The importance of hormone status in breast cancer patients is because estrogen and progesterone are the key determinants of the therapy. Estrogen (ER) and progesterone (PR) can increase both normal and abnormal breast cell growth. Estrogen and progesterone receptors are highly predictive of breast cancer that will benefit from endocrine therapy. The ER is a nuclear receptor protein that has an estrogen-binding domain and a DNAbinding domain. The ER complex binds directly to the DNA and regulates the expression of other genes including the PR. The PR is a heterodimer encoded by a single gene (Rayter, 1991). ER and PR are specific receptors for estrogen and progesterone occurring in hormone-dependent organs, and can be expressed or over expressed in a variety of malignant tissue. Presently, Immunohistochemistry (IHC) routinely determines a tumor's ER/PR status. The prognostic characterization of breast cancer patients is generally and/or routinely done on clinico-pathological parameters such as stage, histology, grade on the residual tumor after surgery, this diagnosis appears to be inadequate, since patients with similar clinicopathological characteristics often experience different clinical outcome affecting their QOL. Only a few proven biomarkers of breast cancer progression were clinically useful (Pichon et al., 1996). Therefore, the identification of more biological biomarkers related to tumor aggressiveness could be relevant in order to identify patients with different prognosis to increase their chances to respond to chemotherapy. This allows selection for high-risk patients needing therapy that is more aggressive or alternative treatment at the time of initial diagnosis, and a closer follow-up of their QOL. The QOL of patients is now becoming a very important indicator of diagnosis that can be easily determined by using a structured questionnaire and analyzing the data statistically.

In addition, breast cancer affects women's identities and therefore studying quality of life in women who lose their breasts is vital. In addition, it is known that women play an important role in family, thus when a woman develops breast cancer all family members may have some sort of apprehensions to develop some illnesses. Thus, the matter of 'survivorship' has now become an important topic in breast cancer care that demands the investigation of long-term effects of breast cancer diagnosis and treat ment. Although several epidemiological and in vitro studies have demonstrated that, similar to endometrial cancer and ovarian cancer, cell biology appears to influence the biochemical pathways, promoted by the interaction of hormones with their specific receptors. Conflicting data about the possible clinical role of ER and PR in this neoplasm has been reported. Our earlier studies on the polymorphic genes in breast carcinomas (Kumar and Jamil, 2006; Kumar et al., 2007; Khan et al., 2007) indicated that these polymorphic sites are important with respect to progression of the disease, and the genotypes were useful indicators of dose- response to therapies (Suman and Jamil, 2006; Khan and Jamil, 2008). Among the biological parameters proposed as possible prognostic factors in breast cancer, focus is on endocrine factors, especially on steroid hormones and their receptors (Scambia et al., 1998).

The status ER and PR of breast cancer predicts a patient's response to clinical course like hormonal manipulation and select patients for adjuvant systemic therapy. However, there is controversy on the value of ER or PR status, separately, as prognostic indices and for their use in the selection of patients for adjuvant therapy (Clark et al., 1983). Predictive power enhances the ER and PR statuses when considered jointly. For example,tumors that are both ER⁺ and PR⁺ (approximately 70% of breast tumors) show better response to either additive or ablative endocrine therapy, whereas tumors which are ER^-PR^- show poorer response (approximately 10% of tumors) and tumors that are discordant for ER and PR show an intermediate response, irrespective of which receptor is positive (Wittliff, 1984).

In view of the conflicting results, we carried out investigations on hormonal (ER and PR) status in pre and post-menopausal breast cancer cases and objectively evaluated for prognostic biomarkers. In this retrospective study, we have also tried to determine and correlate the frequency of hormonal status and QOL in this group of patients, since it is becoming clear that the presence of the classical ER status is insufficient to recommend for anti-estrogen treatment and the absence of ER is not sufficient to recommend against anti-estrogen therapy.

