New Oral Hepatitis C Virus Treatment Works But Will Cost Billions

Jagpreet Chhatwal Ph.D. Assistant Professor, Department of Health Services Research Division of Cancer Prevention and Population Sciences The University of Texas MD Anderson Center Houston, TXMedicalResearch.com Interview with:
Jagpreet Chhatwal Ph.D
.
Assistant Professor, Department of Health Services Research
Division of Cancer Prevention and Population Sciences
The University of Texas MD Anderson Center
Houston, TX

Medical Research: What is the background for this study? What are the main findings?

Dr. Chhatwal: More than two million people in the U.S. are infected with Hepatitis C (HCV), a virus found in the liver. In 2012, the Centers for Disease Control and Prevention and the U.S. Preventive Services Task Force both recommended a one-time hepatitis C screening for baby boomers – people born between the years 1946 and 1964. Last year, the Food and Drug Administration approved the medications sofosbuvir and ledipasvir for Hepatitis C treatment. The newly approved oral regimen comes at a staggering price to payers – as much as $1,125 per day. As a result, several payers have questioned if the price is justified.

The study results show that using new therapies is cost-effective in the majority of patients. However, the budget required to treat all eligible patients would be $136 billion over the next five years. Compared with the old drugs, new therapies would cost an additional $65 billion, whereas the cost offsets would be only $16 billion.

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Akt3 Protein Makes Brain Tumor Resistant To Treatment

MedicalResearch.com Interview with:
Kristen Turner PhD. (first author) and
Wei Zhang, Ph.D. Professor
Department of Pathology
Director, Cancer Genomics Core Lab
University of Texas MD Anderson Cancer Center
Houston, Texas 77030

Medical Research: What is the background for this study? What are the main findings?

Response: Glioblastoma (GBM) is the most commonly diagnosed type of brain tumor and is among the most aggressive and challenging cancer types to treat. The traditional approaches to combat this pervasive cancer include surgery combined with radiation and chemotherapy (temozolomide); yet, most will succumb to the disease in just over one year.

In this study, we investigated the Akt family of proteins that are known to be highly active in the majority of Glioblastoma cases. We compared each Akt family member and its ability to initiate glioma progression. We discovered that activation of the third Akt member (Akt3) led to glioma progression and very aggressive tumors. We then studied these tumors to compare their molecular attributes and found evidence of increased DNA repair. Finally, we discovered that the Akt3-induced DNA repair function led to increased survival of Glioblastoma cells after treatment with the DNA damaging agents, radiation and temozolomide. Continue reading

Melanoma: Assaying Multiple Proteins Helps Identify BRAF-Inhibitor Resistance

Linda Chin, MD Department Chair, Department of Genomic Medicine, Division of Cancer Medicine The University of Texas MD Anderson Cancer Center Houston, TXMedicalResearch.com Interview with:
Linda Chin, MD

Department Chair, Department of Genomic Medicine, Division of Cancer Medicine
The University of Texas MD Anderson Cancer Center
Houston, TX

Medical Research: What is the background for this study? What are the main findings?

Dr. Chin: BRAF inhibitors have worked very well against melanoma in the clinic, but when the tumors relapse on treatment, it is not always clear what causes it. Without this information, it can be difficult for doctors to identify specific second-line therapies likely to overcome the drug resistance. In this study, we used both mouse and patient melanoma samples to identify patterns of selected protein levels that can categorize modes of drug resistance when other assays such as DNA sequencing are uninformative. We hope that this information can provide missing clues for clinicians. Continue reading

Personalized Medicine: Tailoring Surgical Approach To Ovarian Cancer

Dr. Anil Sood MD Professor of Gynecologic Oncology and Reproductive Medicine The University of Texas MD Anderson Cancer CenterMedicalResearch.com Interview with:
Dr. Anil Sood MD

Professor of Gynecologic Oncology and Reproductive Medicine
The University of Texas MD Anderson Cancer Center

Medical Research: What is the background for this study? What are the main findings?

MedicalResearch: What is the background for this approach? What are the main findings?

Dr. Sood: The background involves several different issues: management approaches have varied quite a bit across the US; definition of “optimal” surgery and rates of complete surgical removal of tumor (R0) have also varied. It is quite apparent that patients who benefit the most from surgery upfront are those who have removal of tumor resection. To address these issues, we have implanted a much more personalized approach whereby patients with suspected advanced ovarian cancer undergo laparoscopic assessment using a validated scoring system (based on the pattern and extent of disease noted during laparoscopic assessment); patients with a score <8 undergo upfront debulking surgery and those with a score ≥8 receive neoadjuvant chemotherapy followed by surgery after 3-4 cycles. To date, this program has been fully implemented as part of the Moonshot Program at M.D. Anderson. This program has already resulted in several benefits – for example, prior to this algorithm being put into place among all patients with suspected advanced ovarian cancer, around 20% would have removal of tumor resection; after the implementation of the algorithm, of those going to upfront debulking surgery (after laparoscopic assessment), almost 85% of times removal of tumor resection can be achieved. Also, this method of treatment is allowing for new and innovative clinical trial designs. Continue reading

Shared Medical Decision Making Improves Cancer Patient Satisfaction

Kenneth L. Kehl, MD Division of Cancer Medicine, MD Anderson Cancer Center Houston, TexasMedicalResearch.com Interview with:
Kenneth L. Kehl, MD

Division of Cancer Medicine, MD Anderson Cancer Center
Houston, Texas

Medical Research: What is the background for this study? What are the main findings?

