A Novel Targeted Multi-Mechanistic Oncolytic Poxvirus Targets Refractory Hepatocellular Carcinoma (HCC)

JX-594, a novel, first-in-class, targeted oncolytic poxvirus designed to selectively replicate in and destroy cancer cells with cell cycle abnormalities and EGFR/ ras pathway activation, may be uniquely suited to treat cancers.

The EGF pathway is a validated pathway and targeted by marketed pharmaceuticals such as cetuximab (Erbitux®, ImClone Systems Incorporated, Branchburg, NJ 08876, Bristol-Myers Squibb Company, Princeton, NJ 08543 and Merck KGaA, Darmstadt, Germany), which is indicated for the treatment of patients with metastasized colorectal cancer whose tumor expresses a protein called an Epidermal Growth Factor Receptor (EGFR), and gefitinib (Iressa®, AstraZeneca Pharmaceuticals, London, United Kingdom), which is indecated for continued treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of both platinum based and docetaxel chemotherapies.

In many cancers EGFR is often inappropriately activated, leading to uncontrolled cell growth. JX-594 is designed to blocks tumor growth and induce tumor regression. The compound, which is currently in Phase II trials, treats patients with advanced, primary liver cancer refractory to standard therapies. In this trial, patients are randomized to receive treatment at one of two dose levels. The 30-patient, multi-national trial is being conducted at clinical sites in the United States, South Korea and Canada.

An engineered virus
Viruses have been engineered for cancer therapy in a variety of ways. Approaches include non-replicating gene therapy vectors, cancer vaccines and oncolytic viruses, but the clinical efficacy of these approaches has been limited by multiple factors. However, a new therapeutic class of oncolytic poxviruses, which includes JX-594, has recently been developed that combines targeted and armed approaches for treating cancer. Although holding much promise for clinical treatment of many cancers, oncolytic viruses general lack of systemic delivery, and insufficient tumor cell killing, so far, limited their usefulness.

In a phase I trial, researchers have now shown that products from this therapeutic class can systemically target cancers in a highly selective and potent fashion using a multi-pronged mechanism of action. Furthermore, efficacy and safety of JX-594 was shown in patients with diverse cancer types in three Phase I trials.

Commenting on the potential of the trial, David H. Kirn, M.D., President and Chief Executive Officer of Jennerex Biotherapeutics (One Market Street, Spear Tower, Suite 2260, San Francisco, CA 94105), a clinical-stage biopharmaceutical company focused on the development and commercialization of first-in-class, breakthrough targeted oncolytic products for cancer and currently involved in the development of JX-594, said: 'We're very excited to have this trial open and enrolling with our lead product, JX-594, which has the potential to revolutionize the treatment of the more than 10,000 patients each year who develop liver cancer in the U.S. alone. The numbers of patients with liver cancer in the EU, Japan and Asia are even higher. These desperate patients represent a huge unmet medical need since few effective therapies are available for them.'

'We have already treated four patients with JX-594 in Korea and are anxious to see the efficacy of JX-594 in these late stage liver cancer patients,' said B.G. Rhee, Ph.D., Executive Vice President of Korea Green Cross Corporation (227, Kugal-ri, Kihung-up, Yong-in, Kyonggi-do 449-900, South Korea), a biotechnology company developing several vaccines and therapeutic proteins, who is developing the new compound in collaboration with Jennerex.

RECIST-criteria
The primary objective for the phase II trial is to study the efficacy of treatment with JX-594 at two different dose levels in preventing tumor progression, as measured by modified RECIST criteria, at eight weeks from initiation of treatment in patients with unresectable primary hepatocellular carcinoma. In addition, safety and tolerability, as well as tumor response and progression-free survival, of JX-594 administered at the two dose levels will be evaluated. Up to 30 total patients will be treated.

A new therapeutic approach
The new compound uses a vaccinia viruses that has been engineered to target, attack and eradicate cancer. Unlike 'vectors' or 'vaccines', JX-594 replicates in cancer cells, leading to cancer cell destruction. As a result of this uniek mechanism of action, JX-594 is able to infect and eradicate other tumor cells both locally and in distant sites in the body. The cycle of JX-594 replication, cancer cell destruction, release and spread is then repeated. Normal, healthy, cells are not affected by JX-594 resulting in safety and tolerability.

Poxvirus offers an uniek Mechanism of Action
The comound is activated by genetic pathways that are critical to the vast majority of human cancers, including common solid tumors such as lung, colon, prostate, breast, pancreas and melanoma. They employ a novel primary mechanism-of-action that is effective even against cancers that are resistant to standard therapies such as chemotherapy, small molecule tyrosine kinase inhibitors, antibodies and radiotherapy. Simultaneously, a therapeutic cascade is initiated by product replication resulting in tumor vasculature shutdown and anti-tumoral immune attack.

The poxvirus strain backbone of JX-594 has been used safely in millions of people as part of a worldwide vaccination program. This strain naturally targets cancer cells due to common genetic defects in cancer cells. JX-594 was engineered to enhance this natural safety and cancer-selectivity by deleting its thymidine kinase (TK) gene, thus making it dependent on the cellular TK expressed at persistently high levels in cancer cells. To enhance product efficacy, JX-594 is also engineered to express the GM-CSF (hGM-CSF) protein. GM-CSF complements the cancer cell lysis work of the product candidate, leading to a cascade of events resulting in tumor necrosis, tumor vasculature shutdown and an anti-tumoral immune attack.

Based on the results so far, researcher believe that JX-594 holds promise as an i.v.-delivered, targeted virotherapeutic.

For additional information, please read:

• Kirn DH, Thorne SH. Targeted and armed oncolytic poxviruses: a novel multi-mechanistic therapeutic class for cancer. Nat Rev Cancer. 2009 Jan;9(1):64-71
• Liu TC, Hwang T, Park BH, Bell J, Kirn DH. The targeted oncolytic poxvirus JX-594 demonstrates antitumoral, antivascular, and anti-HBV activities in patients with hepatocellular carcinoma. Mol Ther. 2008 Sep;16(9):1637-42. Epub 2008 Jul 15
• Park BH, Hwang T, Liu TC, Sze DY, et al. Use of a targeted oncolytic poxvirus, JX-594, in patients with refractory primary or metastatic liver cancer: a phase I trial. Lancet Oncol. 2008 Jun;9(6):533-42. Epub 2008 May 19.
• Alemany R. A smart move against cancer for vaccinia virus. Lancet Oncol. 2008 Jun;9(6):507-8
• Kim JH, Oh JY, Park BH, Lee DE, et al. Systemic armed oncolytic and immunologic therapy for cancer with JX-594, a targeted poxvirus expressing GM-CSF. Mol Ther. 2006 Sep;14(3):361-70
• Kirn DH, Wang Y, LeBoeuf F, Bell J, Thorne SH. Targeting of interferon-beta to produce a specific, multi-mechanistic oncolytic vaccinia virus. PLoS Med. 2007 Dec;4(12):e353
• Guo ZS, Bartlett DL. Vaccinia as a vector for gene delivery. Expert Opin Biol Ther. 2004 Jun;4(6):901-17
• McCart JA, Ward JM, Lee J, Hu Y. Systemic cancer therapy with a tumor-selective vaccinia virus mutant lacking thymidine kinase and vaccinia growth factor genes. Cancer Res. 2001 Dec 15;61(24):8751-7.

Also see:

• JX-594, Mode of Action (how does it work)

Waste from Olive Grinding May Inhibit Colorectal Cancer

Researchers from the University of Granada and the University of Barcelona have shown that treatment with maslinic acid, a triterpenoid compound isolated from olive-skin pomace, results in a significant inhibition of cell proliferation and causes apoptotic death in colorectal cancer cells.

Triterpenoids, which also includes maslinic or crataegolic acid, are compounds present in a wide range of plants used in traditional medicine and known to have anti-carcinogenic properties. Low concentrations of maslinic acid, a pentacyclic terpene, can be found in plants with medicinal properties. However, the compound is present in high concentrations in the leaf and the olive skin wax extracted from alpeorujo, the crushed olive waste from olive grinding, or dry olive-pomace oil.

Based on the results of the study, the researchers feel that the compound has the capacity to inhibit or prevent cancer as well as regulating apoptosis or programmed death in human HT29 colon adenocarcinoma cell lines via the intrinsic mitochondrial pathway. Scientifics now suggest that this mechanism of action could be a useful new therapeutic strategy for the treatment of colorectal cancer as it allows controlling the hyperplasia and hypertrophy processes.

A novel compound
This study is the first to investigate the precise molecular mechanisms of the anti-carcinogenic and pro-apoptotic effects of maslinic acid against colorectal cancer. Chemopreventive agents of a natural origin, often a part of our daily diet, may provide a cheap, effective way of controlling such diseases such as colorectal cancer. A wide range of European studies in recent years has shown that triterpenoids hinder carcinogenesis by intervening in pathways such as carcinogen activation, DNA repair, cell cycle arrest, cell differentiation and the induction of apoptosis in cancer cells.