Breast cancer cells that are ER⁺ depend on estrogen to grow,hence anti-estrogen hormonal therapy administered blocks the receptors or to reduce the amount of estrogen that can get to the receptors, so that the cancer cells may shrink or die. Our results showed that several post-menopausal women were ER⁺. As mentioned earlier hormone therapy was the initial treatment for metastatic breast cancer with ER/ PR positive tumors. Thus, tamoxifen- a non-steroidal anti-estrogen drug was the first choice for the patients who developed metastatic disease. More recently, two modern aromatase inhibitors like Anastrozol and Letrozol are used. These agents were more effective in postmenopausal women and are less toxic. Patients who did not respond to initial hormonal therapy were receiving chemotherapy mostly to cater for their QOL

Updates on the recent developments in this area show that the adrenal glands produce another hormone, which converts into estrogen, by the body. This estrogen can stimulate the tumor growth, and the women show ER⁺ status (even after menopause). Another exciting new hypothesis is that a new ER coded by a different gene identified. This ER is termed ERb, and expressed in normal breast and tumor tissue and reported to be up-regulated after 48 hours of estrogen treatment. Hence, the ER-b may help predict the tumor response to anti estrogen therapy.

Another hypothesis, which researchers have suggested, is that two enzymes like acetylase and deacetylase, alternately add or remove acetyl group at the receptor and thus affect the estrogen receptors and the hormone-binding proteins that bind to estrogens inside cells. However it is not yet clear how the modification of natural receptors and how an addition of acetyl group regulates the activity of receptors in response to estrogens. Our Database searches have provided us useful information for locating breast cancer genes spread over the chromosomal spectrum and their functional aspects ( Shanker et al., 2007; Khan and Jamil, 2008). This information has been of additional benefit in understanding the data of the multiple locations of the breast cancer genes.

Since breast carcinoma is a steroid hormone-dependent tumor it is obvious that sex steroid hormones, especially estrogen, play an important role in the development of breast cancer. Early menarche, late menopause, benign breast disease and hormone replacement therapy have been shown to be associated with increased risk for breast cancer (Trentham-Dietz et al., 1998). However, the role of progesterone in breast cancer development is still resistance factor. One hypothesis proposed to explain the parity effect is that hormonal stimulation by estrogen and progesterone induce a differential switch in a specific stem cell population that results in changes in the intracellular pathway governing proliferation and response to carcinogens. Hormone receptor status is one of the most important prognostic factors affecting the QOL for breast cancer patients. An increase in hormone receptor expression is associated with inhibition of cell proliferation and subsequently weakens tumorigenesis. ER+ tumors show a lower incidence of recurrence and a longer disease-free interval, regardless of tumor size or lymph node status (Suzuki et al., 2005). However, the prognostic value of PR status is controversial. It is important to take the PR status be taken into account with ER status because patients with both ER⁺ and PR⁺ tumors usually have a better prognosis than patients with ER⁺ and PR^- tumors.

When we compared the receptor status between pre and postmenopausal women, out of total 79 cases we found that 35.44% (25cases) were premenopausal and 64.55% (54 cases) were postmenopausal. We also found that 8.86% (7cases) in premenopausal and 12.65% (10cases) in postmenopausal were ER⁺/PR⁺ status. 15.18% (12 cases) in premenopausal and 29.11% (23cases) in postmenopausal were ER⁺/PR^- status. However we did not observe any cases in premenopausal women and only 1.26% (one case) in postmenopausal with ER^-/PR⁺ status, and 7.59% (6 cases) in premenopausal and 25.31% (20 cases) in postmenopausal were ER^-/PR^- status (Table 1).

The clinical and biologic tumor characteristics are summarized in Table 1. Overall, in women more than 45 years of age, ER ⁺ /PR ^- and ER^- and PR^- tumors were found more frequently than ER ⁺ /PR ⁺ tumors (82% versus 77% respectively; P <.001). However, ER ⁺ /PR ^- tumors were larger (greater than 2 cm in diameter) than ER ⁺ /PR ⁺ tumors (51% versus 45%, respectively. In addition, 21.51% and 17.72% of patients whose tumors were ER ⁺ /PR ^- and ER^-/PR^- had four or more axillary nodes involved with tumors compared to patients with 7.59% ER ⁺ /PR ⁺ tumors.