Response: Prior studies have demonstrated that most patients with cancer wish to participate in their treatment decisions.  We studied a cohort of patients with lung or colorectal cancer and assessed whether patient involvement in decision-making was associated with perceived quality of care or ratings of physician communication.  We found that patients who described a more shared decision-making process gave higher ratings of their care quality and physician communication.  This effect was independent of patients’ stated preferences regarding involvement in decision-making.

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What Makes Growth Factor Switch From Tumor Suppressor to Tumor Promoter?

Dihua Yu, M.D., Ph.D. Hubert L. & Olive Stringer Distinguished Chair in Basic Science Professor and Deputy Chair Department of Molecular and Cellular Oncology Co-Director, Center of Biological Pathways The Univ. Texas MD Anderson Cancer Center Houston, TX 77030MedicalResearch.com Interview with:
Dihua Yu, M.D., Ph.D.
Hubert L. & Olive Stringer Distinguished Chair in Basic Science
Professor and Deputy Chair
Department of Molecular and Cellular Oncology
Co-Director, Center of Biological Pathways
The Univ. Texas MD Anderson Cancer Center Houston, TX 77030

Medical Research: What is the background for this study?

Dr. Yu: Transforming growth factor β (TGF-β) functions as a tumor suppressor in premalignant cells but may also function as a metastasis promoter in cancer cells. This study aimed to understand how the growth factor makes this switch between tumor suppressor to tumor promoter.

Medical Research: What are the main findings?

Dr. Yu: We reported that 14-3-3ζ overexpression (14-3-3ζ+++) can switch TGF-β’s function from tumor suppressor to metastasis promoter by changing Smad partners. Specifically, 14-3-3ζ+++ led to destabilization of p53, a Smad determinant in pre-malignant cells, thus disrupting p53/Smad complex, and consequently inhibiting TGF-β-induced p21 expression and cytostatic function in non-malignant human mammary epithelial cells (HMECs). On the contrary, 14-3-3ζ+++ stabilized Gli2, a Smad partner in cancer cells, and Gli2 complexed with Smads to promote TGF-β-induced parathyroid hormone-related protein (PTHrP) expression, which enhanced breast cancer bone metastasis. Remarkably, both transcriptomic analyses and clinical pathology data indicated that 14-3-3ζ+++ is associated with the loss of TGF-β’s tumor suppressor function and the gain of its metastasis promoter function by changing contextual partners of Smads. Taken together, we have identified 14-3-3ζ as a novel molecular switch of TGF-β’s function by altering Smad partners from p53 in pre-malignant cells to Gli2 in cancer cells. The study provided important answers to the long-standing questions of how and when TGF-β switches its functional roles from a tumor suppressor to a metastasis promoter. The findings established a scientific base for a new strategy of selectively targeting TGF-β signaling in cancer by inhibiting the cancer-specific Smad partner without blocking TGF-β’s tumor suppressor function in normal tissues.

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Comorbiditites Contribute To Unplanned Hospitalizations Among GI Cancer Patients

MedicalResearch.com Interview with:
Joanna-Grace M. Manzano, MD

Assistant Professor
Department of General Internal Medicine

Maria E. Suarez-Almazor, MD, PhD
Barnts Family Distinguished Professor
Chief, Section of Rheumatology &
Deputy Chair, Dept. of General  Internal Medicine
UT MD Anderson Cancer Center Houston, TX

Medical Research: What are the main findings of the study?

Response: Our study established that unplanned hospitalization among elderly patients with GI cancer are very common – 93 events per 100-person years.

Certain characteristics were found to have an increased risk for an unplanned hospitalization in our cohort, namely: older age, black race, advanced disease, higher comorbidity score, residing in poor neighborhoods and dual eligibility for Medicare and Medicaid. Esophageal and gastric cancer had the highest risk for unplanned hospitalization among all GI cancer types.

Some of the observed reasons for unplanned hospitalization were potentially preventable and related to the patient’s comorbid illness.
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Proton Therapy May Decrease Overall Costs While Improving Quality of Cancer Care

Steven J. Frank, M.D. Associate Professor of Radiation Oncology Medical Director of the Proton Therapy Center The University of Texas MD Anderson Cancer CenterMedicalResearch.com Interview with:
Steven J. Frank, M.D.
Associate Professor of Radiation Oncology
Medical Director of the Proton Therapy Center
The University of Texas MD Anderson Cancer Center

MedicalResearch.com Editor’s Note:

A recent research published in Oncology Payers, discusses the quality of life benefits and cost-savings of intensity modulated proton therapy (IMPT or proton therapy) with traditional x-ray therapy for advanced stage head and neck cancer. The senior author of the paper, Dr. Steven Frank, highlights two oropharyngeal cancer patients, one of whom received proton therapy and the other x-ray treatments. Both patients received chemotherapy.