Therapeutic use in HIV
In a number of previous but unrelated studies, researchers from the university of Granada have also shown that maslinic or crataegolic acid inhibits serine proteases or serine endopeptidases,
an enzyme used by HIV to release itself from the infected cell into the extracellular environment and, consequently, to spread the infection into the whole body. They determined that the use of maslinic acid can effective reduce, up to 80%, AIDS spreading in the body. Furthermore, maslinic acid is very active against opportunistic parasitic infections, including protozoa Cryptosporidium, a parasite commonly found in HIV-patients presenting with intestine infection and diarrhea.

The therapeutic effects of maslinic acid in the fight against AIDS are now simultaneously being studied by the researchers in Granada and by Professor Dr. Vallejo Nájera and his team at the Hospital Carlos III in Madrid, Spain.

Anti-inflammatory properties
While maslinic acid is only one of the compounds found in the leaf and the olive skin wax, researches have long observed the potential health and medical benefits of olive oil. Researchers from the Lipids and Atherosclerosis Unit at the Hospital Universitario Reina Sofía de Córdoba in Spain, carried out a study in order to determine the influence of the micronutrients of certain fats on cardiovascular diseases, diabetes or cancer. They also tried to discern if the consumption of these micronutrients could possibly modify the inflammatory process in healthy people.

Doctor Pablo Pérez Martínez, one of the researchers, studying these effects, said that ‘the main property of olive oil is its richness of antioxidants, which makes it a unique fat. Therefore, we must clarify which is the added value of its components, including maslinic acid, as that is the only way to establish that a healthy diet must contain olive oil as its main fat.’ Martínez believes that because ‘olive oil is… the main source of fats… in the Mediterranean diet, it provides [this diet] with high-nutritional-value micro-components.’ According to the researcher, such a diet reduces LDL-C, brings arterial pressure down, improves diabetes control and lessen effects from thrombosis.

For more information, read:

• Reyes-Zurita FJ, Rufino-Palomares EE, Lupiáñez JA, Cascante M. Maslinic acid, a natural triterpene from Olea europaea L., induces apoptosis in HT29 human colon-cancer cells via the mitochondrial apoptotic pathway. Cancer Lett. 2009 Jan 8;273(1):44-54. Epub 2008 Sep 14.

Also read PubMed abstracts:

• Parra A, Rivas F, Lopez PE, et al. Solution- and solid-phase synthesis and anti-HIV activity of maslinic acid derivatives containing amino acids and peptides. Bioorg Med Chem. 2008 Dec 25. [Epub ahead of print].
• Juan ME, Planas JM, Ruiz-Gutierrez V, et al. Antiproliferative and apoptosis-inducing effects of maslinic and oleanolic acids, two pentacyclic triterpenes from olives, on HT-29 colon cancer cells. Br J Nutr. 2008 Jul;100(1):36-43. Epub 2008 Feb 26.
• Juan ME, Wenzel U, Ruiz-Gutierrez V, Daniel H, Planas JM. Olive fruit extracts inhibit proliferation and induce apoptosis in HT-29 human colon cancer cells. J Nutr. 2006 Oct;136(10):2553-7. Contact the authors.
• Juan ME, Wenzel U, Daniel H, Planas JM. Erythrodiol, a natural triterpenoid from olives, has antiproliferative and apoptotic activity in HT-29 human adenocarcinoma cells. Mol Nutr Food Res. 2008 May;52(5):595-9. Contact the authors.
• Reyes FJ, Centelles JJ, Lupiáñez JA, Cascante M. (2Alpha,3beta)-2,3-dihydroxyolean-12-en-28-oic acid, a new natural triterpene from Olea europea, induces caspase dependent apoptosis selectively in colon adenocarcinoma cells. FEBS Lett. 2006 Nov 27;580(27):6302-10. Epub 2006 Oct 27.
• Gamet-Payrastre L, Li P, Lumeau S, Cassar G, et al. Sulforaphane, a Naturally Occurring Isothiocyanate, Induces Cell Cycle Arrest and Apoptosis in HT29 Human Colon Cancer. Cells. Cancer Res. 2000 Mar 1;60(5):1426-33.

Trastuzumab Given Prior to Surgery Improves the Chance of Survival in HER2-positive Breast Cancer

Primary efficacy analysis of the NeOAdjuvant Herceptin trial (NOAH) presented at the 31st Annual CRTC-AACR San Antonio Breast Cancer Symposium (SABCS, December 10 - 14, 2008) by Professor Luca Gianni, MD, from the Istituto Nazionale Tumori in Milan, a leading investigator of the NOAH trial, demonstrated that standard one year treatment with trastuzumab (Herceptin®, Genentech, 1 DNA Way South San Francisco, CA 94080-4990/F. Hoffmann-La Roche, Grenzacherstrasse 124, CH-4070 Basel, Switzerland) provides long-term benefit to patients with high risk of recurrence of their breast cancer.

Incidence, Mortality and Prevalence
Breast cancer is, according to the World Health Organization (WHO), the most common cancer among women. Based one the GLOBOCAN 2002 data, each year more than one million new cases of breast cancer are diagnosed worldwide, and nearly 400,000 people will die of the disease annually.

Poor response
In HER2-positive breast cancer, increased quantities of the HER2 protein are present on the surface of the tumour cells. This is known as ‘HER2-positivity’ breast cancer. High levels of HER2 are present in a particularly aggressive form of the disease which responds poorly to chemotherapy. Research shows that HER2-positivity affects approximately 20 percent of women with breast cancer.

Mode of Action
Trastuzumab is a humanised antibody, designed to target and block the function of HER2, a protein produced by a specific gene with cancer-causing potential. The mode of action of trastuzumab is unique in that it activates the body’s immune system and suppresses HER2 to target and destroy the tumour. Trastuzumab has demonstrated unprecedented efficacy in treating both early and advanced (metastatic) HER2-positive breast cancer. Given on its own as monotherapy as well as in combination with or following standard chemotherapy, trastuzumab has been shown to improve response rates, disease-free survival and overall survival while maintaining quality of life in women with HER2-positive breast cancer.

Locally advanced breast cancer or LABC, including inflammatory breast cancer, is more common in Europe than in the US and accounting for about 10% of all new cases. The median survival time remains low, ranging from 3 years (for inflammatory breast cancer) to 6 years. Thus, new treatment approaches are critically important.

The largest neoadjuvant trial
The NeOAdjuvant Herceptin trial (NOAH) is the largest multicentre, randomised, open-label, Phase III trial, evaluating the benefits of giving neoadjuvant trastuzumab in combination with anthracycline- and taxane-based chemotherapy versus chemotherapy alone to women with locally advanced HER2-positive breast cancer.

A total of 228 patients with centrally confirmed locally advanced HER2-positive breast cancer, a particularly aggressive form of the disease, participated in this neoadjuvant study. 115 patients received standard chemotherapy plus trastuzumab (for one year) and 113 patients received chemotherapy alone before surgery. The primary end point was event-free survival (EFS), defined as the time between randomisation and disease recurrence or progression, or death from any cause. Secondary end points were pathological complete response (pCR), overall response rate (ORR), overall survival (OS) and safety.

Improving event free survival
The results of this study show that trastuzumab plus chemotherapy improved event free survival at 3 years to 70% vs 53% with chemotherapy alone - the addition of trastuzumab to chemotherapy reduced the relative risk of recurrence by about half (HR 0.56, p=0.006). In addition, trastuzumab plus chemotherapy was shown to completely eradicate the tumor (a pathological complete response to treatment) in nearly twice as many patients, 39%, compared with only 20% of patients treated with chemotherapy alone (p=0.002). The overall response rate was also significantly increased (89% vs 77%, p=0.02).

Treatment options
Standard treatment for locally advanced breast cancer currently includes neoadjuvant chemotherapy. In this study, outcomes were assessed in HER2-positive patients with locally advanced breast cancer treated with chemotherapy (3 cycles of doxorubicin and paclitaxel, 4 cycles of paclitaxel, 3 cycles of CMF; n=113) or with chemotherapy + trastuzumab (n=115). A control group of HER2-negative patients with LABC received chemotherapy only (n=99). The primary endpoint was event-free survival (EFS), with a median follow-up time of 3 years. For HER2-positive patients who received chemotherapy and trastuzumab, EFS was significantly improved compared with HER2-positive patients who only received chemotherapy (70.1% vs 53.3%, respectively; HR=0.56, P=.006). Overall survival, a secondary endpoint, was also improved in patients receiving trastuzumab, but the difference was not significant (85.3% vs 80.4%, respectively; HR=0.65, P=.18). EFS was similar in the HER2-positive arm treated with chemotherapy alone and the HER2-negative control arm over the first 18 months, but showed a divergence in favor of HER2-negative patients over a longer period of time. Adverse events from the 2 therapy regimens were within acceptable limits. Cardiac toxicity, as reflected by changes in left ventricular ejection fraction (LVEF), was minimal in the majority of patients (>95% of patients with CTC grade 0 or 1), with 2 cardiac events reported in the group receiving trastuzumab.

About 70% of women with locally advanced HER2-positive breast cancer were free of their disease three years after initiation of therapy when treated with trastuzumab plus chemotherapy before surgery, compared to only around 50% of patients receiving pre-operative chemotherapy alone.

The results from the final analysis of the NOAH (NeOAdjuvant Herceptin) phase III study offer welcome news as patients with this early, but locally advanced breast cancer whose disease has spread to tissues around the breast such as the skin, muscle or lymph nodes generally face a high chance of recurrence and short life-expectancy.

