San Francisco
Medical Research: What is the background for this study?
Dr. Sanlorenzo: We recently performed a meta-analysis and found an increased risk of melanoma in pilots and cabin crew. One of the possible occupational hazards responsible for this risk is UV radiation.
Medical Research: What are the main findings?
Dr. Sanlorenzo: We performed UV measurements in airplane cockpits during flight and we found that windshields blocked UV-B but allowed UV-A transmission. We compared the UV-A dose in airplanes with the UV-A dose in tanning beds, whose use is a known risk factor for melanoma. Pilots flying for 56.6 minutes at 30,000 feet received the same amount of UV-A carcinogenic effective radiation of a 20-minute tanning beds session.
17 Dec Over Half Colon Cancer Deaths Due To Not Getting Screened
MedicalResearch.com Interview with: Reinier G.S. Meester, M.Sc Department of Public Health, ErasmusMC, Rotterdam, Netherlands Medical Research: What is the background for this study? What are the main findings? Response: Despite decreasing death rates from colorectal cancer over the past decades, it still ranks as the second leading cause of cancer deaths in the U.S. Screening for colorectal cancer is highly effective, but only 58% of the eligible population reported up-to-date with screening. This suggests that a substantial proportion of current colorectal cancer deaths in the U.S. are avoidable. We found that approximately 60% (32,200 deaths) of current deaths from colorectal cancer may be due to not receiving screening.17 Dec Gene Mutation Identified In Metastatic Breast Cancer
MedicalResearch.com Interview with:
Dr. Ryan Hartmaier PhD
Postdoctoral Associate
Magee-Womens Research Institute (MWRI)
and the University of Pittsburgh Cancer Institute
Medical Research: What is the background for this study? What are the main findings?
Response: The inhibition of signaling through the estrogen receptor is a major target in breast cancer therapy. However, within recurrent disease others have recently identified point mutations within the estrogen receptor as a mechanism of resistance to this therapy.
We undertook a comprehensive study of breast cancer progression by applying many next-generation sequencing technologies to a collection of paired primary-metastasis tissue samples from 6 patients. We placed special emphasis on the identification of structural variants (i.e. translocations, duplications, inversions, and deletions) acquired in metastatic breast cancer. In one patient with recurrent disease while on endocrine therapy, we identified a fusion gene between ESR1 (estrogen receptor alpha) and DAB2 (disabled-2). In vitro functional studies indicate that this fusion is constitutively active and hormone independent.
17 Dec Zinc Isotopes May Be Breast Cancer Biomarker
MedicalResearch.com Interview with:
Fiona Larner, PhD Postdoctoral Research Associate
Department of Earth Sciences, University of Oxford, South Parks Road, Oxford, UK
Department of Earth Science & Engineering, Imperial College London, Exhibition Road, South Kensington, London, UK
Medical Research: What is the background for this study? What are the main findings?
Response: Zinc has been identified to have a role in breast tissue and breast cancer for over a decade. Zinc has several isotopes (different versions of zinc due to varying numbers of neutrons), which require slightly different amounts of energy to go through biological processes. By measuring the changes in the zinc isotopic signature, we can probe it's behaviour to a greater resolution to that currently available in medical institutions. We looked at the isotopic signatures in different tissues of healthy patients and those with breast cancer in order to understand the mechanisms involved in more detail and in search for a biomarker that uses these signatures to diagnose breast cancer.
We found that preferentially retains the lighter isotopes of zinc to a greater extent than healthy breast tissue. This means that the partnering heavy isotopes must be ejected from the cell, and may provide a biomarker for cancer in the future.
16 Dec Breast Cancer: Ovarian Suppression May Benefit Some Young Patients
MedicalResearch.com Interview with:
Prudence A. Francis, M.D
Associate Professor, Peter MacCallum Cancer Centre
Melbourne, Australia
Medical Research: What is the background for this study? What are the main findings?
Response: The background for this study was the observation that premenopausal women diagnosed with hormone receptor positive breast cancer under age 35, had an increased risk of recurrence, as compared with older premenopausal women. We postulated that this might be because this age group was less likely to enter menopause after receiving chemotherapy, and so their ovaries were continuing to produce estrogen, which might have the effect of stimulating any remaining cancer cells.