The study showed that although the upfront costs of proton therapy were three times that of standard x-ray treatments, the proton therapy patient was spared the necessity of a feeding tube, nutritional and supportive care and weight loss that accompanied the x-ray treatments. By the end of the treatment period, the total care costs for the proton therapy patient were 20% lower than the x-ray treatment plan.

To evaluate the costs, Dr. Frank has been employing a costing tool used elsewhere at MD Anderson called Time-driven Activity-based Costing that places the emphasis on the value of medical care, both monetary and in terms of quality of life. Dr. Frank plans to enroll 360 patients over the next five years as well as to open the study to other cancer centers. He notes that the results will be especially valuable as health insurance companies look to further bundled insurance payments.

Dr. Frank was kind enough to answer several questions regarding his work for the MedicalResearch.com audience.

Medical Research: From a patient’s perspective, what are the main differences between traditional x-ray therapy and proton therapy for cancer treatment?

Dr. Frank: In proton therapy, the radiation hits the cancer, while with traditional x-ray the radiation hits the cancer and the normal tissues in the head and neck, causing more side effects during and after treatment. The main advantage is that proton therapy eliminates unnecessary radiation. As radiation oncologists, our primary goal is to effectively kill cancer while sparing the patient the side effects of excessive radiation. Proton therapy achieves this for many patients with a variety of cancers, including lymphoma, lung, head and neck, prostate, esophageal and pediatric cancers.
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Socioeconomic Factors Contribute to Disparities in Breast Cancer Surgery

sabelle Bedrosian, M.D., F.A.C.S. Associate Professor, Department of Surgical Oncology, Division of Surgery Medical Director, Nellie B. Connelly Breast Center The University of Texas MD Anderson Cancer Center, Houston, TXMedicalResearch.com: Interview with:
Isabelle Bedrosian, M.D., F.A.C.S.
Associate Professor, Department of Surgical Oncology, Division of Surgery
Medical Director, Nellie B. Connelly Breast Center
The University of Texas MD Anderson Cancer Center, Houston, TX

Medical Research: What are the main findings of the study?
Dr.
Bedrosian:
•       National BCT (breast conserving therapy) rates have increased during the last two decades.
•       Disparities based on age, geographic facility location and type of cancer treatment facility have lessened over time.
•       Insurance type and travel distance remain persistently associated with underutilization of breast conserving therapy.
•       Annual income of less than $35K may be emerging as a new association with underutilization of breast conserving therapy.
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Links Between Breast Cancer and Obesity Studied

Sai-Ching Jim Yeung, MD, PhD, FACP Professor of Medicine The University of Texas MD Anderson Cancer Center Department of Emergency Medicine Department of Endocrine Neoplasia & Hormonal Disorders Houston, Texas  77230-1402MedicalResearch.com Interview with
Sai-Ching Jim Yeung, MD, PhD, FACP
Professor of Medicine
The University of Texas MD Anderson Cancer Center
Department of Emergency Medicine
Department of Endocrine Neoplasia & Hormonal Disorders
Houston, Texas  77230-1402

MedicalResearch: What are the main findings of the study?

Dr. Yeung: We believe that this study has bridged a significant gap in knowledge between epidemiological data (the association of obesity and poor breast cancer prognosis) and biological mechanisms mediating the impact of obesity on cancer. This study provides an important mechanistic insight into the causal relationship between obesity and breast cancer growth.

  1. Direct evidence for the links between obesity-associated changes in the biological processes and hallmarks of cancer in human estrogen receptor-positive (ER+) breast cancer. 

It is well known that obesity is associated epidemiologicaly with decreased survival in ER+ breast cancer patients. Although a body of experimental literature exists to suggest important roles for estrogen, insulin/IGF-1 and adipokine signaling and inflammation in the mechanisms mediating the impact of obesity on cancer, direct evidence for these mechanisms and their importance relative to one another is lacking in cancers from obese humans.

Functional transcriptomic analysis of a prospective observation cohort with treatment-naïve ER+ breast cancer samples identified the insulin/PI3K signaling and secretion of cytokines among the top biological processes involved. Many of the obesity-associated changes in biological processes can be linked to cancer hallmarks.  Upstream regulator analysis identified estrogen (?-estradiol), insulin (INS1), insulin-like growth factor-1 (IGF1), and adipokines [vascular endothelial growth factor A (VEGFA), tissue necrosis factor (TNF), interleukin-6 (IL6), oncostatin-M (OSM), chemokine ligand 5 (CCL5), leptin (LEP), leukemia inhibitory factor (LIF), C-reactive protein (CRP), adiponectin (ADIPOQ), and interleukin-10 (IL10)] in mediating the impact of obesity on human ER+ breast cancer.