‘The positive results of the NOAH study show that starting trastuzumab treatment prior to surgery offers long-term benefits to women with HER2-positive breast cancer,’ said William M. Burns, CEO Division Roche Pharmaceuticals. ‘Herceptin continues to provide women with early breast cancer a much improved prognosis, even if their cancer has advanced locally.’

Commenting on the results, Professor Gianni explained: ‘Women with locally advanced HER2-positive breast cancer are difficult to treat,’ ‘The results of the NOAH study imply that starting chemotherapy with one year of Herceptin should become the standard of care for women with locally advanced HER2-positive breast cancer’.

The aim of pre-surgery (neoadjuvant) therapy given to women with breast cancer is to improve the local control of the tumour to facilitate surgery. At the same time, the objective is to determine the sensitivity of the tumour towards a specific treatment. The results of this study demonstrate that starting trastuzumab treatment prior to surgery helps shrink locally advanced breast cancer and improve long term outcomes.

For more information, read:

• Gianni L, Eiermann W, Semiglazov V, et al. Neoadjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer: primary efficacy analysis of the NOAH trial. (General Session 3) Abstract 31 San Antonio Breast Cancer Symposium

Also read:

• Full Herceptin prescribing information (USA).
• Summary of Product Characteristics (European SPC / EMEA / English Version).
• Description of trastuzumab's mechanism of action.
• The international comprehensive Herceptin resource for healthcare professionals outside the United States of America.
• Roche - Product Information: Herceptin
• Comprehensive Herceptin resourse for the United States of America
• Structural Bioinformatics / Protein NMR Structure Gallery
• Ferlay J., Bray F., Pisani P. and Parkin D.M. GLOBOCAN 2002. Cancer Incidence, Mortality and Prevalence Worldwide. IARC CancerBase No.5, Version 2.0. IARCPress, Lyon, 2004.

Also read PubMed abstract:

• Glück S, McKenna EF Jr, Royce M. XeNA: capecitabine plus docetaxel, with or without trastuzumab, as preoperative therapy for early breast cancer. Int J Med Sci. 2008;5(6):341-6. Epub 2008 Nov 4
• Sánchez-Muñoz A, García-Tapiador AM, Martínez-Ortega E. et al. Tumour molecular subtyping according to hormone receptors and HER2 status defines different pathological complete response to neoadjuvant chemotherapy in patients with locally advanced breast cancer. Clin Transl Oncol. 2008 Oct;10(10):646-53. Contact the authors.
• Madarnas Y, Trudeau M, Franek JA. et al. Adjuvant/neoadjuvant trastuzumab therapy in women with HER-2/neu-overexpressing breast cancer: a systematic review. Cancer Treat Rev. 2008 Oct;34(6):539-57. Epub 2008 May 27. Contact the authors.
• Kulkarni S, Hicks DG. HER2-positive early breast cancer and trastuzumab: a surgeon's perspective. Ann Surg Oncol. 2008 Jun;15(6):1677-88. Epub 2008 Apr 9. Contact the authors.
• Lazaridis G, Pentheroudakis G, Pavlidis N. Integrating trastuzumab in the neoadjuvant treatment of primary breast cancer: accumulating evidence of efficacy, synergy and safety. Crit Rev Oncol Hematol. 2008 Apr;66(1):31-41. Ep.ub 2007 Sep 4. Review

Reduction in Breast Density Predicts Potential Benefit of Tamoxifen

A reduction in breast density appears to be one of the strongest indicators of a woman’s response to tamoxifen (Nolvadex®, Istubal®, Valodex®, AstraZeneca, 15 Stanhope Gate , W1K 1LN, United Kingdom), an orally active selective estrogen receptor modulator (SERM) that is used treat and to decrease breast cancer risk. This is one of the conclusions of a study by a team of British researchers led by Jack Cuzick, Ph.D., the study’s lead investigator and head of the Cancer Research UK Centre for Epidemiology, Mathematics and Statistics in London, United Kingdom, presented at the 31 Annual CTRC-AACR San Antonio Breast Cancer Symposium (SABCS) in San Antonio, Texas (December 10 – 14, 2008).

The result of this study may lead to a re-evaluation of the importance of breast density, which is far the most undervalued and underutilized risk factor for breast cancer. Commenting on the study, Cuzick said that ‘Apart from age and BRCA1 and BRCA2 mutations, increased breast density is the leading risk factor for breast cancer.’

Density is a factor
Because of the differences in tissue composition and differences in the radiographic attenuation properties of fat, stroma, and epithelium, mammographic appearance of the breast varies among women.

In a study published in the January 2004 edition of Radiology, the journal of the Radiological society of North America, Dr Jennifer A. Harvey, MD and Dr Viktor E. Bovbjerg, PhD of the Departments of Radiology and Health Evaluation Sciences, of the University of Virginia in Charlottesville say that a plausible explanation of the association of breast density with increased breast cancer risk is the development of premalignant lesions such as atypical ductal hyperplasia, levated growth factors, or increased estrogen production within the breast due to overactive aromatase. The amount of breast density may also be due in part to genetic heredity.

Harvey and Bovbjerg noted that, unlike other risk factors, breast density may be influenced. 'Because breast density is very hormonally responsive, it may be influenced by lifestyle factors such as alcohol intake and diet,' Harvey explained. 'Breast density may reflect increased risk due to other causes or it may be an independent risk factor,' she continued. While weight, body mass index, age, menopausal status, age at first birth, nulliparity, family history, hormone use, and previous breast biopsy may all influence breast density, it is consistently identified as an independent risk factor after adjustment for other variables associated with both density and breast cancer risk

A number of studies in varied settings and populations have shown that women with dense tissue in 75% or more of the breast have a risk of breast cancer four to six times as great as the risk among women with little or no dense tissue. Based on this and other observations, Dr Karla Kerlikowske, MD, of the University of California in San Francisco, suggested, in an editorial in the January 2007 edition of the New England Journal of Medicine, that breast density should be measured in clinical practice and used to maximize primary and secondary prevention of cancer.

A Biomarker
However, for mammographic density to be considered as a biomarker, it is necessary to demonstrate that the risk reduction induced by a preventive intervention can be predicted by change in density, and that patients experiencing the largest change are most likely to benefit from treatment. Cuzick said that if their findings are validated in follow-up studies, women at risk for developing breast cancer should have a baseline mammogram before starting use of tamoxifen, and then a follow-up scan a year or two later to monitor breast density.

‘If there is a reduction, the agent is having an effect; if density is the same, it may not be a beneficial drug for the individual woman,' Cuzick noted. ‘It is important to find a way to predict who will respond to tamoxifen, and changes in breast density may constitute an early indicator of benefit,' he continued. ‘This is important to know because other preventive options now exist or are being tested.’

IBIS-1 and tamoxifen
Cuzick also led the International Breast Intervention Study I (IBIS-I), an international trial in which postmenopausal women at high risk of breast cancer were given tamoxifen to see how effective this drug is in preventing them from developing the disease. This trial involved more than 7,000 participants.

‘In the IBIS-1 study, tamoxifen reduced the risk of breast cancer by about 40%,’ Cuzick explained. In this study, we focus on whether the change in breast density after 12-18 months of prophylactic treatment predicts the subsequent impact of tamoxifen on the development of breast cancer.

Results of this study found the agent reduces the risk of estrogen-positive (ER) breast cancer by 30 to 40% among women at high risk. During that study, researchers collected baseline mammograms, as well as mammograms at 18, 36, and 54 months to check for breast cancer development. Based on analysis of these mammograms, Cuzick and his colleagues later found a strong correlation between reduction of breast density in women who use tamoxifen and lowered breast cancer risk. But for the rest of the women - where tamoxifen did not reduce breast density – risk of the disease was not significantly reduced.

In this follow-up study, the investigators examined a subpopulation of the IBIS-I participants (120 women who developed breast cancer and 943 who didn’t), to see if their mammograms changed over time and if tamoxifen treatment reduced breast density. They also looked at changes in other variables, such as hormone status, body weight and familial factors. They found that only change in mammographic density predicted reduction of risk for ER-positive breast cancer.

Confirmation required
For the 46 percent of women in the tamoxifen-treatment group whose breast density was reduced by 10 percent or more, the risk of breast cancer was reduced by 52 percent relative to the control group (women who did not develop breast cancer). Conversely, the 54 percent of women whose density was not reduced by 10 percent only had a non-significant, 8 percent reduction in breast cancer risk. The findings suggest that the impact of tamoxifen on risk reduction is predictable by changes it induces on breast density after 12 to 18 months of treatment, Cuzick said.

Although these findings need confirmation in an independent study, based on this data, Cuzick and his team concluded that changes in breast density may constitute an early indicator of treatment efficacy, which would be useful for the evaluation of new chemoprevention therapies. They also believe that by measuring density changes between baseline and initial follow up mammograms in high-risk patients receiving tamoxifen, it may be possible to determine which women are actually benefiting from the intervention (and should therefore continue treatment), and those who might benefit more from alternative risk reducing strategies.

A step towards personalized medicine
Researchers at the Cancer Research UK Cambridge Research Institute recently discovered the mechanism by which tamoxifen operates in breast cancer patients and how some women build up resistance to the drug.

