Breast cancer

Every 10th woman will develop breast cancer during her life. In Norway in 2005, there were 2,780 women who received this diagnosis.

Breast malignancy Overview

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Breast Overview

In comparison, the disease affected 1,235 women in 1970. Breast cancer affects first and foremost women over the age of 50. Only 5.6% of new cases occurred in women under 40 years in 2004. The disease constitutes 40% of all cancer in women between the ages of 30 to 54 years. The average age at diagnosis is 59. The risk increases with age, but isolated cases occur in women under 30 years of age.

Background

Breast cancer is by far the most common form of cancer in women. The disease is characterized by a varied course, from rapidly growing tumors with early distant metastasis, to slow growing tumors which remain in the breasts without metastasizing. Twenty-five to 35% of breast tumors are aggressive. The majority of breast tumors are carcinomas. Sarcoma tumors are rare, but are important to be aware of as they are treated differently from other breast carcinomas.

Survival after diagnosis and treatment has continually improved over many decades. This is in part due to increased use of mammography screening, which provides early detection of the disease, and improved treatment. Approximately 2/3 of patients are cured of the disease. Five year survival without a sign of relapse, all stages considered, is more than 80%. In 2004, 694 women and 3 men died of breast cancer in Norway. Of these, 423 were over 65 years. Breast cancer is the most important cause of lost years of life in women under 65 years and ranks before both heart/vascular diseases and accidents. At the end of 2005, there were 31,548 women with the diagnosis.

How to improve prognosis

Early diagnosis is, despite great differences in biology, the most important means of improving the prognosis. The prognosis is also strongly dependent on stage. Five year relative survival where the disease is limited to the breast is 94.1%, compared to 16.9%, if there is distant metastasis at the time of diagnosis.

Seventy to 80% of invasive breast carcinomas are histologically of the infiltrating ductal type. Ten to 20% are of the infiltrating lobular type, while other types constitute the rest.

Stages of Breast Cancer

Premalignant lesions are recognized microscopically by abnormal proliferative activity (cell growth) in the ductal system or in the glands (lobular), but where there are no signs that the epithelial cells have penetrated the basal membrane. The lesions can be classified according to proliferation, cellular atypia and tissue architecture as shown below:

• Lobular and ductal epithelial hyperplasia without atypia
• Lobular and ductal epithelial hyperplasia with atypia
• Lobular carcinoma in situ (LCIS)
• Ductal carcinoma in situ (DCIS) grade 1-3 (van Nuys grading) (2)

DCIS, also known as intraductal carcinoma, should not be confused with invasive carcinoma of the ductal type. Previously, DCIS was considered a rare condition and constituted only between 1.4 and 5.3% of all newly diagnosed breast cancer cases. After the introduction of mammography screening, more women are diagnosed with DCIS (10-30%).

In areas with established mammography screening programs, DCIS constitutes 25-30% of new breast cancer cases in the first screening round. In later screening rounds, the number is 10-20%. The main problem with DCIS is that the risk for local recurrence in the breast after resection alone is much greater than with other pre-malignant lesions in breast tissue. In addition,a large majority of DCIS will not develop into invasive carcinoma if left untreated. For this reason, there is a great need for dependable prognostic markers.

Prognostic markers

DNA ploidy by image analysis is established as a general diagnostic marker and as a prognostic/predictive marker for gynecological cancers and oral dysplasias. The potential as a prognostic marker is great, and multiple studies have evaluated the correlation between DNA ploidy and prognosis for breast cancer. The results from these studies are, however, sparse and many of the studies are too small or insufficient. Due to the lack of data, the American Society of Clinical Oncology has repeatedly recommended that DNA ploidy should not be used as a prognostic marker for breast cancer. Because of the inconsistent results from studies on correlation between DNA proliferation and prognosis, Bagwell et al. from Baylor College of Medicine developed a model which categorizes patients into different risk groups by adjusting the classification of ploidy histograms and S-phase fraction. The study was based on a cohort of 961 node-negative patients and gave promising and significant results. The model also gave similar improvements in prognostic value of DNA when used on Swedish and French breast cancer databases for 210 and 220 cases, respectively. Today, there are multiple groups using composite models to support breast cancer diagnosing.

Nucleotyping represents among other features an objective assessment of nuclear atypia, one of the most important features of histopathological diagnosis and prognosis. It a allows for a qualitative assessment of chromatin structure, and the method is also sensitive for larger chromosomal aberrations. Of even greater importance is the methods ability to map and quantify functional changes in DNA organization. Such changes are, to a large extent, sub-visual, and are therefore not detected by traditional microscopy. Nucleotyping might be described as interphase cytogenetics, or an interphase version of karyotyping, where organisational and functional domains of DNA are mapped and described. We will investigate the value of nucleotyping as a prognostic marker for breast cancer.

Breast Cancer Materials

Normal breast

This material consists of 43 normal breast specimens which can be used as control material. We have previously measured DNA ploidy for all cases.

Ductal carcinomas in situ

Ductal carcinoma in situ represents a special diagnostic challenge, since around 20% develop into invasive cancer and there is no clear maker for identification. We have a total of 121 patients separated into 75 patients from Nottingham (75 DCIS + 25 samples which later developed into invasive tumor) and 43 patients from Oslo University Hospital.

Breast cancer stage I/II

We have a total of 480 patients with a clear prognosis (good prognosis: disease free > 10 years after treatment, poor prognosis: recurrence or death within 5 years from the disease). This pilot study is for DNA ploidy and nucleotyping as a prognostic marker for breast cancer. The material can also be used for a comparative investigation of alternative methods for DNA ploidy determination. We have previously made TMA blocks for the project. The material has been used for a collaboration project with CCB (Kirsten Sandvig) where the purpose is to investigate the clinical significance of Flotillin 1 and 2, and the connection between expression levels of Flotillins and the known clinical biomarker ErbB2.