  1. Experimental evidence that obesity causes accelerated oncogene-driven ER+ breast cancer carcinogenesis.

While it is not possible to conduct a human experiment to prospectively examine the causal relationship between obesity and breast cancer, we created a transgenic mouse model with genetically induced obesity and oncogene-driven breast cancer.  With this model we found strong in vivo evidence using both longitudinal experiments and cross-sectional experiments that obesity accelerated oncogene-driven breast carcinogenesis.
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Breast Cancer: Black Patients Had Fewer Sentinel Lymph Node Biopsies

Dalliah Black, MD F.A.C.S. Department of Surgical Oncology The University of Texas MD Anderson Cancer Center, HoustonMedicalResearch.com Interview with:
Dalliah Black, MD F.A.C.S.

Department of Surgical Oncology
The University of Texas
MD Anderson Cancer Center, Houston

 

MedicalResearch: What are the main findings of the study?

Dr. Black: This is a retrospective study from 2002 – 2007 using the SEER/Medicare database of over 31,000 women with node negative breast cancer evaluating the utilization of sentinel node biopsy (SNB) as it transitioned from an optional method for axillary staging to the standard of care instead of complete axillary lymph node dissection (ALND).  We found that SNB use increased each year in both white and black breast cancer patients throughout the study period.  However, SNB was less often performed in black patients (62.4%)compared to white patients (73.7%) and this disparity persisted through 2007 with a 12% difference.  Appropriate black patients more often had an ALND instead of the minimally invasive sentinel node biopsy which resulted in worse patient outcomes with higher lymphedema rates in black patients.  However, when black patients received the minimally invasive SNB, their rates of lymphedema were low and comparable to white patients who received SNB.
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Breast Cancer: Choice To Use Needle Biopsy Influenced by Surgeon

Dr. Benjamin D. Smith MD Associate Professor Department of Radiation Oncology The University of Texas MD Anderson Cancer Center Houston, TX 77030 MedicalResearch.com Interview with:
Dr. Benjamin D. Smith MD
Associate Professor
Department of Radiation Oncology
The University of Texas MD Anderson Cancer Center
Houston, TX 77030

MedicalResearch: What are the main findings of the study?

Dr. Smith: Although use of needle biopsy to diagnose breast cancer increased during the time period we studied, it remained lower than targeted benchmarks. The patient’s surgeon seemed to exert a major influence on use of needle biopsy.
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Cancer: Financial Strain and Modifiable Risk Factors in African Americans

Dr. Lorraine R. Reitzel Ph.D Associate Professor in the Health Program of the Department of Educational Psychology College of Education, University of Houston in Houston, Texas.MedicalResearch.com Interview with:
Dr. Lorraine R. Reitzel Ph.D
Associate Professor in the Health Program of the Department of Educational Psychology
College of Education, University of Houston in Houston, Texas.
MedicalResearch.com: Please tell us about your study.

Dr. Reitzel: The current study represented a secondary analysis of data that were collected by Dr. Lorna McNeill and colleagues at The University of Texas MD Anderson Cancer Center. The parent study was focused on better understanding factors associated with cancer risk among African American adults, and several faculty members including myself contributed ideas about the variables we thought might play a role. The current study represents one of several studies emerging from these data. The current study was led by Ms. Pragati S. Advani, a graduate student on my research team, who was interested in better understanding the associations between financial strain and modifiable behavioral risk factors for cancer among African American adults. Financial strain represents an unfavorable income to needs ratio and was assessed using a questionnaire that tapped into current difficulty affording things that represent pretty basic components of life, including suitable food, clothing, and housing for the respondent and their family. The modifiable behavioral risk factors for cancer examined included smoking cigarettes, at-risk alcohol use, being overweight/obese, getting insufficient physical activity, and having inadequate fruit and vegetable intake. We also included a tally of the total number of these factors (0 to 5) as an outcome variable of interest.
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HPV: Experimental Eradication with AHCC Supplement

Dr. Judith A. Smith is an Associate Professor in the Department of Gynecologic Oncology & Reproductive Medicine in the Division of Surgery at The University of Texas MD Anderson Cancer Center in Houston (UTMDACC),MedicalResearch.com Interview with:
Dr. Judith A. Smith Pharm.D.
Associate Professor
Department of Gynecologic Oncology & Reproductive Medicine
Division of Surgery
The University of Texas MD Anderson Cancer Center in Houston

MedicalResearch.com: What are the main findings of the study?

Dr. Smith: This study first demonstrated in vitro suppression of HPV expression. After a single dose at 24 hours and with repeated dosing every 24 hours for 7 days followed by 7 days of no treatment, HPV eradication was achieved. These findings were confirmed with in vivo animal studies. HPV expression was eradicated with once daily AHCC dosing for 90 days and sustained after 30 day observation off treatment.  Immune modulation (increase) of IFNα (p < 0.03), IFNβ (p <0.03), and IFN (p< 0.03) and IgG1 (P < 0.05) was observed in AHCC treated mice compared to untreated controls.

AHCC mechanism of immune modulation of the IFN pathways to eradicate HPV was particularly relevant because E6/E7 oncogenic activity in HPV infection is believed to be related to suppression of IFN expression/signaling.  These data suggest AHCC may help clear HPV infections and have a potential role in the prevention of HPV-related cancers.

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Hepatitis C: Does Chemotherapy Cause Viral Relapse?