Dr Lesley Walker, PhD., Cancer Research UK's director of cancer information, said: ‘Tamoxifen has been a huge success story helping to prevent breast cancer recurring for many women. Understanding why it occasionally stops working is really important because it allows us to identify new targets for drug development and who will need such treatments.’

Commenting on the importance of this study, she added: ‘We are moving into an era of personalised medicine and now, Professor's Cuzick's work has increased our knowledge of which high risk women will benefit from tamoxifen as a preventative drug, and which women won't benefit. This is a key advance as we try to ensure women get the most suitable treatment.’

For more information, read:

• Cuzick J, Warwick J, Pinney L, Warren R, et al. Change in breast density as a biomarker of breast cancer risk reduction; results from IBIS-1. (General Session 6) Abstract 61 San Antonio Breast Cancer Symposium. Contact the author.

For additional information:

• Understanding Cancer Series: Estrogen Receptors/SERMs (National Cancer Institute)
• Nolvadex® full prescribing information

Also read PubMed abstracts:

• Cuzick J, Forbes JF, Sestak I, Cawthorn S, et al. Long-term results of tamoxifen prophylaxis for breast cancer--96-month follow-up of the randomized IBIS-I trial. J Natl Cancer Inst. 2007 Feb 21;99(4):272-82.
• Poweles TJ, Ashley S, Tidy A, et al. Twenty-year follow-up of the Royal Marsden randomized, double-blinded tamoxifen breast cancer prevention trial. J Natl Cancer Inst. 2007 Feb 21;99(4):283-90 Contact the author.
• Boyd NF, Guo H, Martin LJ, Sun L, et al. Mammographic density and the risk and detection of breast cancer. N Engl J Med. 2007 Jan 18;356(3):227-36. Contact the author. Full text article (PDF).
• Kerlikowske K. The mammogram that cried Wolfe. N Engl J Med. 2007 Jan 18;356(3):297-300.
• Vachon CM, van Gils CH, Sellers TA, Ghosh K et al. Mammographic density, breast cancer risk and risk prediction Breast Cancer. Res. 2007;9(6):217. Contact the author.
• McCormack VA, dos Santos Silva I. Breast density and parenchymal patterns as markers of breast cancer risk: a metaanalysis. Cancer Epidemiol Biomarkers Prev 2006;15:1159-69 Contact the author.
• Boyd NF, Rommens JM, Vogt K, et al. Mammographic breast density as an intermediate phenotype for breast cancer. Lancet Oncol 2005;6:798-808.
• Harvey JA, Bovbjerg VE. Quantitative assessment of mammographic breast density: relationship with breast cancer risk. Radiology 2004;230:29-41 Contact the author. Full text article.
• Ursin G, Ma H, Wu AH, et al. Mammographic density and breast cancer in three ethnic groups. Cancer Epidemiol Biomarkers. Prev 2003;12:332-8.
• Byrne C, Schairer C, Brinton LA, et al. Effects of mammographic density and benign breast disease on breast cancer risk (United States). Cancer Causes Control 2001;12:103-10.
• Duncan JA, Reeves JR, Cooke TG. BRCA1 and BRCA2 proteins: roles in health and disease. Mol Pathol. 1998 Oct;51(5):237-47.
• Boyd NF, Byng JW, Jong RA, et al. Quantitative classification of mammographic densities and breast cancer risk: results from the Canadian National Breast Screening Study. J Natl Cancer Inst 1995; 87:670-5.
• Byrne C, Schairer C, Wolfe J, et al. Mammographic features and breast cancer risk: effects with time, age, and menopause status. J Natl Cancer Inst 1995;87:1622-9.
• Wolfe JN, Saftlas AF, Salane M. Mammographic parenchymal patterns and quantitative evaluation of mammographic densities: a case-control study. AJR Am J Roentgenol 1987;148:1087-92.

HER2-Positive, Small Tumors Linked with Poor Prognosis

Patients with breast cancer whose tumors were HER2-positive and one centimeter or smaller, also caled T1a,bN0M0 tumors, have a significant risk of relapse compared with other tumor types, according to a new study presented at the 31st Annual CRTC-AACR San Antonio Breast Cancer Symposium (SABCS, December 10 - 14, 2008).

HER2-positive breast cancer is a breast cancer that tests positive for a protein called human epidermal growth factor receptor-2 (HER2). HER2 promotes the growth of cancer cells and its presence generally correlates with a poorer prognosis at any state of cancer. While approximately 15 – 20% of every breast cancers is HER2-positive, overexpression of the protein also occurs in other cancers such as ovarian cancer and stomach cancer.

A targeted therapy
In the past few years many encouraging advancements have been made in understanding the molecular mechanisms underlying carcinogenesis and tumor progression. These improvements have led to the identification of promising new targets for cancer therapy. Patients with HER2-positive breast cancer can now be effectively treated with targeted drugs, a humanized monoclonal antibody (MAb) called trastuzumab (Herceptin®, Genentech, 1 DNA Way South San Francisco, CA 94080-4990/F. Hoffmann-La Roche, Grenzacherstrasse 124, CH-4070 Basel, Switzerland). Studies have shown that, in the treatment of early stage and metastatic breast cancer, this drug reduces the recurrence of HER2-positive breast cancers by anout 50%.

Mechanism of Action
Some breast cancer cells divide and grow when human epidermal growth factor or EGF, a protein that naturally occurs in the body, attaches itself to another protein known as HER2, which is found on the surface of some breast cancer cells. Trastuzumab interferes with this process by attaching itself to the HER2 protein.

This interfering antitumor activity induces HER2 receptor downmodulation and, as a result, inhibits critical signalling pathways (i.e. ras-Raf-MAPK and PI3K/Akt) and blocks cell cycle progression by inducing the formation of p27/Cdk2 complexes. Trastuzumab also inhibits HER2 cleavage, preceding antibody-induced receptor downmodulation, and this effect might contribute to its antitumor activity in some cancers. Additionally, trastuzumab inhibits, in vivo, angiogenesis and induces antibody-dependent cellular cytotoxicity.

Studies have shown that because trastuzumab works on both the extracellular and the intracellular domains of the HER2 receptor, it continuously suppresses HER2 activity that may lead to tumor proliferation, leads to cell stasis and death, may enhanced the effects of chemotherapy and provides constant inhibition of the HER2 receptor.

Immune system response
Because antibodies are part of the body's normal defense against bacteria, viruses and abnormal cells such as cancer cells, trastizumab not only blocks the epidermal growth factor from reaching cancer cells, but it also invokes the body’s own immune cells to help destroy them.

Current guidelines
Although the data presented during the SABCS may suggest that women with small, early-stage HER2-positive cancer could possibly benefit from aggressive treatment, current treatment guidelines recommend a different approach for HER2-positive tumors less than one-half centimeter in size. And, until now, there were no study available that investigated the effectiveness of trastuzumab in women with small, HER2-positive, tumors.

Commenting on this, Ana M. Gonzalez-Angulo, M.D., assistant professor in the Departments of Breast Medical Oncology and Systems Biology at the University of Texas M. D. Anderson Cancer Center (MDACC) said: ‘The current guidelines call for no further therapy if the tumors are less than five millimeters or consider therapy if the tumors are from six to 10 millimeters, but this data challenges that thinking and shows this group of women may benefit from additional therapy.’

Gonzalez-Angulo and Ronjay Rakkhit, chief fellow of Hematology-Oncology at M. D. Anderson, and colleagues retrospectively studied 965 patients from MDACC and validated their findings with 350 patients from two European institutions. Patients with a lack of receptor information, and/or who had received adjuvant chemotherapy or trastuzumab at any time were excluded.

‘This is the largest study of its kind in a patient population, and as our ability to detect tumors improves, this patient population will only continue to increase. Further, it answers a common question oncologist have in daily practice – which early stage patients may be in need of additional therapy,’ said Gonzalez-Angulo.

Patients were diagnosed between 1990 and 2003. The median age of these patients at diagnosis was 57 years. All tumors were one centimeter or smaller. Most of the tumors (68 percent) were hormone receptor-positive, while 10 percent were HER2-positive and 23 percent were triple receptor-negative.

Five-year, recurrence-free survival was 77.1 percent and 93.7 percent in patients with HER2-positive and HER2-negative tumors, respectively, and five-year distant recurrenc-free survival was 86.4 percent and 97.2 percent, in patients with HER2-positive and HER2-negative tumors, respectively. Patients with HER2-positive tumors had 2.68 times greater risk of recurrence and 5.3 times higher the risk of distant recurrence than those with HER2-negative tumors.

Patients with HER2-positive tumors had 5.09 times the risk of recurrence and 7.81 times the risk of distant recurrence compared to patients with hormone receptor-positive tumors. 'Data on 350 additional patients treated at two other institutions showed reproducibility,' said Gonzalez.

‘This paper shows that patients with HER2-positive tumors one centimeter or less have a significant risk of relapse and should be considered for clinical trials of systemic anti-HER2 adjuvant therapy, or if a clinical trial is not available, adjuvant therapy should be discussed with them’, Gonzalez-Angulo noted.

