Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
2001-07-27
2004-03-09
Myers, Carla J. (Department: 1634)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S091200, C536S023500, C536S024310, C536S024330
Reexamination Certificate
active
06703204
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to nucleic acid microarray markers for cancer, particularly for breast cancer. The invention also relates to methods for diagnosing cancer as well as optimizing cancer treatment strategies.
BACKGROUND OF THE INVENTION
Breast cancer is a malignant proliferation of epithelial cells lining the ducts or lobules of the breast (Harrison's Principles of Internal Medicine 1998). Although much progress has been made toward understanding the biological basis of cancer and in its diagnosis and treatment, it is still one of the leading causes of death in the United States. Inherent difficulties in the diagnosis and treatment of cancer include among other things, the existence of many different subgroups of cancer and the concomitant variation in appropriate treatment strategies to maximize the likelihood of positive patient outcome.
The traditional method of breast cancer diagnosis and staging is through the use of biopsy examination. Once a diagnosis is made, the options for treating breast cancer are assessed with respect to the needs of the patient. These options traditionally include surgical intervention, chemotherapy, radiotherapy, and adjuvant systemic therapies. Surgical therapy may be lumpectomy or more extensive mastectomy. Adjuvants may include but are not limited to chemotherapy, radiotherapy, and endocrine therapies such as castration; administration of LHRH agonists, antiestrogens, such as tamoxifen, high-dose progestogens; adrenalectomy; and/or aromatase inhibitors (Harrison's Principles of Internal Medicine 1998).
Of key importance in the treatment of breast cancer is the selection and implementation of an appropriate combination of therapeutic approaches. For example, depending on a breast cancer patient's prognosis, therapy may include surgical intervention in combination with adjuvant therapy or it may only include surgical intervention. In addition, for some patients pretreatment with chemotherapy or radiotherapy is utilized prior to surgical intervention, but in other patients adjuvant therapies are used following surgical intervention.
It is difficult to predict from standard clinical and pathologic features the clinical course of early stage breast cancer, particularly lymph node-negative tumors in premenopausal patients. Current practice in the United States is to offer systemic chemotherapy to most of these women. Because the majority of these women would have good outcome even without chemotherapy, the rate of “over-treatment” is high. Chemotherapy itself carries a 1% mortality rate. Therefore, unnecessary deaths could be avoided if it were possible to subdivide these patients into high and low risk subgroups, and only undertake adjunctive treatment for those judged to be high risk.
Selection of a suitable treatment regimen for breast cancer is based on the subgroup of cancer. Current strategies used to make therapeutic decisions in the management of patients with breast cancer are based on several factors including hormone receptor status, her-2
eu staining, flow cytometry, and the mitotic activity index (MAI). The MAI is a widely utilized predictor of outcome in cancers, particularly in invasive breast cancer. The definition of the MAI is “the total number of mitoses counted in 10 consecutive high-power fields (objective, ×40; numeric aperture, 0.75; field diameter, 450 microns), in the most cellular area at the periphery of the tumor, with the subjectively highest mitotic activity” (Jannink et al., 1995). For the procedure, hematoxylin-eosin stained sections of breast cancer tumor are assessed for the total number of mitotic figures in ten consecutive high-power fields and based on these numbers the breast cancer is assigned to either good outcome (MAI<10) or poor outcome (MAI>10). MAI classification correlates to standard parameters such as death, recurrence, and metastases, which are known to those of ordinary skill in the art to predict clinical outcome.
Determination of appropriate treatment for an individual cancer patient is complex with a wide variety of treatments and possible treatment combinations. For example, chemotherapy is a common method of cancer treatment, with more than 50 different chemotherapeutic agents available. These therapeutic agents can be used in a wide range of dosages both singly and in combinational therapies with other chemotherapeutic agents, surgery, and/or radiotherapy.
The available methods for designing strategies for treating breast cancer patients are complex, time consuming, and inexact. The wide range of cancer subgroups and variations in disease progression limit the predictive ability of the healthcare professional. In addition, continuing development of novel treatment strategies and therapeutics will result in the addition of more variables to the already complex decision-making process involving matching the cancer patient with a treatment regimen that is appropriate and optimized for the cancer stage, extent of infiltration, tumor growth rate, and other factors central to the individual patient's prognosis. Because of the critical importance of selecting appropriate treatment regimens for breast cancer patients, the development of guidelines for treatment selection is of key interest to those in the medical community and their patients. Thus, there presently is a need for objective, reproducible, and sensitive methods for predicting breast cancer patient outcome and selecting optimal treatment regimens.
SUMMARY OF THE INVENTION
It now has been discovered that particular sets of genes are expressed differentially in tumors characterized as high MAI or low MAI tumors. These sets of genes can be used to discriminate between high and low MAI tumors. Accordingly, diagnostic assays for classification of tumors, prediction of tumor outcome, selecting and monitoring treatment regimens and monitoring tumor progression/regression can now be based on the expression of sets of genes.
According to one aspect of the invention, methods for diagnosing breast cancer in a subject suspected of having breast cancer are provided. The methods include obtaining from the subject a breast tissue sample and determining the expression of a set of nucleic acid molecules or expression products thereof in the breast tissue sample. The set of nucleic acid molecules includes at least two nucleic acid molecules selected from the group consisting of SEQ ID NOs:1-51. In preferred embodiments, the breast tissue sample suspected of being cancerous.
In some embodiments the set of nucleic acid molecules includes more than 2 and up to all of the nucleic acid molecules set forth as SEQ ID NOs:1-51, and any number of nucleic acid sequences between these two numbers. For example, in certain embodiments the set includes at least 3, 4, 5, 10, 15, 20, 30, 40 or more nucleic acid molecules of the nucleic acid molecules set forth as SEQ ID NOs:1-51.
In other embodiments, the method further includes determining the expression of the set of nucleic acid molecules or expression products thereof in a non-cancerous breast tissue sample, and comparing the expression of the set of nucleic acid molecules or expression products thereof in the breast tissue sample suspected of being cancerous and the non-cancerous breast tissue sample.
According to another aspect of the invention, methods for identifying a set of nucleic acid markers or expression products thereof are provided. The methods are effective for determining the prognosis of cancer. The methods include obtaining a plurality of tumor tissue samples from a plurality of subjects afflicted with cancer, classifying the plurality of tumor tissue samples according to mitotic activity index (MAI) into high MAI and low MAI groups and determining differences in the expression of a plurality of nucleic acid molecules or expression products thereof in the tumor tissue samples. The methods further include selecting as a set of nucleic acid markers the nucleic acid molecules or expression products thereof which are differentially expressed in the
Baak Jan P. A.
Mutter George L.
Myers Carla J.
Sakelaris Sally
The Brigham & Women's Hospital, Inc.
Wolf Greenfield & Sacks P.C.
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