Harrys A. Torres, MD, FACP Assistant Professor Director of Hepatitis C Clinic Department of Infectious Diseases, Infection Control and Employee Health The University of Texas MD Anderson Cancer CenterMedicalResearch.com Interview with:
Harrys A. Torres, MD, FACP
Assistant Professor, Director of Hepatitis C Clinic
Department of Infectious Diseases, Infection Control and Employee Health
The University of Texas MD Anderson Cancer Center

MedicalResearch.com: What are the main findings of the study?

Dr. Torres: The main findings of the study were that patients with hepatitis C virus (HCV) infection who were successfully treated with antivirals and attained sustained virologic response (SVR) did not have a relapse of HCV infection after receiving immunosuppressive chemotherapy for cancer. Patients in the study received different chemotherapeutic agents, including rituximab and systemic corticosteroids. Durability of SVR was maintained up to 14 years after chemotherapy in cancer patients.
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HER2-positive Breast Cancer and Adjuvant Chemotherapy

Dr. Kelly K. Hunt, M.D., F.A.C.S. Professor, Department of Surgical Oncology, Division of Surgery Chief, Breast Surgical Oncology Section, Department of Surgical Oncology The University of Texas MD Anderson Cancer Center, Houston, TXMedicalResearch.com Interview with:
Dr. Kelly K. Hunt, M.D., F.A.C.S.
Professor, Department of Surgical Oncology, Division of Surgery
Chief, Breast Surgical Oncology Section, Department of Surgical Oncology
The University of Texas MD Anderson Cancer Center, Houston, TX

MedicalResearch.com: What are the main findings of the study?

Dr. Hunt: The primary endpoint of the Z1041 trial was the proportion of patients who had pathological complete response in the breast, defined as the percentage of women who started the neoadjuvant treatment with no histological evidence of disease in the breast at surgery.  We found that high pathologic response rates were observed in both treatment groups with similar cardiac safety profiles in both arms of the trial.  Specifically, 56.5% of patients in the sequential group (fluorouracil, epirubicin and cyclophosphamide on day one of a 21-day cycle for four cycles followed by paclitaxel plus trastuzumab weekly for 12 weeks) had a complete pathological response versus 54.2% of the patients who received the concurrent regimen (paclitaxel and trastuzumab weekly for 12 weeks followed by fluorouracil, epirubicin and cyclophosphamide on day one of a 21-day cycle with trastuzumab on days one, eight and 15 of the 21-day cycle for four cycles).  The difference in pathologic complete response rates between the treatment arms was not statistically significant.  Cardiac safety was a secondary endpoint of the trial and we found that both regimens had acceptable cardiac safety profiles.
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Proton Therapy Radiation: Decreased Need for Feeding Tubes in Oropharnygeal Cancer Patients

Steven J. Frank, M.D., associate professor of Radiation Oncology at The University of Texas MD Anderson Proton Therapy CenterMedicalResearch.com Interview with:

Steven J. Frank, M.D., associate professor of Radiation Oncology at The University of Texas MD Anderson Proton Therapy Center discusses the findings of his latest study, “Gastrostomy Tubes Decrease by Over 50% with Intensity Modulated Proton Therapy during the Treatment of Oropharyngeal Cancer Patients.”


MedicalResearch.com: What are the main findings of the study?

Dr. Frank: The study found that the use of feeding tubes in oropharyngeal carcinoma (OPC) cancer patients treated with intensity modulated proton therapy (IMPT) decreased by more than 50% percent compared to patients treated with intensity modulated radiation therapy (IMRT). This suggests that proton therapy may offer vital quality of life benefits for patients with tumors occurring at the back of the throat.

Of the 50 OPC patients enrolled in the study:

  • Twenty-five patients were treated with IMPT and 25 received IMRT.
  • Five patients treated with IMPT required the use of feeding tubes (20%) compared to 12 patients treated with IMRT (48%).
  • IMPT patients were spared from serious side effects, usually a result of IMRT, such as loss of taste, vomiting, nausea, pain, mouth and tongue ulcers, dry mouth, fatigue, and swallowing difficulty.
  • IMPT patients could better sustain their nutrition and hydration levels, often leading to faster recovery during and after treatment.

IMPT is an advanced form of proton radiation therapy and a treatment currently only offered in North America at The University of Texas MD Anderson Proton Therapy Center. It delivers protons to the most complicated tumors by focusing a narrow proton beam and essentially “painting” the radiation dose onto the tumor layer by layer. Unlike IMRT, which destroys both cancerous and healthy cells, IMPT has the ability to destroy cancer cells while sparing surrounding healthy tissue from damage. Therefore, important quality of life outcomes such as neurocognitive function, vision, swallowing, hearing, taste and speech can be preserved in head and neck patients.
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Breast Cancer: 7 Triple-Negative Subtypes and Chemotherapy Response

MedicalResearch.com Interview with:

Hiroko Masuda MD

Morgan Welch Inflammatory Breast Cancer Research Program and Clinic; Departments of 2Breast Medical Oncology, 3Bioinformatics and Computational Biology
The University of Texas MD Anderson Cancer Center, Houston, Texas;

W. Fraser Symmans, MD
Anderson Cancer Center, Department of Pathology, Unit 85, 1515 Holcombe Blvd., Houston, TX 77030-4009;

Naoto T. Ueno, MD
Anderson Cancer Center, 1515 Holcombe Blvd., Unit 1354, Houston, TX 77030.