For more information, read:

• Rakkhit R, Broglio K, Peintinger F, Cardoso F, et al. Significant increased recurrence rates among breast cancer patients with HER2-positive, T1a,bN0M0 tumors. Poster Discussion Session: HER2 as a Biomarker.

Also read:

• Full Herceptin prescribing information (USA).
• Summary of Product Characteristics (European SPC / EMEA / English Version).
• Description of trastuzumab's mechanism of action.
• The international comprehensive Herceptin resource for healthcare professionals outside the United States of America.
• Roche - Product Information: Herceptin
• Comprehensive Herceptin resourse for the United States of America
• HER2-positive breast cancer: What is it?
• Roche introduces a new global packaging design for prescription medicine
• Structural Bioinformatics / Protein NMR Structure Gallery

Also read PubMed abstracts:

• Fischgräbe J, Wülfing P. Targeted therapies in breast cancer: established drugs and recent developments. Curr Clin Pharmacol. 2008 May;3(2):85-98. Review.
• Lee-Hoeflich ST, Crocker L, Yao E, Pham T. A central role for HER3 in HER2-amplified breast cancer: implications for targeted therapy. Cancer Res. 2008 Jul 15;68(14):5878-87
• Arnould L, Gelly M, Penault-Llorca F. Trastuzumab-based treatment of HER2-positive breast cancer: an antibody-dependent cellular cytotoxicity mechanism? Br J Cancer. 2006;94:259-267.
• Bianco AR. Targeting c-erb2 and other receptors of the c-erB family: rationale and clinical applications. J Chemother. 2004;16:52-54.
• Pegram MD, Konecny GE, O'Callaghan C, Beryt M, Pietras R, Slamon DJ. Rational combinations of trastuzumab with chemotherapeutic drugs used in the treatment of breast cancer. J Nat Cancer Inst. 2004;96:739-749.
• Albanell J, Codony J, Rovira A, Mellado B, Gascón P. Mechanism of action of anti-HER2 monoclonal antibodies: scientific update on trastuzumab and 2C4. Adv Exp Med Biol. 2003;532:253-68.
• Yakes FM, Chinratanalab W, Ritter CA, King W, Seelig S, Arteaga CL. Herceptin-induced inhibition of phosphatidyli-nositol-3 kinase and Akt is required for antibody-mediated effects on p27, cyclin D1, and antitumor action. Cancer Research. 2002;62:4132-4141. Full text article (PDF).
• Yarden Y. Biology of HER2 and its importance in breast cancer. Oncology. 2001;61:1-13. Click here to contact the author.
• Harari D, Yarden Y. Molecular mechanisms underlying ErbB2/HER2 action in breast cancer. Oncogene. 2000;19:6102-6114.
• Sliwkowski MX, Lofgren JA, Lewis GD, Hotaling TE, Fendly BM, Fox JA. Nonclinical studies addressing the mechanism of action of trastuzumab (Herceptin). Semin Oncol. 1999;26:60-70.
• Baselga J, Norton L, Albanell J, Kim Y-M, Mendelsohn J. Recombinant humanized anti-HER2 antibody (HerceptinTM) enhances the antitumor activity of paclitaxel and doxorubicin against HER2/neu overexpressing human breast cancer xenografts. Cancer Res. 1998;58:2825-2831. Click here to contact the author.
• Lewis GD, Figari I, Fendly B. Differential responses of human tumor cell lines to anti-p185HER2 monoclonal antibodies. Cancer Immunol Immunother. 1993;37:255-263.
• Carter P, Presta L, Gorman CM, et al. Humanization of an anti-p185HER2 antibody for human cancer therapy. Proc Natl Acad Sci. 1992;89:4285-4289. Full text article (PDF).
• Shalaby MR, Shepard HM, Presta L, Rodrigues ML, et al. Development of humanized bispecific antibodies reactive with cytotoxic lymphocytes and tumor cells overexpressing the HER2 protooncogene. J Exp Med. 1992 Jan 1;175(1):217-25.

Zoledronic Acid May Have Anti-Tumor Properties

Early evaluations of the bisphosphonate zoledronic acid (Zometa® , Novartis Oncology) suggest a possible direct anti-tumor effect when combined with neoadjuvant chemotherapy in breast cancer treatment, according to data presented to scientists and other medical professionals gathered at the Henry B. Gonzales Convention Center in San Antonio to hear and present the latest scientific findings in breast cancer research during the CTRC-AACR San Antonio Breast Cancer Symposium (December 10-14, 2008 ).

There is substantial in vitro evidence that zoledronic acid has direct antitumour effects and synergy with chemotherapy agents. Bisphosphonates may therefore be an adjuvant therapeutic strategy of potential importance.

‘Zoledronic acid is primarily targeted to bone and metastasis within the bone marrow microenvironment, but it may also be enhancing the response in the primary breast tumor,’ explained Robert Coleman, M.D., FRCP, professor of medical oncology at the University of Sheffield in the United Kingdom.

Coleman is the lead researcher on the AZURE (Adjuvant Zoledronic Acid to Reduce Recurrence) trial, a prospective, randomised, open label, parallel group trial designed to to evaluate the effect of zoledronic acid on breast cancer. ‘Although the larger AZURE trial is still being evaluated, if the findings in this smaller study are confirmed, the effect could be practice changing,' Coleman said.

The AZURE trial opened to recruitment in September 2003. Patients were recruited from 176 centres worldwide, completing accrual in January 2006, 8 months ahead of schedule, and enrolled 3,360 women with stage II/III breast cancer. The trial was set up to determine whether adjuvant treatment with 4 mg zoledronic acid in addition to adjuvant or neoadjuvant chemotherapy would improve the disease-free and bone metastasis-free survival of women with breast cancer at high risk of relapse.

Analysis of the characteristics of the study population shows that both groups are well
matched across all criteria. 51% of patients have T2 tumour at presentation, with 76.6% being ER positive. 60.6% and 33.2% had 1-3 and ≥4 axillary nodes involved respectively and 6.4% were treated in the neoadjuvant setting. Anthracyclines were administered to 92.6% and 22.7% received taxanes, in large part due to accrual into the TANGO trial concurrent with AZURE. Only 4.6% received endocrine therapy alone. Almost half of the patients (44.6%) were premenopausal at randomisation.

Coleman and colleagues performed a retrospective pathology analysis on 205 patients who received neoadjuvant chemotherapy to determine zoledronic acid’s impact on the primary tumor. Zoledronic acid appeared to reduce tumor size from 30 mm in the chemotherapy alone group to 20.5 mm in the combination group.

After adjusting for variables like estrogen receptor status and treatment duration, the difference remained at 42.4 mm in the chemotherapy group and 28.2 mm in the combination group. The pathological complete response rate was 5.8 percent in the chemotherapy arm and 10.9 percent in the zoledronic acid group.

The number of patients requiring mastectomy was 77.9 percent in the chemotherapy group and 65.3 percent in the combination group. ‘Zoledronic acid is currently approved for the treatment of bone metastasis and osteoporosis. If the AZURE trial remains positive, then we’ll file for an additional indication,’ Coleman said.

For more information, read:

• Winter MC, Thorpe HC, Burkinshaw R, Beevers SJ, Coleman RE. The addition of zoledronic acid to neoadjuvant chemotherapy may influence pathological response exploratory evidence for direct anti-tumor activity in breast cancer. Abstract 5101. Poster Session V: Treatment: Neoadjuvant Therapy. San Antonio Breast Cancer Symposium.

Also read:

• Click here for full prescribing information.
• The Institute of Cancer Research

Also read PubMed Abstracts:

• Lyseng-Williamson KA. Zoledronic Acid: a review of its use in breast cancer. Drugs. 2008;68(18):2661-82
• Brufsky A. Management of cancer-treatment-induced bone loss in postmenopausal women undergoing adjuvant breast cancer therapy: a Z-FAST update. Semin Oncol. 2006 Apr;33(2 Suppl 7):S13-7.

Triple-negative breast cancer: risk factors to potential targets

Breast cancer is not one single disease, but knows different subgroups originating in the breast. Triple-negative breast cancer, one of these subgroups, has recently been recognized as an important subgroup of breast cancer with a distinct outcome and therapeutic approach when compared with other subgroups of breast cancer. Triple-negative breast cancer comprises primarily, but not exclusively, of the basal-like subtype and refers to a specific subtype of breast cancer that does not express the genes for estrogen receptor (ER), progesterone receptor (PR) or Her2/neu.

Depending on its stage of diagnosis, triple-negative breast cancer can be extremely aggressive and is more likely to recur and metastasize than other subtypes of breast cancer. It typically is responsive to chemotherapy, although it can be more difficult to treat because it is unresponsive to the most effective receptor targeted treatments

Late last year, researchers from the Indiana University Department of Medicine, Melvin and Bren Simon Cancer Center, Indianapolis, led by Dr. Bryan Paul Schneider MD, reported details of a new studies and findings in the area of breast cancer risk factors. The results were published in the journal Clinical Cancer Research.

Commenting on the research results, Schneider explained: ‘We do not yet have an assay to identify basal-like breast cancer in clinical samples, so triple-negative breast cancer has become a commonly used proxy for this subtype. The molecular biology and pathophysiology of triple-negative breast cancer are not completely understood, but understanding is improving rapidly with the advent of sophisticated molecular biology platforms.’

