Novel Cancer Drug Test May Results in Safer and More Effective Clinical Trials

A group of scientists from Hamburg may have taken a big step towards more effective cancer drug development. Dr Ilona Schonn, Director of Cell Culture Research at Indivumed GmbH, a company specialized in the analysis and procurement of highly standardized tissue samples and data of tumor patients, told the audience at Europe’s largest cancer congress, the joint 15th European CanCer Organisation (ECCO) and 34th European Society for Medical Oncology (ESMO) Multidisciplinary Congress, September 20 – 24 in Berlin, Germany, that they had developed a preclinical drug test platform that would enable researchers to analyze tumor tissue for individual patient drug responses on the molecular level.

To date most tests for drug metabolism and toxicity testing have used tissue slices of normal organs like liver, kidney and lung. The new test was created specifically for oncology drug testing and uses tumor tissues from colorectal and lung cancer patients.

A major problem of drug development at present is the inability to extrapolate response in preclinical cell models to patients. “Approximately 90% of clinical trials fail because the drugs used are too ineffective or too toxic,” explained Dr Schonn. “Not only does this result in unacceptably high costs for drug development, but it also exposes patients to risks from toxicity or simply wastes their time in testing a substance which proves to be ineffective.”

The problem arises from the fact that patients respond individually to drugs. In addition, each tumor consists of a variety of different cancer cells that interact in different ways with the framework of individual non-tumor cells, resulting in highly variable growth behavior and response to drugs. Dr Schonn and her team set out to try to develop a drug test that would eliminate these problems and provide an accurate model of individual patient response.

“Based on freshly cultivated intact tissue from surgically treated cancer patients we are now able to analyze numerous tumors from different patients, to identify differences in drug response between those patients, and to understand variations of response in cell subtypes within one tumor,” said Dr Schonn.

The new test allows scientists to translate findings from commonly used cell lines to a preclinical model which is as close as possible to using the same drug in the clinical setting, thus enabling a better estimate of the number of patients who are likely to respond to the treatment. It also helps to identify biomarkers that can predict drug response for patients entering a clinical trial, allowing researchers to include only those patients whose participation will provide a significant answer to the question being asked.

“Together with all the clinical patient data and several analytical test systems such as signaling pathway analysis, we have been able to characterize individual tumors in more detail. This will improve the understanding of drug effects and treatments, a step forward towards the goal of individualized cancer therapy,” she said. “The test is of particular interest to pharmaceutical companies because it allows the analysis of samples from meaningful number of patients with different tumors in a short period of time, and can, therefore, accelerate progression of a potential new treatment to clinical trials.”

In addition, it can help gain more knowledge about the mode of action of a new compound in patients, and identify optimal disease areas, for example tumors with particular mutations or over-expression of target receptors, and dosage.

To date the test has only been validated in colon, non-small cell lung (NSCLC), and breast cancer tumors but there is no reason to think that it would not be equally accurate in other solid tumor types, the scientists say.

“Because the test allows us to maintain the complex environment of the primary cancer tumor, we believe that it holds out great promise for the quick and effective elucidation of response to anticancer drugs,” said Dr Schonn. “We hope to be able to apply it to a growing number of drugs emerging from the labs of pharmaceutical companies to help to shorten development time and to make clinical trials both more efficient and safer for patients.”

The test can analyze numerous tumors from different patients, identify the patients’ diverse reactions to the test compounds and elucidate their varying effects on cell subtypes within the same tumor. Says Prof Dr Hartmut Juhl, CEO and founder of Indivumed. “In the long run, our test paves the way to personalized medicine, because it helps to understand and to embrace the individual reactions of the patients to a certain therapy.”

For more information:

• Abstract no: 1013, Basic Science/Translational Research poster discussion, Wednesday 17.00 – 18.00 hrs CEST (Hall 14.2)

Test Identifies Low-risk Subgroup in HER2-positive Breast Cancer

HER2, human epidermal growth factor receptor 2, is a protein found on the surface of breast cancer cells. When functioning normally, HER2 is a key component in regulating cell growth. However, when altered, extra HER2 protein receptors may be produced.

This overexpression of HER2 is considered a negative prognostic factor and associated with increased cell growth and reproduction, often resulting in a more aggressive form of breast cancer with increased disease recurrence and worse prognosis. Studies show that HER2/neu is overexpressed in approximately 15-20% of invasive breast cancers. Because HER2+ tumors tend to grow and spread more quickly than tumors that are not HER2+, accurate and timely diagnostic procedures are crucial.

High Risk
There are a number of different kinds of breast cancer and each is treated differently. Patients with Her2+ breast cancer are generally classified as high risk. As a result, current treatment guidelines recommend adjuvant trastuzumab (Herceptin®, Genentech, 1 DNA Way South San Francisco, CA 94080-4990, co-marketed by F. Hoffmann-La Roche, Grenzacherstrasse 124, CH-4070 Basel, Switzerland) and chemotherapy as the best treatment option for all HER2-positive breast cancer patients at high risk of relapse, increasing their chance of living longer. At the same time, results from the HERA-trial (HERceptin Adjuvant), a randomized, two-arm, open label study of the efficacy, safety and tolerability of trastuzumab compared to observation in women who have completed standard adjuvant treatment of HER2 positive primary breast cancer, showed that 74% of patients remained distant recurrence-free at 3 years without trastuzumab.