MedicalResearch.com: What are the main findings of the study?

Answer: Triple-negative breast cancer (TNBC) could be classified into 7 subtypes:
basal-like 1 (BL1), basal-like 2 (BL2), immunomodulatory (IM), mesenchymal (M),mesenchymal stem-like (MSL), luminal androgen receptor (LAR), and unstable (UNS).

Using cluster analysis, Lehmann and Bauer et al. identified these TNBC subtypes in 21 public mRNA gene expression profiles of breast cancer. However, the clinical relevancy of these novel molecular subtypes has not been established. To establish the clinical relevancy, we determined if the subtypes of TNBC have different rates of pathological complete response (pCR) to standard neoadjuvant chemotherapy regimens. In this study, we confirmed that TNBC is heterogeneous and that pCR differs by TNBC subtype using the algorithm proposed by Lehmann and Bauer et al. The BL1 subtype had the highest pCR rate (52%), and BL2 and LAR had the lowest pCR rates (0% and 10%, respectively). TNBC subtype was an independent predictor of pCR status (P=0.022) via a likelihood ratio test. To our knowledge, this was the first study to show that the TNBC subtype can serve as an independent predictor of pCR status in patients who received standard chemotherapy regimens.

This confirms the possible clinical relevance of the 7 molecular subtypes, and these subtypes may lead to innovative clinical trials of personalized medicine for patients with TNBC. Continue reading

Ovarian Cancer and Cardiovascular Comorbidity

Anil K. Sood MD Department of Gynecologic Oncology The University of Texas MD Anderson Cancer Center Unit 1362, PO Box 301439, Houston, TX, 77030MedicalResearch.com Interview with:
Anil K. Sood MD
Department of Gynecologic Oncology
The University of Texas MD Anderson Cancer Center
Unit 1362, PO Box 301439, Houston, TX, 77030

MedicalResearch.com: What are the main findings of the study?

Dr. Sood: For women with newly diagnosed ovarian cancer, high heart rate at diagnosis (tachycardia), venous thromboembolism (VTE) occurring after diagnosis and pulmonary hypertension post-diagnosis are independently related to reduced survival after controlling for tumor stage, grade, and extent of cytoreduction.  Women with tachycardia lived an average of 4.0 years after diagnosis compared with 5.9 years for women without tachycardia, a 32% reduction in duration of survival.  Patients who experienced VTE lived a median 4.1 years after diagnosis, compared with 6.4 yrs for patients who did not experience VTE.

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Node-Positive Breast Cancer: SLN after Chemotherapy

Kelly K. Hunt, MD F.A.C.S. Professor, Department of Surgical Oncology, Division of Surgery Chief, Breast Surgical Oncology Section, Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TXMedicalResearch.com Interview with:
Kelly K. Hunt, MD F.A.C.S.
Professor, Department of Surgical Oncology, Division of Surgery
Chief, Breast Surgical Oncology Section, Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX

MedicalResearch.com: What are the main findings of the study?

Dr. Hunt: We found that 40% of women who had node positive disease at initial presentation (confirmed by needle biopsy) had no evidence of residual cancer in the lymph nodes after chemotherapy.

We performed sentinel lymph node (SLN) surgery followed by axillary lymph node dissection in all of the patients and found a false negative rate of 12.6% with the SLN procedure.

The false negative rate was lower when surgeons used two mapping agents (blue dye and radioisotope) to identify the sentinel nodes and when they removed more than 2 sentinel nodes.
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Novel Susceptibility Variants at 10p12.31-12.2 for Childhood Acute Lymphoblastic Leukemia in Ethnically Diverse Populations

MedicalResearch.com Author Interview: Jun J. Yang, Ph.D.

Assistant Member Dept. of Pharm. Sci.
St. Jude Children’s Research Hospital
262 Danny Thomas Pl., MS313 Memphis, TN 38105

MedicalResearch.com: What are the main findings of the study?

Dr. Yang: We performed a comprehensive survey of inherited genetic variations for their contribution to the susceptibility of acute lymphoblastic leukemia (ALL), the most common cancer in children. This is by far the largest study of its kind (in terms of the number of subjects involved), and also the first one to include multi-ethnic populations. We identified 4 genomic loci related to the predisposition to ALL, 2 of which contributed to racial differences in the incidence of ALL.  This study provided unequivocal evidence for inherited susceptibility of childhood ALL and pointed to novel biology of the pathogenesis of this disease.
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Ovarian cancer patients survive longer with BRCA2 mutated in tumors

HOUSTON – Women with high-grade ovarian cancer live longer and respond better to platinum-based chemotherapy when their tumors have BRCA2 genetic mutations, researchers at The University of Texas MD Anderson Cancer Center and the Institute for Systems Biology report in the Oct. 12 issue of the Journal of the American Medical Association.

