Breast Cancer: is also known as mammary cancer results from several factors such as ionizing radiation, diety, familiar history or exposure to genetic mutagens. Carcinomas of the breast are the eight most prevalent form of cancer and fourth among the most common causes of cancer deaths in the US. It is the most common femal malignancy in most industrialized countries, estimated to affect about 10% of the female population during their lifespan. Breast cancer is the primary killer of women. One in eight American women will develop reast cancer in her lifetime. An estimated 3 million women in the US are living with breast cancer.
Genetic Risks:
BRCA1 gene:
About 1 out of 800 in the general femaile population has a mutation in the BRCA1 gene sequence that places her at high genetic risk of developing breast cancer and ovarian cancer. In any one year, a variation of unkown clinical significiance is identified in about 15 per% of women having tests for unkonw variations in the BRCA1 gene.
The discovery of BRCA1 and BRCA2 has expanded our knowledge of genetic factors which can contribute to familial breast cancer. Germ-line mutations within these two loci are associated with a 50-80% lifetime risk of breast and/or ovarian cancer. However, it is likely that other, non-genetic factors also have a significant effect on the etiology of the disease.
Detection:
The principal manner of identifying breast cancer is through detection of the presence of dense tumorous tissue. This may be accomplished to varying degrees of effectiveness by direct examination of the outside of the breast, or through mammography or other X-ray imagin methods. Mammograms are not recommended for women under 50 since this group is not as likely to develop breast cancers as are older women and mammogram have a small risk of inducing breast tumors.
Diagnostic genetic testing for the existence of BRCA mutations is also an important consideration in the provision of clinical care for breast or ovarian cancer. This testing provides a patient with information on her risk for hereditary breast and ovarian cancers, and thus aids in the difficult decision regarding whether to undertake preventive options, including prophylactic surgery. Myriad Genetics is a leader in this type of testing.
Classification:
Gene expression profiling information dervied using DNA microarrays to analyse expression from multiple thousands of genes has led to the subdivision of breast cancer into at least 5 different subtypes. One subtype “basal-like” is the most aggressive and is thought to arise from basal epithelial cells (WO 2010/127399). The most studied and widely used method of breast tumour-grading is the Elston-Ellis modified Scarff, Bloom, Richardson grading system, also known as the Nottingham grading system (NGS). The NGS is based on a phenotypic scoring procedure that involves the microscopic evaluation of morphologic and cytologic features of tumour cells including degree of tubule formation, nuclear pleomorphism and mitotic count. The sume of these scores stratifies breast tumours into Grade I (G1) (well-differentiated, slow growing), Grade II (G2) (moderately differentiated), and Grade III (G3) (poorly-differentiated, hihgly proliferative) malignancies. Untreated patients with G disease have about a 95% five year survival rate whereas those with G2 and G3 have survival rates of about 75 and 50%, respecitively (WO 2008/048193).
Treatment:
One or more of a variety of treatments such as surgery, radiotherapy, chemotherpay and hormone therapy are used. The treatment course for a certain type of breast cancer is usually selected based on various prognostic parameters, for example, an analysis of specific tumor markers. For example, one factor considered in prognosis and treatment decisions for breast cancer is the presence or absence of the estrogen receptor (ER). ER-positive breast cancers typically respond better to hormonal therapies such as tamoxifen, which acts as an anti-estrogen breast tissue, than ER-negative cancers. A correlation between the expression of TLE3 (transducin-like enhancer of split 3) and a cancer’s response to chemotherapy has also been found. Binding of TLE3 antibodies in samples from treated ovarian cancer patients correlates with improved prognosis (US 2011/0015259).
Antibodies against the HER-2 protoongogene: The HER2 protooncogene encodes a 185-kDa transmembrane protein (p185HER2) with extensive homology to the epidermal growth factor (EGF) receptor. Clinical and experimental evidence supports a role for overexpression of the HER2 protooncogene in the progression of human breast, ovarian, and non-small cell lung carcinoma. The anti-p185HER2 murine monoclonal antibody (muMAb) 4D5 is one of over 100 monoclonals that was derived following immunization of mice with cells overexpressing p185HER2. The monoclonal antibody (see Herceptin below) is directed at the extracellular (ligand binding) domain of this receptor tyrosine kinase and presumably has its effect as a result of modulating receptor function. (Shepard J Clin Immunol. 1991 May;11(3):117-27.)
–HERCEPTIN® (Genetech Inc) is an antibody that has been used successfully to treat breast cancer. HERCEPTIN is a recombinant DNA derived humanized monoclonal antibody that selectively binds to the extracellular domain of the human epidermal growth factor receptor 2 (HER2) proto-oncogene. HER2 overexpression is observed in 25-30% of primary breast cancers. Perjeta (pertuzumab) (also from Genentech) is a monoclonal antibody/HER-dimerization inibitor that targets a diffferent epitope on the HER2 receptor than Herceptin and can be used in combination with Herceptin (trastuzumab) and Taxotere (docetaxel) for metastatic HER2/neu-overexpressing breast cancer. In a phase 3 Cleopatra trial, women who received the Perjeta-Herceptin-Taxotere combination achieved a 6.1 month improvement in pregression-free survival over those in the control group receiving Herceptin and Taxotere plus placebo.
A recombinant humanized version of the murine HER2 antibody 4D5 (huMAb4D5-8, rhuMab HER2, Trastuzumab or HERCEPTIN (see US5,821,337) is clinically active in patients with HER2 overexpressing metastatic breast cancers that have recieved extensive prior anti-cancer therapy (Baselga, J. Clin Oncol. 14 (1996) 737-744). Trastuzumab received marketing form the FDA in 1998.
Topoisomerase Inhibitors:
–Tradelvy (sacituzumab govitecan-hziy) (Gildead): is an injection for intravenous use. It is a Trop-2 directed antibody and topoisomerase inhibitor conjugate indicated fo teh treatment of adult patients with (i) unresectable locally advanced or metastatic triple-negative breast cancer (“TNBC”) who have received two or more prior systemic therapiies, at least one of them for metastatic disease, and (unresectble locally advanced or metastatic hormone receptor-positive, human epidermal growth factor receptor 2-ngative (“HRplus/minuus HER2-“) breast cancer who have recieved endocrine-based therapy and at least two additional systemic therapies in the metastatic setting.
Relapse:
Despite earlier diagnosis of breast cancer, about 1-5% with newly diagnosed breast cancer have a distant metastasis at the time of the diagnosis. In addition, about 50% of the patients with local disease who are primarily diagnosed eventually relapse with metastasis. 85% of these recurrences take place within the first 5 years after the primary manifestation of the disease. The most common site for distant metastasis is the bone followed by lung and liver. The median survival from the manifestation of distant metastases is about 3 years.