OncotypeDX Breast Cancer Assay

Most cancer cells originate from the lactiferous (milk) ducts in the breast (ductal cancer) or in the milk production glands (lobular cancer).
Invasive breast cancer Invasive breast cancer is a term that describes a malignant tumor that has spread to the tissue near the lactiferous duct or nodule, and which may spread to other areas of the body.
Breast cancer in situ is noninvasive breast cancer. The descriptor in situ indicates that the tumor cells are limited to one site and have not yet spread to the tissue surrounding the lobule (LCIS – lobular carcinoma in situ) or outside the ducts (DICS – ductal carcinoma in situ).

In recent years we have witnessed increasing awareness of the importance of early diagnosis of breast cancer. Routine periodical mammography examinations help diagnose many tumors in very early stages – before metastases are sent to the lymph nodes. In these cases the chance of achieving a cure using surgical measures is greater. Often it is asked whether in addition to surgical treatment, an additional treatment is to be added – adjuvant therapy.

Adjuvant therapy for breast cancer is a treatment that is given after an operation for excising the tumor whose aim is to improve the chances for complete recovery from the disease. This treatment reduces the degree of risk of recurrence of the disease and may be based on radiotherapy of the chest, chemotherapy, hormonal and biological therapy.

Most breast cancers are estrogen receptor positive, meaning that they “obey” the instructions given to them by the female sex hormone estrogen. This hormone, which is responsible for the development of breasts in adolescence and other sex signs and sexual functioning of the adult women, encourages the proliferation of healthy breast tissue cells but also malignant cells.

When the tumor is diagnosed as being “receptor positive”, this means that the woman may be administered adjuvant therapy, which includes, among other things, drugs that are intended to reduce the effect of the hormone estrogen over the tumor tissue in the breast, thus increasing the degree of confidence of the patient’s full recovery after the operation.

Reduction of the effect of estrogen is achieved in one of two ways: blocking the activity of estrogen receptors in the breast tissue, which is usually performed using the drug tamoxifen, and by reducing the production of the hormone estrogen, which may be performed by a number of drugs that are collectively known as aromatase inhibitors.

The chances of recurrence of the disease after 10 years in patients who are treated with tamoxifen after surgical excision are about 15 percent.

The decision to combine adjuvant chemotherapy in cases of early stage breast cancer when there is no lymph node involvement must take into account on the one hand the risk of recurrence of the disease due to local (radiation) therapy only, and on the other hand the expected benefit, toxicity and morbidity that are associated with administering systemic chemotherapy. The prognosis of the disease is affected by a number of factors, the most important of which are patient age, tumor size, degree of differentiation of the tumor cells and the number of lymph nodes involved.

In the case of early breast cancer, which expresses estrogen receptors, which does not involve lymph nodes, the decision to administer systemic chemotherapy is more complex, in view of the fact that only 15% of patients (treated with tamoxifen) will experience reoccurrence of the disease within 10 years. In other words, adjuvant chemotherapy may be effective only for a small percentage of patients. The means that to achieve efficacy in those 15%, the remaining 85% must be treated unnecessarily.

In breast cancer that expresses estrogen receptors and involves lymph nodes, there is a clear tendency to start adjuvant chemotherapy. However, there are cases, in which the risk for disease recurrence after resection of the tumor and lymph nodes is very low. Must adjuvant chemotherapy be combined with treatment with tamoxifen in these cases too?

There are a number of methods and algorithms of assessing the risk and benefit of adding adjuvant chemotherapy in these women. Some of the methods weigh in physical factors of the tumor, while others base the risk assessment or probability of disease recurrence on testing of the genetic code / the molecular profile of the tumor cells – an assessment that allows for more comprehensive testing of the tumor cells, beyond their physical characteristics.

A study that was published in the Journal of Clinical Oncology in 2011 showed that the addition of prognostic indices (such as age, tumor size and tumor differentiation level) relative to the molecular prediction algorithm did not give any additional significant information for assessing the benefit expected from adding adjuvant chemotherapy among estrogen receptor positive cancer patients without lymph node involvement.