“BRCA2-mutated tumors are more vulnerable to these DNA-damaging agents, which is really exciting because there are a number of drugs in clinical trials now that block DNA repair that might prove effective against these tumors in combinations,” said senior author Wei Zhang, Ph.D., professor in MD Anderson’s Department of Pathology.

BRCA2 and its cousin, BRCA1, are tumor-suppressing genes involved in DNA repair that, when mutated, raise a woman’s risk for having breast or ovarian cancer.

“Uncovering the separate potential effects of BRCA1 and BRCA2 mutations takes us a step towards a more personalized approach to treating ovarian cancer, and perhaps other cancers,” Zhang said. “This paper suggests those two genes, and the many others involved in DNA repair, are prime targets for further research.”

Past studies of the possible clinical impact of BRCA1 and BRCA2 mutations tended to look at the two genes together and were limited by small sample sizes.

First author Da Yang, Ph.D., an Odyssey Fellow in MD Anderson’s Department of Pathology, said their in-depth study was made possible by The Cancer Genome Atlas project. TCGA published a study of 489 cases of high-grade serous ovarian cancer, the most common form of the disease, that combined an exhaustive analysis of each tumor’s genome with comprehensive clinical data on each patient.

“TCGA gave us enough analytical power to differentiate between BRCA1 and BRCA2 mutations and conduct a survival analysis,” Yang said.

Improved overall survival

Of 316 cases, 29 tumors had BRCA2 mutations tumors and 37 had BRCA1 mutations. Tumors were similar in grade and stage. Findings include:

  • 61 percent of patients with BRCA2 mutations survived for five years, compared with 25 percent of those with normal BRCA2 in their tumors.
  • 44 percent of those with BRCA2 mutations lived three years after surgery and platinum treatment without disease progression, compared with 16 percent of those with normal BRCA2.
  • BRCA1 mutations in tumors were not associated with survival.
  • All of those with BRCA2 mutations responded to platinum chemotherapy, compared to 82 percent with the normal gene and 80 percent whose tumors had BRCA1 mutations.
  • Their response to chemotherapy lasted 18 months, compared with 11.7 months for normal BRCA2 and 12.5 months for BRCA1 mutations.
  • Tumors with BRCA2 variations also are hypermutants – they had more genetic mutations – with 84 mutations per tumor sample compared to 52 for normal BRCA2

Zhang said this last aspect – called the hypermutator phenotype – might be both a factor in the development and growth of the tumor and a sign of its vulnerability.

BRCA2 is normally involved in the repair of double-strand DNA breaks. Cells with BRCA2 mutants are less capable of repair, allowing other genetic mutations to survive and grow, the type of genomic instability that cancer thrives upon.

However, cancer cells in turn rely on DNA repair to defend themselves against DNA-damaging drugs, such as platinum-based agents. So adding drugs that inhibit DNA repair could increase the effectiveness of chemotherapy, Zhang noted. PARP-inhibitors, a new class of drug in clinical trials, block DNA repair and may also be effective in treating BRCA2 mutated ovarian cancer.

Additional studies of the function of BRCA1 and BRCA2 mutations are needed to more fully understand and exploit their findings to treat cancer, Zhang and colleagues note.

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The Cancer Genome Atlas is a joint project of the National Cancer Institute and the National Human Genome Research Institute, both of the National Institutes of Health, to comprehensively characterize changes in genetic mutation and regulation of various cancers.

Co-authors with Zhang and Yang are Sofia Kahn, Ph.D., and Yan Sun, M.D., Ph.D., of MD Anderson’s Department of Pathology; Kenneth Hess, Ph.D., of MD Anderson’s Department of Biostatistics, Anil Sood, M.D., of MD Anderson Departments of Cancer Biology and Gynecologic Oncology and Reproductive Medicine and the Center for RNAi and Non-Coding RNA; and Ilya Shmulevich, Ph.D., Institute for Systems Biology in Seattle.

This research was funded by the National Cancer Institute; the Blanton-Davis Ovarian Cancer Research Program, MD Anderson’s NCI Specialized Program in Research Excellence in Ovarian Cancer; MD Anderson’s Odyssey Fellows Program; and an ASLA-Fulbright Research Grant.

About MD Anderson

Study: Gene therapy causes breast cancer stem cells to self-destruct

Targeted agent avoids healthy cells, blocks proteins that prevent cell death in tumors

HOUSTON — Gene therapy delivered directly to a particularly stubborn type of breast cancer cell causes the cells to self-destruct, lowers chance of recurrence and helps increase the effectiveness of some types of chemotherapy, researchers at The University of Texas MD Anderson Cancer Center reported in the Sept. 13 edition of Cancer Cell.

In cellular and mouse studies, scientists found the gene mutation BikDD significantly reduced treatment-resistant breast-cancer initiating cells (BCICs), also known as breast cancer stem cells, by blocking the activity of three proteins in the Bcl-2 family. This genetic approach increased the benefits of lapatinib, one of the most common chemotherapy drugs for breast cancer.