The established risk factors of breast cancer as a whole may not apply to this unique subgroup of patients. Because triple-negative breast cancer is defined by the absence of a target, there are currently limitations to using a tailored therapeutic approach, leaving conventional cytotoxic therapies as the mainstay.

‘Active preclinical and clinical research programs focus on defining the clinical behavior, delineating the risk factors, and more completely understanding the molecular biology of triple-negative breast cancer to improve prevention, optimize conventional agents, and unveil novel therapeutic targets,' Schneider said.

For more information, read:

• Schneider BP, Winer EP, Foulkes WD, Garber J, et al. Triple-negative breast cancer: risk factors to potential targets. Clin Cancer Res. 2008 Dec 15;14(24):8010-8
• Click here to contact the author.

Also read PubMed abstracts:

• Liu ZB, Liu GY, Yang WT, Di GH, et al. Triple-negative breast cancer types exhibit a distinct poor clinical characteristic in lymph node-negative Chinese patients Oncol Rep. 2008 Oct;20(4):987-94.
• Reis-Filho JS, Tutt AN. Triple negative tumours: a critical review. Histopathology. 2008 Jan;52(1):108-18. Review.
• Sasa M, Bando Y, Takahashi M, Hirose T, Nagao T Screening for basal marker expression is necessary for decision of therapeutic strategy for triple-negative breast cancer. J Surg Oncol. 2008 Jan 1;97(1):30-4.
• Rakha EA, El-Sayed ME, Green AR, Lee AH, et al. Prognostic markers in triple-negative breast cancer. Cancer. 2007 Jan 1;109(1):25-32

See online video:

• CNN's Dr. Sanjay Gupta looks into tripple-negative breast cancer, an aggressive and drug-resistant form of cancer affecting black women.
• About tripple-negative breast cancer on Truveo.
  

Upcoming Phoenix conference highlights 'molecular oncology' for oncologists and their patients

Physician-scientists from the Arizona based Translational Genomics Research Institute (TGen), a non-profit organization dedicated to conducting groundbreaking medical research in with life changing results, and Scottsdale Healthcare, a primary clinical research site for TGen in the Virginia G. Piper Cancer Center in Scottsdale, AZ, will present their latest findings and techniques at a national conference designed to provide cancer doctors with new treatments for their patients.

'Molecular Oncology: The Sixth Vital Sign, What Every Oncologist Should Know' is intended to help oncologists provide better diagnosis, early detection as well as drugs and other treatments that in some cases can slow the growth or even shrink tumors.

'Given the explosion of new information on the genetic and cellular features of malignancy, the modern oncologist must master the significance and application of cancer-related sciences,' said Dr. Ramesh K. Ramanathan, Medical Director of TGen Clinical Research Services at Scottsdale Healthcare, a partnership between TGen and Scottsdale Healthcare Corp.

Personalized Medicine
Beyond the five vital signs of pulse, respiration, temperature, blood pressure and pain, is a new sixth 'vital sign' – molecular therapeutics. This new 'vital sign' offers oncologists the opportunity to identify the causes of disease at the molecular level in order to provide the right drugs in the right amounts at the right times for the specific needs of individual patients. This new approach is becoming better known in health circles as personalized medicine or theragnostics.

However, the the concept that information about a patient's genotype or gene expression profile can be used to tailor medical care to an individual's needs requires understanding of the link between the mechanisms of action of novel therapeutics and specific tumor geneticts, thereby unifying molecular diagnostics and therapeutics.

Given the explosion of new information on the genetic and cellular features of malignancy and the rapidly growing armamentarium of targeted therapeutics, oncologists today must master the understanding, appreciate the significance and value the application of cancer-related basic and clinical sciences. 'This gap in knowledge and its application in clinical practice will be addressed in this conference,' Ramanathan explained.

Dr. Ramanathan is the co-program director of the conference, along with Dr. Daniel Von Hoff, TGen's Physician-In-Chief and the Chief Scientific Officer at TCRS. Both doctors conduct groundbreaking personalized-medicine research and clinical drug trials at TCRS in Scottsdale, and both are on the clinical faculty of the University of Arizona College of Medicine. Both will present at the conference.

Other TGen and Scottsdale Healthcare scientists scheduled to present include: Dr. Jeffrey Trent, TGen's President and Scientific Director; Dr. Raoul Tibes, Director of the Hematological Malignancies Program at TCRS and an Associate Investigator at TGen; Dr. Stephen P. Anthony, Chief Medical Officer of TGen Drug Development Services (TD2) and a Senior Investigator at TGen; Dr. John Carpten, Director of TGen’s Integrated Cancer Genomics Division and a Senior Investigator at TGen; and Gayle Jameson, M.S.N., Director of Supportive Care at TCRS and an Associate Investigator at TGen.

Target audience
Besides oncologists, the target audience includes all physicians and health professionals involved in caring for cancer patients, and researchers interested in new cancer diagnostics and therapeutics.

Key objectives of the conference include:

• Explaining the molecular and cellular features of malignancy in diagnostic and therapeutic approaches to the treatment of cancer, and identifying new diagnostic tools.
• Assessing the effects and early clinical results of new, targeted drug therapies on solid tumors and malignant blood cancers.
• Identifying new drug therapies that optimize treatment results and minimize side effects in specific biologic and clinical scenarios.
• Evaluating clinical trials and translational methods of care and their proper use in clinical decision-making and patient management.

The conference is sponsored by TGen, Scottsdale Healthcare's Virginia G. Piper Cancer Center and Physicians' Education Resource (PER) of Dallas. The conference is certified for Continuing Medical Education.

For more information:

• 'The Sixth Vital Sign' runs Jan. 22-24, 2009 at the Arizona Grand Resort.
• Personalized Medicine Coalition

Also read PubMed abstracts:

• Acharya CR, Hsu DS, Anders CK, Anguiano A, et al. Gene expression signatures, clinicopathological features, and individualized therapy in breast cancer. JAMA 2008 Apr 2;299(13):1574-87. Click here for a full text version of this article.
• Pene F, Courtine E, Cariou A, Mira JP. Toward theragnostics. Crit Care Med. 2009 Jan;37(1 Suppl):S50-8.

A Tumor Suppressor Gene Inactivated in Myeloproliferative Neoplasms

Research by Dr. Francois Delhommeau MD, and his team at the Saint-Antoine Hospital, Paris, France (Hôpital Saint Antoine, Service d’hématologie, 184, rue du Faubourg Saint Antoine, 75012 Paris) on treatment advances in leukemia and lymphoma, presented as late-breaking news during the 50th Annual Meeting of the American Society of Hematology in San Francisco, CA,(December 6 – 9, 2008), led to the discovery of a new tumor suppressor gene called TET2 (Ten-Eleven Translocation–2).

Because TET2 is altered in 14 percent of patients with myeloproliferative disorders, the discovery provides scientists with a greater understanding of the underlying biology of these conditions, as well as a potential target for the development of future treatments.

All blood cells start out as hematopoietic, or blood-forming, stem cells and have the potential to become mature red blood cells, white blood cells, or platelets. Myeloproliferative disorders develop when the DNA of a stem cell is altered in the bone marrow, causing the overproduction of some blood cells.

Previous research has detected mutations in other genes– JAK2 and MPL – in the blood stem cells of patients with myeloproliferative disorders. These JAK2 and MPL defects cause the overproduction of mature malignant blood cells, but multiple lines of evidence suggest that these are not the only molecular lesions responsible for abnormalities in the stem cell in these disorders. Greater analysis of blood cell development in myeloproliferative disorders with the JAK2 V617F mutation led researchers to identify two subsets of patients. The first subset of patients (85 percent) had an overproduction of malignant cells mainly dependent on the late stages of blood cell differentiation, far downstream from the stem cell. In contrast, a second subset of patients (15 percent) had an early expansion of very immature malignant progenitor cells, close to the stem cell.

Researchers then hypothesized that the second subset of patients had a pre-existent molecular defect able to promote the early expansion of the malignant cells. With high-resolution arrays, researchers were able to identify one single gene, TET2, which belongs to a family of three genes of unknown function.

Researchers then further analyzed cells in five patients with TET2 mutations, which demonstrated that TET2 defects target hematopoietic stem cells. Moreover, they show that in these five patients TET2 inactivation precedes the JAK2 V617F mutation, suggesting that this new molecular lesion could be an early event in cancer stem cell formation.

To further test these findings, researchers sequenced TET2 in 181 unselected JAK2 V617F patients with myeloproliferative disorders. TET2 mutations were found in 25 of the 181 patients, resulting in an overall 14 percent frequency.

For more information, read:

• Delhommeau F, Dupont S, James C, Masse A, et al. TET2 Is a Novel Tumor Suppressor Gene Inactivated in Myeloproliferative Neoplasms: Identification of a Pre-JAK2 V617F Event. (Late-Breaking Abstracts) Blood (ASH Annual Meeting Abstracts) 2008 112: Abstract LBA-3

Also read PubMed abstracts:

• Delhommeau F, Pisani DF, James C., et al. Oncogenic mechanisms in myeloproliferative disorders. Cell Mol Life Sci. 2006 Dec;63(24):2939-53
• Delhommeau F, Dupont S, Tonetti C, Massé A. et al. Evidence that the JAK2 G1849T (V617F) mutation occurs in a lymphomyeloid progenitor in polycythemia vera and idiopathic myelofibrosis. Blood. 2007 Jan 1;109(1):71-7. Epub 2006 Sep 5.