Because there is a correlation between the risk of later recurrence of disease and the benefit in adjuvant chemotherapy, it is important to determine the molecular profile of the tumor.

Molecular profiling may assist in planning personalized treatment, assessing the risk for later recurrence of the disease and the expected benefit from adjuvant chemotherapy on women who have an increased risk for disease recurrence. In addition, the molecular profiling test may save systemic chemotherapy (which has significant side effects) for women who are at low risk of later disease recurrence.

Other studies have proved the benefit of using the test when there is lymph node involvement. These studies have shown that the results of the test show which of the patient will benefit from adding systemic chemotherapy in addition to hormonal therapy.

In addition, studies show that there is benefit in performing the test for breast cancer patients when the patient is a candidate for preoperative (neoadjuvant) therapy. The results of the study help determine the risks for a clinical and pathological (cellular) response of the tumor to chemotherapy or hormonal therapy.

A study that was published in the Journal of Clinical Oncology in 2006 found a significant positive correlation between risk of disease recurrence and the efficacy of chemotherapy in estrogen receptor positive cancer patients without lymph node involvement. Patients who were diagnosed as being at high risk for disease recurrence gained great benefit from chemotherapy (absolute reduction of 27.6% in the rate of disease recurrence after 10 years), while patients who were diagnosed as being of low risk of disease recurrence did not gain benefit from chemotherapy (without a decrease in risk for disease recurrence after 10 years).

A study that was published in the magazine The Lancet, in 2009, in estrogen receptor positive, postmenopausal breast cancer patients with lymph node involvement (1-3 involved nodes) showed that patients who were diagnosed as having a high risk of disease recurrence after 10 years gained great benefit from chemotherapy in addition to hormonal therapy (19% absolute reduction in the rate of disease recurrence after 10 years), while patients who were diagnosed as being of low risk of disease recurrence did not gain benefit from chemotherapy (without a decrease in risk for disease recurrence after 10 years), despite lymph node involvement.

In order to clarify the risk for late recurrence of the tumor, an analysis is performed that assesses the expression of 21 genes in the tumor cells, which are taken from a biopsy that is routinely taken during surgical excision. This analysis is called the Breast Oncotype test – OncotypeDX Breast.

Out of the 21 genes tested, 5 genes are used as controls. The expression of the 16 remaining genes is associated with risk of late disease recurrence. The results of the OncotypeDX Breast test are weighted to form a single score that indicates the risk for late recurrence of the disease over the next 10 years.

This score is called a recurrence score, and has a value ranging from 0-100.

In 2007, the American Society of Clinical Oncology (ASCO) published an update on the use of tumor markers in prevention, screening tests, treatment and follow up of breast cancer. In this update it was written that for breast cancer patients treated with tamoxifen whose disease did not involve lymph nodes and whose tumors had estrogen receptors, the OncotypeDX breast test could serve for predicting the risk of recurrence of the disease. OncotypeDX Breast may identify patients who are expected to gain maximum benefit from hormonal therapy with tamoxifen only and who do not need chemotherapy. In addition, patients with a high recurrence score probably gain greater benefit from chemotherapy than hormonal therapy with tamoxifen only.

In 2008, a similar recommendation was also published by the NCCN (National Comprehensive Cancer Network) in which it was written that the OncotypeDX Breast test was recommended for use in early breast cancer patients for predicting the risk of disease recurrence and predicting the expected benefit from tamoxifen.

Within the 12th international conference on breast cancer that was held in Saint Gallen (in March 2011), 84% of panelists agreed that the OncotypeDX Breast test could be used for assessing the expected response to chemotherapy in tumors that reacted to hormones.

Concerning the degree of spread of disease, the panel experts believed that lymph node involvement itself did not constitute an indication for use of chemotherapy, although most experts in the group used chemotherapy when there was involvement of more than three nodes.