“There are no effective methods to target BCICs, and they’re urgently needed, especially for relapsed breast cancer patients,” said senior author Mien-Chie Hung, Ph.D., vice president for basic research, professor and chair of MD Anderson’s Department of Molecular and Cellular Oncology. “This research suggests a potential therapeutic approach to breast cancer stem cells that will minimize recurrence and drug resistance.”

Special delivery system targets cells

Gene therapy was deposited directly into breast cancer cells with an innovative delivery system called VISA, short for versatile expression vector, which was developed at MD Anderson. It includes a targeting agent, also called a promoter, two components that boost gene expression in the target tissue and a payload — a Bik mutant gene called BikDD known to kill cancer cells. It’s all packaged in a fatty ball called a liposome and delivered intravenously.

This system has been successfully applied in pancreatic, lung, liver and ovarian cancer preclinical models. MD Anderson clinical researchers are preparing a phase I clinical trial for pancreatic cancer.

Stem cells frequently stymie treatment

Breast cancer stem cells, often resistant to chemotherapy and radiotherapy, are a major obstacle for breast cancer treatment, Hung said. If any of these cells remain after treatment, a new tumor often forms. Although lapatinib, known commercially as Tykerb®, can stabilize the level of these cells, no drugs are available to reduce them.

The Bcl-2 family of proteins – especially the subtypes Bcl-2, Bcl-xL and Mcl-1 — is essential for breast cancer tumor growth and treatment resistance. If too many of these three proteins are present, they can cause poor prognosis and resistance to chemotherapy drugs including lapatinib, as well as paclitaxel, doxorubicin and cisplatin.

This study shows that Bcl-2 proteins help breast cancer stem cells survive, causing resistance to treatment and likelihood of recurrence. However, using VISA to deliver BikDD can block the three key Bcl-2 proteins, eliminating the stem cells.

VISA-claudin4-BikDD cuts tumor burden

The researchers engineered a VISA that contained claudin4, a protein over-expressed in breast cancer, as a targeting agent to preferentially express BikDD in breast cancer cells. This process silenced the three Bcl-2 proteins and caused the cancer cells to self-destruct. Since the VISA focused the BikDD on cancer cells, normal cells were not affected.

Treating mice with the VISA-claudin4-BikDD therapy reduced tumor volume by 75 percent compared to control mice.

They also compared VISA-claudin4-BikDD therapy to BikDD packaged with a non-specific strong promoter from cytomegalovirus. Both versions reduced tumor burden and extended survival of mice, but tumor volume in mice treated with VISA-claudin4-BikDD was half that of the CMV-BikDD-treated mice. In a safety study using an unusually high dose, 60 percent of mice treated with CMV-BikDD survived after three days; all mice treated with VISA-Claudin4-BikDD survived for the duration of the 14-day safety profile study.

In cell line experiments, the CMV-BikDD also invaded and destroyed normal cells, while the VISA-Claudin4-BikDD did not.

Agent energizes lapatinib, other drugs

BikDD made HER2-positive breast cancer cells more sensitive to lapatinib when all three Bcl-2 proteins were inhibited but not when they were inhibited separately. HER2-positive breast cancer is a particularly aggressive type that makes too much human epidermal growth factor 2; it accounts for about 20 percent of breast cancers. BikDD also sensitized EGFR+ (epidermal growth factor positive) breast cancer cells to lapatinib and several other breast cancer cells lines to paclitaxel.

Moving discovery forward

Hung said this approach is promising for breast cancer treatment, especially recurrent disease.

“VISA-claudin4-BikDD gene therapy may provide an effective strategy to inhibit breast tumor growth,” he said. “It demonstrates virtually no toxicity in normal cells and produces a profound killing effect in multiple breast cancer cell lines and synergy with other agents.”

Hung said the next step is to move VISA-claudin4-BikDD into a Phase I clinical trial to test its effect on patients with breast cancer.

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This work was supported by grants from the National Cancer Institute, including MD Anderson’s Specialized Program in Research Excellence grant, the MD Anderson/China Medical University Hospital Sister Institution Fund, the Breast Cancer Research Foundation, National Breast Cancer Foundation, Inc., Patel Memorial Breast Cancer Research Fund, MD Anderson’s Center for Biological Pathways and NCI Cancer Center Support Grant, and the Taiwan Department of Health Cancer Center Research of Excellence Grant.

In addition to Hung, MD Anderson researchers include first author Jing-Yu Lang, Ph.D., first author, Jennifer Hsu, Ph.D., Chun-Ju Chang, Ph.D., Qingfei Wang, Ph.D., Xiaoming Xie, Ph.D., Yi Bao, Ph.D., Hirohito Yamaguchi, Ph.D. and Dihua Yu, M.D., Ph.D., Department of Molecular and Cellular Oncology; Funda Meric-Bernstam, M.D., Department of Surgical Oncology; Wendy Woodward, M.D., Ph.D., Department of Radiation Oncology; and Gabriel Hortobagyi, M.D., Department of Breast Medical Oncology.

Hung and Hsu hold joint appointments at China Medical University and Asia University, Taichung, Taiwan. Xie holds an appointment at Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China.