New Data Shows Major Advances in Several Blood Disorders

Late breaking data presented at the 50th Annual Meeting of the American Society of Hematology in San Francisco, CA,(December 6 – 9, 2008) highlighted major research advances in the treatment of cancer and sickle cell disease.

One of the highlighted studies examined the ability of an investigational agent to improve endothelial dysfunction, a malfunction in the inner lining of blood vessels, in patients with sickle cell disease.

‘Abnormal function of the cells lining blood vessels may contribute to the complications of sickle cell disease. Disruption in the synthesis of nitric oxide, an important regulator of blood vessel relaxation, contributes to these abnormalities,' said Nancy Berliner, MD, 2009 ASH President and Chief of Hematology at Brigham and Women’s Hospital in Boston. ‘This study showcases a novel investigational treatment that aims at improving nitric oxide production and reducing endothelial dysfunction.’

Other late-breaking studies are showcasing the results of the first large-scale study examining mortality rates in patients with cancer taking erythropoiesis-stimulating agents (ESAs) for the treatment of anemia, and the discovery of a new tumor suppressor gene in patients with myeloproliferative disorders.

'There is now additional evidence concerning the use of ESAs in patients with cancer. Last year, ASH collaborated with the American Society of Clinical Oncology to release an evidence-based clinical practice guideline on the use of ESAs, and the findings of this study are consistent with the guideline’s recommendations,' said Samuel Silver, MD, Chair of the ASH Subcommittee on Reimbursement and Professor of Internal Medicine at the University of Michigan in Ann Arbor, MI. ‘However, we plan to reconvene the guideline panel to determine whether any updates should be made as a result of these new data.'

Also read blog entry:

• A Tumor Suppressor Gene Inactivated in Myeloproliferative Neoplasms
• A Novel Therapy for Endothelial Dysfunction in Sickle Cell Disease
• Understanding Recombinant Human Erythropoiesis Stimulating Agents in individual Cancer Patients

Immunochemotherapy with Fludarabine, Cyclophosphamide, and Rituximab Improves Response Rates and Progression-Free Survival of Previously Untreated Pat

Results from this multinational phase III clinical trial presented by during the 50th Annual Meeting of the American Society of Hematology (ASH) in San Francisco, CA (December 6 – 9) by Dr. Michael Hallek, MD from the University of Cologne, Cologne, Germany, and the German CLL Study Group, suggest that fludarabine, cyclophosphamide, and rituximab (FCR) chemoimmunotherapy may become the new standard first-line therapy for the treatment of advanced chronic lymphocytic leukemia.

In this study, a total of 817 patients with previously untreated chronic lymphocytic leukemia were randomized to receive six 28-day cycles of fludarabine (25 mg/m2 intravenously on days 1 to 3) and cyclophosphamide (FC) (250 mg/m2 intravenously on days 1 to 3) alone or FCR (375 mg/m2 intravenously at start of first cycle and 500 mg/m2 on day 1 for all subsequent cycles). The primary objective of the study was to determine response rates and progression-free survival.

After an average follow-up of 25.5 months, a total of 761 patients were evaluable for response and 787 were evaluable for progression-free survival and overall survival. The overall response rate was significantly higher in the FCR arm (95 percent) as compared with the FC arm (88 percent). The complete response rate was also significantly higher in the FCR arm (52 percent) as compared with the FC arm (27 percent).

At two years, the progression-free survival rate was 76.6 percent in the FCR arm as compared with 62.3 percent in the FC arm. While FCR was found to cause more neutropenia (33.6 percent versus 20.9 percent) and leukopenia (24 percent versus 12.1 percent), it did not increase the incidence of severe infections (18.8 percent versus 14.8 percent) as compared with FC. Taken together, treatment with fludarabine, cyclophosphamide, and rituximab chemoimmunotherapy improves response rate (RR) and progression free survival (PFS) and can be considered a safe first-line treatment for chronic lymphocytic leukaemia.

For more information, read:

• Hallek M, Fingerle-Rowson G, Fink AM, Busch R, et al. Immunochemotherapy with Fludarabine (F), Cyclophosphamide (C), and Rituximab (R) (FCR) Versus Fludarabine and Cyclophosphamide (FC) Improves Response Rates and Progression-Free Survival (PFS) of Previously Untreated Patients (pts) with Advanced Chronic Lymphocytic Leukemia (CLL). (Oral Session). Blood (ASH Annual Meeting Abstracts) 2008 112: Abstract #325

Also read PubMed Abstracts:

• Borthakur G, O’Brien S, Wierda WG, Thomas DA, et al. Immune anaemias in patients with chronic lymphocytic leukaemia treated with fludarabine, cyclophosphamide and rituximab--incidence and predictors. Br J Haematol. 2007 Mar;136(6):800-5.

New Drug Shows Promise in the Treatment of Patients With Relapsed or Refractory Peripheral T-Cell Lymphoma

One of the largest prospective clinical trials in patients with relapsed or refractory peripheral T-cell lymphoma (PTCL), the PROPEL trial (Pralatrexate in patients with Relapsed Or refractory PEripheral T-cell Lymphoma), found that the investigational chemotherapy agent pralatrexate produces CR (complete responses or disappearance of all signs of cancer) in patients who had previously failed an average of three treatment regimens, including an autologous stem cell transplant for some patients.

Peripheral T-cell lymphoma or PTCL is a biologically diverse group of blood cancers that account for 1 in 100 cases of non-Hodgkin's lymphoma (NHL) in the United States. The disease is more common in adults than in children, and it affects slightly more men than women. The average five-year survival is approximately 25 percent.

Dr. Owen A. O'Connor MD, PhD, the Principal Investigator of the PROPEL trial and the Director of the Lymphoid Development and Malignancy Program and Chief of the Lymphoma Service at the Herbert Irving Comprehensive Cancer Center at New York-Presbyterian Hospital/Columbia University Medical Center, and Associate Professor of Medicine at Columbia University College of Physicians and Surgeons, who presented the results of the trial during the 50th Annual Meeting of the American Society of Hematology (ASH) in San Francisco, explained: ‘Presently, there are no FDA-approved treatments for patients with PTCL, either in the first-line or relapsed or refractory setting. This underscores the need for new therapies to treat this challenging disease. Pralatrexate has the potential to play a clinically meaningful role in the treatment of these patients.’

Pralatrexate, a novel targeted antifolate, is in the same class of drugs as methotrexate, a chemotherapy drug that has been available for several decades, but it is far more potent. The new drug is a designed to accumulate in high concentrations in tumor cells, inhibiting DNA synthesis.

Based on preclinical studies, pralatrexate is thought to selectively enter cells expressing RFC-1, a protein that is over expressed on cancer cells compared to normal cells. Once inside cancer cells, pralatrexate is efficiently polyglutamylated, which leads to high intracellular drug retention. Polyglutamylated pralatrexate essentially becomes ‘trapped’ inside cancer cells, making it less susceptible to efflux-based drug resistance. Acting on the folate pathway by ‘mimicking folic acid,’ pralatrexate interferes with DNA synthesis and triggers cancer cell death. Researchers believe that pralatrexate has the potential to be delivered as a single agent or in combination therapy regimens.

A total of 115 patients were enrolled into this phase II, single-arm, non-randomized, open-label study and received weekly intraveneous infusions of pralatrexate (30 mg/m2) for seven weeks. All patients also received vitamin B12 and folic acid throughout the study in order to prevent potential side effects of the pralatrexate. The primary endpoint of the study was the objective response rate (ORR), including all patients who had some response of their disease to therapy. Secondary endpoints included duration of response, progression-free survival, and overall survival.

Interim data of the first 65 evaluable patients showed that 29 percent of patients responded to treatment, with 11 percent experiencing a complete response and 18 percent experiencing a partial response. The most common severe (grade 3 and 4) side effects associated with pralatrexate were thrombocytopenia (31 percent), mucositis (14 percent), anemia (12 percent), and neutropenia (11 percent).

Orphan drug status and Fast-track approval
This is the first promising treatment to be developed in years and based on the promising results of this and previous studies the US Food and Drug Administration granting orphan drug statusand a fast-track approval process to pralatrexate for T-cell lymphoma.

Commenting on the PROPEL trial, Dr Owen O'Connor concluded: ‘This [ ..] trial demonstrate that pralatrexate produced durable, complete responses in heavily pre-treated patients.’

Allos Therapeutics Inc., the maker of the drug, will submit a NDA for pralatrexate for the treatment of patients with relapsed or refractory PTCL to the FDA once the Phase II data has been fully reviewed. This is expected sometime in the first half of 2009.

Pralatrexate was developed by a team of researchers at Memorial Sloan-Kettering Cancer Center (MSKCC) and the Southern Research Institute, including Dr. O'Connor, while at MSKCC. Dr. O'Connor and his colleagues identified the unique activity of pralatrexate in patients with lymphoma. Dr. O'Connor has continued to study pralatrexate at NewYork-Presbyterian/Columbia, now focusing on determining how the drug works in T-cell lymphoma, and on how best to combine it with other drugs to improve the treatment of patient with hematologic cancers.