Previous studies reported that risk of ER+PR+ breast cancer is positively associated with nulliparity, a later age at first birth, a later age at menarche, and a higher body mass index (BMI; weight in kg/height in m2), but these factors were inversely related to the risk of ER^-PR^- tumors (Taucher et al., 2003; Giuffrida et al., 1992). These observations suggest that tumors subclassified by joint steroid receptor status may actually represent distinct forms of breast cancer with differing etiologies.Family history of breast or ovarian cancer nor medical radiation exposure to the chest did not relate to ER⁺PR⁺ tumors, yet both factors increased ER^-PR^- tumor risk. As age increased, the proportion of women with ER⁺PR⁺ tumors increased, and this finding corresponded primarily with a decline in the proportion of women diagnosed as having ER^-PR^- tumors. Recent data indicate that ER⁺PR^- disease is characterized by a lower response rate to estrogen deprivation, has a worse prognosis compared to ER⁺ PR⁺ disease, and may be dependent on other signaling pathways.

More features that are aggressive were the characteristics of ER⁺/PR^- tumors, common in older patients, compared to ER⁺/PR⁺ tumors. Incidence rates for ER⁺/PR⁺ and ER^-PR^- breast cancer differed by age and menopausal status. The influence of parity and past use of postmenopausal hormones differed between the two tumor types. Metastatic and adjuvant treatment determined that tamoxifen is less efficacious in ER ⁺ /PR^- tumors than in ER ⁺ /PR ⁺ tumors.

In this investigation, the cases were categorized into premenopausal and postmenopausal groups, 45 years of age being arbitrarily taken as the outer limit for premenopausal group. The choice of this was to reflect the fact that most women who were menstruating were < 45 years, whereas those > 45 years had either irregular / infrequent cycles or no menstruation. Out of 79 cases, overall 34.44% were premenopausal and 64.55% were postmenopausal. Further sub-classification of the cases was based on estrogen receptor status such as 15.18% cancers were premenopausal and 29.11% postmenopausal with ER⁺ / PR-ve, whereas 7.59% cases were premenopausal and 25.31% postmenopausal with ER^-/ PR-ve, and 8.86% cases were premenopausal and 12.65% postmenopausal with ER⁺/ PR +ve statuses. The frequencies of ER⁺/ PR^- and ER^-/PR^- receptors were higher in postmenopausal women. One possible explanation for this could be due to the levels of circulating estrogen and progesterone, occurring in this group at that time which influences the QOL of the patients suffering from breast cancer.

Women with tumors that are ER⁺PR⁺ have longer diseasefree and overall survival compared to those identified with ERPR negative cancers, while women with ER+PR- tumors show intermediate survival (McGuire et al., 1991). Although it has been concluded that ER⁺PR⁺ ("hormonally responsive") tumors and ER-PR negative tumors("hormonally unresponsive") represent two distinct tumor-types from a biological and clinical perspective (Thorpe et al., 1987). Tumors discordant for ER and PR status may represent additional profiles (Fuqua et al., 1993). Clinical data have shown that ER^-PR^- and ER⁺PR⁺tumors differ from each other in their natural history, their response to therapy, and their biological characteristics. In contrast, limited current evidence suggests that women with ER^-PR⁺ tumors appear to fit a profile which strongly resembles ER⁺PR⁺ tumors, and that these tumors may represent a subset of ER⁺PR⁺ tumors or be false negative for ER status (Fisher et al., 1980). A mutant ER may characterize some tumors with constitutive transcriptional activity (Montazeri et al., 2008). However, several aspects of this hormonal therapy are still puzzling, since there are a large number of ER⁺ breast cancer patients who do not respond to anti-estrogens. In addition, there are patients who initially respond to anti-estrogen therapies eventually acquire anti-estrogen resistance despite retention of ER in many tumor cells. Besides, there are some reports of ER negative patients who benefit from anti-estrogen treatments. These hormonal statuses also influence the survivability and QOL of patients.