A highly sensitive prognostic tool
Dr. Michael Knauer, MD, from the Netherlands Cancer Institute presented the results from a study investigating the benefits of a highly sensitive diagnostic assay during the 2008 San Antonio Breast Cancer Symposium (SABCS). In the study, researchers used MammaPrint®, (Agendia BV, Amsterdam Science Park, Kruislaan 406, NL-1098 SM Amsterdam, The Netherlands), a prognostic genomic test developed with micro-array technology that has the potential to greatly improve risk assessment and treatment decision making for early breast cancer, to identify a subgroup of patients with low risk and favorable outcome. This test looks at the expression of 70 genes linked to breast cancer with an accuracy level of 96.7% as determined by a study published in the New England Journal of Medicine. This prognostic signature of genetic 'fingerprint' is validated as an independent prognostic indicator for patients with up to three positive lymph nodes.

Knauer showed that the highly accurate MammaPrint was able to differentiate between patients at high risk for recurrence and a low risk subgroup of HER2+ patients. The assay helped uncover a substantial group of traditionally miscategorized low risk HER2+ patients.

Study results
In the study population of 169 HER2+ patients, Mammaprint, the first ‘in vitro diagnostic multivariate index assay’ (IVDMIA) cleared by the U.S. Food and Drug Administration (FDA) designed to identify patients with early metastasis, classified 16 percent of patients as having a good prognosis signature with a 10-year distant disease-free survival (DDFS) of 89 percent, even in the absence of (neo)adjuvant trastuzumab and chemotherapy, compared to 84 percent of patients classified as having a poor prognosis signature with a DDFS of 64 percent. Additionally, in a subgroup of highly endocrine responsive HER2/neu positive patients, MammaPrint low risk patients had no relapse.

All 169 patients with HER2-positive breast cancer were selected from a pooled dataset of 1280 patients with known HER2-status. Patients had a unilateral T1-3, N0-1 tumor and were treated with either breast-conserving therapy or mastectomy. Samples were analyzed and classified by the 70-gene signature as good or poor prognosis by Agendia Laboratories.

The strength of the assay is underscored by the 70 gene panel unique to the test and a resulting gene profile that covers all molecular pathways associated with breast cancer.

Personalized medicine
MammaPrint accurately identified a subgroup of patients with a good clinical outcome in HER2+ early breast cancer. These patients will be further studied in the ongoing MINDACT-trial (EORTC 10041/ BIG 3-04), a multicentre, prospective, phase III trial coordinated by the EORTC (European Organisation for Research and Treatment of Cancer) and run under the BIG and TRANSBIG network, which will accrue 6000 node-negative patients designed to determine the prospects of withholding chemotherapy and/or trastuzumab in HER2+, MammaPrint low risk patients.

This study compares MammaPrint to traditional clinical-pathological methods to assess the risk of breast cancer recurring in women with lymph node negative disease. Since breast cancer tumors with similar clinicopathological characteristics can have strikingly different outcomes, the traditional selection for adjuvant chemotherapy is far from accurate.

Based on the initial results with MammaPrint, it is hypothesized that using the genomic test in addition to traditional methods will result in more accurate risk assessment. It is expected that 10% to 20% of patients with node negative breast cancer will, in the future, safely be able to avoid chemotherapy and its potential side effects.

The current trend in research cancer is to develop ways of individualizing breast cancer treatment. This goal toward ‘personalized medicine’ requires better identification of type of systemic treatment and better identification of patients who are highly likely to develop distant metastases, and therefore, may benefit the most from adjuvant chemotherapy.

MammaPrint may be one of the tools helping to realize these goals.

For more information, read:

• Knauer M, Cardoso F, Mook S. et al. Identification of a low risk subgroup in Her2-positive breast cancer by the 70-gene prognosis signature. SABCS, Saturday, December 13, 2008 - 7:00 AM Poster Session IV: Late Acceptances (7:00AM-9:00AM). Abstract 4171.

Watch:

• Options for HER2+ Breast Cancer (video).

Also review PubMed abstracts:

• Haibe-Kains B, Desmedt C, Piette F, et al. Comparison of prognostic gene expression signatures for breast cancer. BMC Genomics. 2008 Aug 21;9:394. Free Full Text Article (PDF);
• Mook S, Schmidt MK, Viale G, et al. The 70-gene prognosis-signature predicts disease outcome in breast cancer patients with 1-3 positive lymph nodes in an independent validation study. Breast Cancer Res Treat. 2008 Jul 27. [Epub ahead of print];
• Cardoso F, Van't Veer L, Rutgers E, et al. Clinical application of the 70-gene profile: the MINDACT trial. J Clin Oncol. 2008 Feb 10;26(5):729-35.
• Marchionni L, Wilson RF, Marinopoulos SS et al. Impact of gene expression profiling tests on breast cancer outcomes. Evid Rep Technol Assess (Full Rep). 2007 Dec;(160):1-105;
• Mook S, Van't Veer LJ, Rutgers EJ et al. Individualization of therapy using Mammaprint: from development to the MINDACT Trial. Cancer Genomics Proteomics. 2007 May-Jun;4(3):147-55;
• Van de Vijver MJ, He YD, van't Veer LJ, et al. A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med. 2002 Dec 19;347(25):1999-2009.

More information:

• EORTC – The Mindact brochure.
• EORTC – The Mindsact website.
• Clinical trial: Trastuzumab in Treating Women With Primary Breast Cancer (EORTC, NCIC, BIG); Phase III.

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.

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.