‘We are very excited by these results. If approved, the launch of pralatrexate will represent a first to market opportunity for Allos,' said Paul L. Berns, President and Chief Executive Officer of Allos. 'And we would like to extend our appreciation to the patients who participated in the PROPEL trial, as well as to their families, for helping us to identify a potential new treatment option for this disease.’

Other Pralatrexate studies
During the 50th Annual Meeting of the American Society of Hematology results from two other pralatrexate studies were presented as posters. One poster reported interim data from a Phase 1 trial of pralatrexate as a single agent in patients with relapsed or refractory cutaneous T-cell lymphoma (CTCL). The second poster reports interim data from a Phase 1/2a trial of pralatrexate in combination with gemcitabine in patients with relapsed or refractory non-Hodgkin's lymphoma (NHL) or Hodgkin's lymphoma.

The first poster (Pralatrexate is Active in Cutaneous T-Cell Lymphoma: Preliminary Results of a Multi-center Dose-finding Trial; abstract 1569) presented interim data from an ongoing Phase 1 trial of pralatrexate in patients with relapsed or refractory CTCL.

Dr Steven Horwitz, M.D., Assistant Attending Physician, Lymphoma Service, Memorial Sloan-Kettering Cancer Center, the Principal Investigator of the study and his team presented the data which included 24 patients, with 22 evaluable patients who completed at least one cycle of treatment at doses ranging from 10-30 mg/m(2) as part of a weekly schedule for two or three weeks followed by one week of rest. Responses were observed in 12 of 22 evaluable patients (55%), including one complete response and 11 partial responses. Patients received a median of four prior systemic therapies. The most common adverse event was mucosal inflammation, with Grade 1/2 mucosal inflammation observed in 11 of 24 patients and Grade 3 mucosal inflammation observed in 4 of 24 patients. There was no Grade 4 mucosal inflammation and no thrombocytopenia above Grade 1. Up to 56 evaluable patients will be enrolled in the study with the objective of determining the optimal dose and schedule for pralatrexate in this patient population.

The second poster (A Phase 1/2a Open-label Study of Pralatrexate and Gemcitabine in Patients with Relapsed or Refractory Lymphoproliferative Malignancies’; abstract 1570) presented interim data from an ongoing Phase 1/2a open-label, multi-center study of pralatrexate in combination with gemcitabine in patients with relapsed or refractory non-Hodgkin's lymphoma (NHL) or Hodgkin's lymphoma. This data included 27 patients, 22 of whom were evaluable for response. Patients have been enrolled in eight cohorts with different doses and schedules. Partial responses were observed in 6 of 22 evaluable patients, including five patients on a sequential dosing schedule and one patient on a same-day dosing schedule. Patients received a median of three prior systemic regimens. The most common adverse event was thrombocytopenia, with Grade 3 observed in four patients and Grade 4 observed in seven patients. The maximum tolerated dose for the sequential dosing schedule was established as 10 mg/m(2) of pralatrexate followed by 300 mg/m(2) of gemcitabine, once every two weeks. Enrollment in the trial is ongoing to determine the maximum tolerated dose for the same same-day dosing schedule.

For more information, read

• Owen A. O’Connor OA, Pro B, Pinter-Brown L, Popplewell L, et al. PROPEL: A Multi-Center Phase 2 Open-Label Study of Pralatrexate (PDX) with Vitamin B12 and Folic Acid Supplementation in Patients with Replapsed or Refractory Peripheral T-Cell Lymphoma. (Oral Session), Blood (ASH Annual Meeting Abstracts) 2008 112: Abstract #261

Other abstracts:

• Horwitz SM, Duvic M,Kim Y,Zain JM, et al. Pralatrexate (PDX) IS Active in Cutaneous T-Cell Lymphoma: Preliminary Results of a Multi-Center Dose-Finding Trial. (Poster Session) Blood (ASH Annual Meeting Abstracts) 2008 112: Abstract #1569
• Horwitz SM, Vose JM, Advani R, Sankhala K, et el. A Phase 1/2A Open-Label Study of Pralatrexate and Gemcitabine in Patients with Relapsed or Refractory Lymphoproliferative Malignancies. (Poster Session), Blood (ASH Annual Meeting Abstracts) 2008 112: Abstract #1570

Also read PubMed Abstracts:

• Toner LE, Vrhovac R, Smith EA, et al. The schedule-dependent effects of the novel antifolatepralatrexate and gemcitabine are superior to methotrexate and cytarabine in models of human non-Hodgkin's lymphoma. Clin Cancer Res 2006;12(3):924-932.
• O'Connor OA, Hamlin PA, Gerecitano J, et al. Pralatrexate (PDX) produces durable complete remissions in patients with chemotherapy resistant precursor and peripheral T-cell lymphomas: results of the MSKCC Phase I/II experience. (Abstract 400). Presented at The American Society of Hematology's 48th Annual Meeting. Blood 2006;108(11):122a-3a.
• O'Connor O, Hamlin P, Neylon E, et al. Early phase experience with pralatrexate (10-propargyl-10-deazaaminopterin [PDX]), a novel antifolate with high affinity for the reduced folate carrier, in patients with chemotherapy refractory lymphoproliferative malignancies. (Abstract 461). Eur J Cancer 2006;4(Suppl 12):141.
• O'Connor OA. Pralatrexate: an emerging new agent with activity in T-cell lymphomas. Curr Opin Oncol 2006;18(6):591-597.
• Krug LM, Heelan RT, Kris MG, et al. Phase II Trial of Pralatrexate (10-Propargyl-10-deazaaminopterin, PDX) in Patients with Unresectable Malignant Pleural Mesothelioma. J Thorac Oncol 2007;2(4):317-320.
• Azzoli CG, Krug LM, Gomez J, et al. A phase 1 study of pralatrexate in combination withPaclitaxel or docetaxel in patients with advanced solid tumors. Clin Cancer Res2007;13(9):2692-8.
• O'Connor OA, Hamlin PA, Portlock C, et al. Pralatrexate, a novel class of antifol with highaffinity for the reduced folate carrier-type 1, produces marked complete and durableremissions in a diversity of chemotherapy refractory cases of T-cell lymphoma. British Journal of Haematology 2007;139(3):425-428.
• Izbicka E, Diaz A, Campos D, et al. Differential activity and potential mechanism of action of pralatrexate (PDX) methotrexate, and pemetrexed (Alimta) in human cancer models in vivo and in vitro (abstract A135). Proceedings of AACR-NCI-EORTC International Conference Molecular Targets and Cancer Therapeutics: Discovery, Biology, and Clinical Applications October 22-26, 2007:108.
• James LP, Azzoli CG, Krug LM, et al. Phase I study of the antifolate pralatrexate given with vitamin B12 and folic acid supplementation in patients with advanced non-small cell lung cancer (NSCLC) (abstract A143). Proceedings of AACR-NCI-EORTC International Conference Molecular Targets and Cancer Therapeutics: Discovery, Biology, and Clinical Applications October 22-26, 2007:111.
• O'Connor OA, Hamlin PA, Portlock C, et al. A Phase '2-1-2' study of two different doses and schedules of pralatrexate, a high affinity substrate for the reduced folate carrier (RFC-1), in patients with relapsed or refractory lymphoma reveals marked activity in T-cell malignancies (abstract C85). Proceedings of AACR-NCI-EORTC International Conference Molecular Targets and Cancer Therapeutics: Discovery, Biology, and Clinical Applications October 22- 26, 2007:283.
• Leitenberger JJ, Berthelot CN, Polder KD, et al. CD4+ CD56+ hematodermic/plasmacytoid dendritic cell tumor with response to pralatrexate. J Am Acad Dermatol 2008;58(3):480-4.
• Damaj BB. In vitro and in vivo effects of pralatrexate (PDX) on the survival and growth of the A549 non-small cell lung cancer cell line. (Abstract 2298). American Association for Cancer Research (AACR) 2008 Annual Meeting; 2008 14-18 Apr 2008 San Diego, CA; 2008.
• O'Connor OA-, Hamlin P, Moskowitz C, et al. Pralatrexate (PDX) produces a high and durable complete response rate in patients with chemotherapy resistant T-cell lymphomas. (Abstract 138). Ann Oncol (ESMO Conference Proceedings) 2008;19(4):iv128.
• Horwitz S, Duvic M, Kim Y, et al. Low dose pralatrexate (PDX) is active in cutaneous T-celllymphoma: Preliminary results of a multi-center dosse finding trial. (abstract 261). Ann Oncol (ESMO Conference Proceedings) 2008;19(4):iv162.
  O'Connor OA. New drugs for the treatment of T-cell lymphoma. (abstract 134). Ann Oncol (ESMO Conference Proceedings) 2008;19(4):iv127.
• Molina JR. Pralatrexate, a dihydrofolate reductase inhibitor for the potential treatment ofseveral malignancies. IDrugs 2008;11(7):508-21
  

Clinical trials:

Study of Pralatrexate With Vitamin B12 and Folic Acid in Patients With Relapsed or Refractory Peripheral T-Cell Lymphoma. Allos Therapeutics, ClinicalTrials.gov Identifier: NCT00364923