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The Lancet Oncology

Monday, February 2, 2009

New Genetic Model Improves Breast Cancer Screening

Researchers using the OncoVue® (InterGenetics Inc,655 Research Parkway, Suite 300, Oklahoma City, OK 73104) clinical breast cancer model for assessing genetic risk had much higher accuracy when compared with the more commonly used Gail model, according to data presented at the 31st Annual CTRC-AACR San Antonio Breast Cancer Symposium (SABCS, December 10 - 14, 2008).

By using a combination of a questionnaire and a saliva test, the OncoVue® model takes into account genetic variation in single nucleotide polymorphisms, or SNPs, that the traditional Gail model, which bases risk calculation primarily on traditional risk factors like woman's own personal medical history (number of previous breast biopsies and the presence of atypical hyperplasia in any previous breast biopsy specimen), her own reproductive history (age at the start of menstruation and age at the first live birth of a child), and the history of breast cancer among her first-degree relatives (mother, sisters, daughters) to estimate her risk of developing invasive breast cancer over specific periods of time, does not.

The single nucleotide polymorphisms or SNPs used by the OncoVue model, are small genetic changes within DNA that underlie individuality, including disease risk.

The initial research considered 117 common SNPs as candidates, but during test development the list was ultimately narrowed to 22 SNPs in 19 genes that proved to be most informative in estimating a woman’s individualized risk of developing breast cancer.

‘Women are clamoring for genetic tests like this one. The traditional Gail model looks at personal and clinical risk factors, but not at the inherited genetic variation in SNPs,’ explained lead investigator Kathie Dalessandri, M.D., a physician scientist who led the research team along with colleagues at the University of California, San Francisco, and the Buck Institute for Age Research.

Buccal cell DNA had been collected from 177 women without breast cancer who comprised the control group and 169 women diagnosed with breast cancer between 1997 and 1999 in Marin County, California. This region has been recognized for many years as having higher than average breast cancer incidence and mortality rates. Despite their elevated risk, Marin women who develop breast cancer have similar risk factors as Marin women who do not develop breast cancer when assessed by the classical Gail model characteristics. The researchers theorized that the OncoVue model which integrates the influence of genetic variation along with personal and clinical information would be able to more accurately estimate risk for these Marin women.

DNA was genotyped for 22 SNP variants, and the researchers assessed the fraction of case and control patients who were assigned an OncoVue risk score greater than 1.5 times average likelihood of developing breast cancer between ages 30 and 69. In this blinded analysis, the OncoVue® score proved 2.4 times (p=0.036) more accurate than the Gail model characteristics in accurately identifying the Marin cases with their increased risk from Marin controls with their reduced risk.

In this blinded validation study OncoVue exhibited significantly improved performance, compared to the Gail model alone, in estimating individual risk among Marin County, California women. The improved performance of OncoVue was similar to that observed in two previous independent validation sets, thus, supporting the clinical utility of OncoVue for more accurate individualized breast cancer risk estimation.

Additionally, OncoVue exhibited a 51 percent improvement over the Gail model in assigning an elevated risk score to cases. The improvement in risk estimation is significant and Dalessandri believes the OncoVue model will soon become standard clinical practice for evaluating breast cancer risk. ‘Within the next few years there is going to be a definite paradigm shift toward prevention by analysis of genetic material rather than traditional risk factors,’ Dalessandri noted. ‘As these tests become more commonplace we will be able to more effectively target prevention and early intervention to those at highest risk.’

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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.

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  • Options for HER2+ Breast Cancer (video).

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New Test Helps Assess Colorectal Cancer Risk

A new assessment tool can help individuals calculate their risk for colorectal cancer, also known as cancer of the colon or rectum. The test designed by National Cancer Institute (NCI), the University of Utah, and the Kaiser Permanente Medical Care Program of Northern California is now available online.

With more than 108,000 new cases of colon cancer and more than 40,000 new cases of rectal cancer, colorectal cancer is the fourth most common cancer in men and women in the United States and the second leading cause of cancer-related deaths. The symptoms can remain undetected for many years and in most cases will develop quite slowly. However, as a result of better detection and treatment, the death rate from colorectal cancer has been dropping. Caught early, colorectal cancer is often curable.

The new assessment tool is designed for people 50 years of age and older and based on data collected from two large US population-based case control studies of colon and rectal cancer, data from 13 NCI Surveillance, Epidemiology and End Result Registries (SEER data), and the US national mortality rates.

How it works
The Colorectal Cancer Risk Assessment Tool uses the respondent’s answers about risk and preventive factors to calculate that person’s absolute risk for developing colorectal cancer for a specific time period. The online test is interactive, simple and straightforward and takes only 5-8 minutes to complete. After answering the questions, the tool will calculate an individual’s risk for colorectal cancer.

To validate the accuracy, the model was tested in a large population. The results show that the tool is accurate in predicting absolute risk. Because the majority of participants in the case-control studies were non-Hispanic white males and females, relative risks for other racial or ethnic groups could not be estimated. Researchers are in the process of updating the tool by using SEER rates for minority populations to allow the tool to produce more accurate results for men and women in these populations. When available, the expanded functionality will include additional ages and racial/ethnic groups.

The risk calculator will be updated periodically as new data or research become available. In addition, the tool may prove useful to researchers who are designing research intervention studies.

Man and Women
To help assess the risk for, the tool is gender specific. For men, the model included a cancer-negative sigmoidoscopy/colonoscopy in the last 10 years, polyp history in the last 10 years, a history of colorectal cancer in a first-degree relatives, use of aspirin and nonsteroidal anti-inflammatory drug (NSAID), cigarette smoking, body mass index (BMI), current leisure-time vigorous activity, and vegetable consumption.

For women, the model included sigmoidoscopy/colonoscopy, polyp history, a history of colorectal cancer in a first-degree relatives, aspirin and NSAID use, BMI, leisure-time vigorous activity, vegetable consumption, hormone-replacement therapy (HRT), and estrogen exposure on the basis of menopausal status.

Better Understanding
The tool is designed to assist health care providers in counseling their patients. A better understanding of the risk will help patients and their doctor make more informed choices about how to screen and which screening tests they should take to detect signs of cancer before symptoms appear.

Although the questionnaire is suitable for 'self-administrations', researchers stress that it’s important that patients talk with their primary health care provider about the results. Commenting of the test they claim ‘The test is designed to be used by health professionals and their patients. If patients are using the tool at home, we encourage them to discuss the results, and their individual risk of colorectal cancer with their healthcare provider.’

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