Steroid hormone receptors have proven to be the most important predictive markers for selection of systemic treatment. This was clear in the selection of postoperative neoadjuvant chemotherapy, and endocrine treatment for premenopausal as well as postmenopausal patients (Enger et al., 2000). Assessment of systemic treatment were with respect to menopausal and receptor statuses. The premenopausal group (35%) and postmenopausal group (65%) received systemic chemotherapy. When systemic therapy was correlated to receptor status, it was observed that the status of the receptor had a significant impact on treatment choice for both premenopausal and postmenopausal patients. Chemotherapeutic agents were active in breast cancer when given in combination regimens often administered are FAC (Cyclophosphamide, Adriamycine, 5-FU) CMF (Cyclophosphamide, Methotrexate, 5-FU), CAF (Cyclophosphamide, Alurubicin, 5-FU). Our in-vitro studies on drug combinations determined the toxic effects of single versus combined effects of neoplastic drugs (Suman and Jamil, 2006). Another study suggests that Herceptin may be beneficial regardless of the ER/PR status 59.49% cases received FAC combination, and in this group 27.8% were satisfactory (6.3% premenopausal, and 21.5% postmenopausal). 8.8% showed good response (3.7% premenopausal, and 5% postmenopausal), and 22.78% cases showed poor response (15.18% premenopausal, and 7.59% postmenopausal). About 32.9% received CAF combination, and in this group 17.72% were satisfactory (6.3% premenopausal, and 11.39% postmenopausal), 8.8% cases showed good response (1.26% premenopausal, and 7.59% postmenopausal) and 8.8% showed poor response (1.26% premenopausal, and 7.59% postmenopausal). About 3.7% cases which received CMF combination, showed satisfactory response and all cases were premenopausal (Table 5).

Studies on QOL, have shown decreased health-related quality of life because of chemotherapy side effects, may predict early treatment discontinuation in patients On the other hand, some studies on post-treatment adjustment of breast cancer survivors have shown that breast cancer patients might enjoy from a good quality of life. In one study, patients reported poor social functioning following completion of breast cancer treatment. Similarly, studies have found that breast cancer survivors suffer from poor social functioning (Schou et al., 2005; Wefel et al., 2004).

Whether or not receptor status plays an important role as a predictive marker for response to chemotherapy is still an open question. In metastatic breast cancer, Lippman and Allegra, (1980) argued that patients with ER-negative tumors show a much better response rate than those with ER-positive tumors, although other authors did not confirm this data. In the adjuvant situation, chemotherapy appears more beneficial in receptor-negative patients. Furthermore, most of the functional scores did not improve over time and this is in contradiction to the findings from some existing literature (Engle et al., 2003; Engle et al., 2004).

Overall, we found that in postmenopausal women ER⁺/PRand ER^-/PR^- tumors were more frequent than ER⁺/PR⁺ tumors. However, ER⁺/PR^- tumors were larger than ER⁺/PR⁺ tumors. A recent study by Grann and coworkers (Grann et al., 2005) also suggested that the higher risks of mortality was in women with ER⁺/PR^-, ER^-/PR⁺, and ER^-/PR^- tumors, compared to women with ER⁺/PR⁺ tumors. Because hormone receptor status is known to vary by both stage and race, we also stratified this analysis by stage and by nodal status race. The results obtained in this study showed that there were wide ranges of therapy approaches employed by Oncologists in breast cancer therapy (purely the decision of the medical oncologist attending on the patient). The determinant factors correlated with menopausal status, patient's age and, were lower than expected to receptor status. Although hormonal therapy was of comparable efficacy to chemotherapy, but chemotherapy was associated with higher toxicity and lower quality of life (QOL). Engle et al (Engle et al., 2004) reported that their study also showed that overall breast cancer patients perceived benefit from their adjuvant treatment. However, sustained problems such as fatigue, pain, sleep disturbances and arm symptoms were prevalent which were very much similar to our findings. Indeed, management of these by targeted interventional programs is required. In addition, impaired body image, decreased sexual functioning and sexual enjoyment in patients, must be seriously considered in long-term survivors of breast cancer, to improve their overall quality of life. Chemotherapy seems to be preferred more frequently than hormonal therapy for receptor positive metastatic breast cancer. Although data on tumor characteristics may add information regarding treatment; the traditional pathological and morphological examination may be linked to the clinical behavior of tumors, but hormonal status is clearly important as predictive and prognostic factor for therapy. However, this study was limited due to its small cohort of breast cancer patients also there was a drop-outrate of nearly one third of patients during the follow-up courses

Conflict of Interest

The authors declare that they have no conflict of interest