Breast cancer clinical presentation

The measurement of ER has become a standard assay in the clinical management of breast cancer. The presence of ERa identifies those breast cancer patients with a lower risk of relapse and better clinical outcome. Receptor status also provides a guideline for those tumors that may be responsive to hormonal intervention. But only about half of ER-positive patients respond to hormonal therapies. Of those who respond initially, most will eventually develop an estrogen unresponsive disease following a period of treatment even though ERa is often still present. Mutant receptors and constitutively active r eceptors as well as hormone-independent activation of the ERa are discussed. The involvement of ER 3 isoforms is under investigation. 

The human PR exists as two functionally distinct isoforms PRA and PRB transcribed from two promoters from a single gene. PRA lacks the N-terminal 164 aa and is a 769 aa protein. PRB functions as a transcriptional activator in most cell and promoter contexts. In contrast, PRA is transcriptionally inactive and functions as a strong ligand-dependent transdominant repressor of SHR transcriptional activity. Different cofactor interactions were demonstrated for PRA and PRB, probably due to an inhibitory domain within the first 140 aa of PRA, which is masked in PRB. Both PR isoforms however, repress estradiol-induced ER activity when liganded. Several other mRNA isoforms are present in PR-positive tissues such as breast cancer with unknown clinical significance. 

A 36-year-old woman who has been in good health presents to your clinic complaining of constipation and abdominal pain. She explains to you that she has been feeling stressed lately because her 40-year-old sister is undergoing chemotherapy for breast cancer, and they just lost there mother to ovarian cancer a few years ago. 

At present, the only SERMs routinely used in clinical practice are tamoxifen and raloxifene. Tamoxifen is used essentially as adjuvant treatment in women with breast cancer. Its use is related to estrogenic effects on the uterus. Specifically, tamoxifen can be associated with an increase not only in endometrial hyperplasia and cancer risk but also in uterine leiomyoma dimensions and in a risk of developing active endometriotic lesions. 

Currently, anastrozole and letrozole are efficacious in early-stage, locally advanced, and mefasfafic disease and fhus they present with the most complete data set for the different stages of breast cancer. Although it seems rather unlikely that one will be able to detect differences with respect to clinical effects at the tumour level, the indirect comparison of different AIs suggests a stronger evidence for the use of exemestane compared with other AIs for breast cancer therapy [90]. 

In Section 3.2.2 we presented data from a clinical trial comparing trastuzumab to observation only after adjuvant chemotherapy in HER2-positive breast cancer. The incidence rates in the test treatment and control groups were respectively 7.0 per cent and 4.7 per cent. 

One of the earliest examples of predicting efficacy has come from studies of breast cancer, where anti-estrogen therapy is clearly effective in patients whose tumors express the estrogen receptor, and ineffective when no such receptors are present. However, even in this well-studied case, current consensus statements recognize an intermediate endocrine response uncertain state, where the exact boundary between endocrine responsive and endocrine response uncertain is undecided, and may well be different in different clinical settings (19). 

Tamoxifen is beneficial in postmenopausal women when used alone or when combined with cytotoxic chemotherapy. The present recommendation is to administer tamoxifen for 5 years of continuous therapy after surgical resection. Longer durations of tamoxifen therapy do not appear to add additional clinical benefit. Results from several randomized trials for breast cancer have established that adjuvant chemotherapy for premenopausal women and adjuvant tamoxifen for postmenopausal women are of benefit to women with stage I (node-negative) breast cancer. While this group of patients has the lowest overall risk of recurrence after surgery alone (about 35-50% over 15 years), this risk can be further reduced with adjuvant therapy. 

A key clinical classification of breast cancer tumors is estrogen receptor (ER) expression. The more ERs are present on tumor cells, the more likely an anti-estrogen therapy such as tamoxifen can be successfully applied. Classification of each tumor is important, as only about 60%) of breast cancers are ER-positive. Initial studies set out to demonstrate that breast cancers with distinct pathological features could be separated by microarrays. Several groups demonstrated that supervised data analysis could be used to distinguish ER-positive from ER-negative tumors (74—76). 

Breast cancer is the most frequendy found cancer in women, with approximately 176,300 new cases and 43,700 deaths in the United States in 1999 (Landis et al., 1999). Present therapies for breast cancer achieve meaningful clinical results in only 30 to 40% of padents, with response duration usually limited to 12 to 18 months (Dickson and Lippman, 1987 Horwitz and McGuire, 1978 Mouridsen et al., 1978 Wakeling, 1993). Five-year survival in women with metastatic disease is still only 10 to 40%. 

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