The main findings were that while not all premenopausal women benefit from the addition of treatment with ovarian function suppression to , the women who underwent chemotherapy and remained premenopausal (median age 40) did have improved breast cancer outcomes. This same group of women had even further improvement in recurrence rates if the ovarian suppression was combined with an aromatase inhibitor exemestane, as compared with tamoxifen. The effects of including ovarian suppression were particularly striking in women under 35 years of age. Those premenopausal women who did not receive chemotherapy (median age 46) after discussion with their doctor, did well with tamoxifen alone and do not appear to benefit from ovarian suppression currently.
14 Dec Breast Cancer: CYP2D6 Remains Important Biomarker of Tamoxifen Effectiveness
MedicalResearch.com Interview with:
Dr. Matthew P. Goetz, MD
Associate Professor of Pncology
Mayo Clinic
Medical Research: What is the background for this study? What are the main findings?
Dr. Goetz: There has been conflicting data with regard to the importance of metabolism as measured by CYP2D6 genetic variation. Two large “negative” studies were reported simultaneously in 2012 and these were referenced by guidelines that CYP2D6 should not be used to select hormonal therapy. Our findings demonstrated that these studies were flawed in part based on analytical validity issues. In short, the use of tumor tissue to derive CYP2D6 germline genotype leads to genotyping error in up to 45% of samples.
12 Dec Hypofractionated Whole-Breast Irradiation for Early-Stage Breast Cancer
MedicalResearch.com Interview with:
Dr. James Yu
Yale School of Medicine
Cancer Outcomes, Public Policy, and Effectiveness Research Center
Yale School of Medicine
Department of Therapeutic Radiology
New Haven, Connecticut
Medical Research: What is the background for this study? What are the main findings?
Response: Hypo fractionated radiation has been shown to be safe and effective, and more convenient for women with early stage breast cancer after lumpectomy. It also has been identified by ASTRO as a practice that physicians can adopt to reduce healthcare expenses for patients and for society. We looked at the National Cancer Database, a database created by the American College of Surgeons for trends in the use of hypo fractionated radiation for breast cancer through 2011. We found that the use of hypofractionated radiation had increased to 22.8% in 2011. I found this remarkable as it predated the ASTRO choosing widely guidelines, and indicated to me that physicians were already thinking of ways of making treatment more convenient and affordable for patients and insurers.
12 Dec Breast Cancer: Older Patients Still Receiving Radiation Therapy Despite Limited Benefit
MedicalResearch.com Interview with:
Rachel Blitzblau, M.D., Ph.D.
Butler Harris Assistant Professor
Department of Radiation Oncology
Duke University Medical Center
Durham, NC 27710
Medical Research: What is the background for this study? What are the main findings?
Dr. Blitzblau: Radiation reduces the risk of loco-regional recurrence. Data from the CALGB 9343 study suggests that the local benefit from adjuvant radiation is less in older women with small, . The potential acute and late toxicities of radiotherapy, patient inconvenience and healthcare costs must be considered given the small clinical benefit associated with adjuvant radiotherapy in this patient group. We looked at rates of radiotherapy in women fitting the entry criteria of this trial before and after publication of 5 year results of the CALGB trial. We found an approximately 5% decrease in use of radiotherapy overall, and noted that there seemed to be a small but significant shift in the type of radiotherapy used for these patients. Less patients received standard whole breast radiotherapy, and more received a short course of treatment to just the tumor bed plus margin called accelerated partial breast irradiation. We concluded that the publication of the trial therefore had only a very small impact on practice patterns.
11 Dec Breast Cancer: Preoperative Axillary MRI Assessment
Posted at 19:39h
in Breast Cancer
MedicalResearch.com Interview with:
Tina J Hieken, MD
Department of Surgery Associate Professor of Surgery
Mayo Clinic College of Medicine
Rochester, MN 55905
MedicalResearch.com: What is the background for this study?
Dr. Hieken: Many newly diagnosed breast cancer patients undergo breast MRI; Breast MRI includes a component of axillary imaging. However, there is limited data on MRI staging of axilla.