Hormone therapy and estrogen receptor expression in breast cancer

Postmenopausal hormone therapy (HT) may increase breast cancer risk and influence tumor characteristics. We investigated 321 postmenopausal women aged 50-65 years, with breast cancer, diagnosed and treated at Radiumhemmet, Karolinska Hospital, during 1993-1997. In women using HT (n =90) estrogen receptor concentration (ER) at diagnosis were lower than in non-users (n =135) (1.17 vs 1.70 fmol/microg; p <0.05). HT users also had a tendency to less multifocal (5 vs 12%) (p <0.05) and metastatic disease (5% vs 2%) however this was not statistically significant. The estrogen receptor expression is always considered in the judgement on hormone dependency and the clinical decision on adjuvant endocrine therapy. A suppression of ER during HT could tentatively influence the treatment decisions in breast cancer patients and maybe disregard patients from endocrine treatment.     

Hormone receptor status influences the locoregional benefit of trastuzumab in patients with nonmetastatic breast cancer

BACKGROUND:

Previous studies have shown that hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status influence the outcome of locoregional treatments. However, the interrelationship of these factors with trastuzumab is unclear. In this study, the role of HR and HER2 status on the locoregional benefit of trastuzumab treatment was investigated in patients with nonmetastatic breast cancer.

METHODS:

Locoregional outcomes of 5683 women treated at The University of Texas MD Anderson Cancer Center from 2000 to 2008 for invasive breast cancer were analyzed using Kaplan‐Meier and Cox regression methods to compare 6 subgroups: HR‐positive (HR+)/HER2‐negative (HER2?), HR?/HER2? (triple‐negative), HR+/HER2+ with or without trastuzumab, and HR?/HER2+ with or without trastuzumab.

RESULTS:

Overall, locoregional recurrence (LRR) was 5% at 5 years among patients with HER2+ disease. Patients with HR+/HER2+ disease treated with trastuzumab had half the rate of LRR as patients who did not receive trastuzumab, whereas patients with HR?/HER2+ disease had similar rates of LRR regardless of trastuzumab treatment. On Cox regression analysis comparing LRR risk to the cohort with HR+/HER2? disease, only the HR+/HER2+ cohort treated with trastuzumab had similar LRR risk (hazard ratio = 1.24, 95% confidence interval = 0.56‐2.73, P = .591). All other subgroups, including the HR+/HER2+ cohort who did not receive trastuzumab, had significantly worse outcomes. LRR risk was highest among patients with triple‐negative disease (hazard ratio = 4.73, 95% confidence interval = 3.42‐6.54, P < .001).

CONCLUSIONS:

Among patients with HR+/HER2+ disease, treatment with trastuzumab reduces LRR risk to the more favorable outcome of patients with HR+/HER2? disease. In contrast, the increased LRR risk among patients with HR?/HER2+ disease remains despite treatment with trastuzumab. Additional locoregional strategies are needed in this subgroup of patients. Cancer 2012. © 2012 American Cancer Society.     

Hormone receptor status,tumor characteristics,and prognosis: a prospective cohort of breast cancer patients

Background  

Breast cancer patients with tumors that are estrogen receptor (ER)-positive and/or progesterone receptor (PR)-positive have lower risks of mortality after their diagnosis compared to women with ER- and/or PR-negative disease. However, few studies have evaluated variations in the risks of breast cancer-specific mortality across ER/PR status by either demographic or clinical characteristics.     

Hormone receptor status and pathologic response of HER2-positive breast cancer treated with neoadjuvant chemotherapy and trastuzumab

Background: The aim of this study was to compare the extent of pathologic response in patients with HER2-positive (HER2+) breast cancer treated with standard neoadjuvant chemotherapy, with or without trastuzumab (H), according to hormone receptor (HR) status.Patients and methods: We included 199 patients with HER2+ breast cancer from three successive cohorts of neo-adjuvant chemotherapy on the basis of paclitaxel (Taxol) (P) administered weekly (w) or three weekly (3-w), followed by 5-fluorouracil (F), doxorubicin (A) or epirubicin (E), and cyclophosphamide (C). Residual cancer burden (RCB) was determined from pathologic review of the primary tumor and lymph nodes and was classified as pathologic complete response (pCR) or minimal (RCB-I), moderate (RCB-II), or extensive (RCB-III) residual disease.Results: In HR-positive (HR+) cancers, a higher rate of pathologic response (pCR/RCB-I) was observed with concurrent H + 3-wP/FEC (73%) than with 3-wP/FEC (34%, P = 0.002) or wP/FAC (47%; P = 0.02) chemotherapy alone. In HR-negative (HR-) cancers, there were no significant differences in the rate of pathologic response (pCR/RCB-I) from 3-wP/FAC (50%), wP/FAC (68%), or concurrent H + 3-wP/FEC (72%).Conclusions: Patients with HR+/HER2+ breast cancer obtained significant benefit from addition of trastuzumab to P/FEC chemotherapy; pathologic response rate was similar to that seen in HR-/HER2+ breast cancers.     

Hormone receptor status and survival in a population-based cohort of patients with breast carcinoma

BACKGROUND: The objective of this study was to assess hormone receptor status as an independent predictor of survival in a population-based cohort of women with breast carcinoma who were followed for up to 11 years. METHODS: Since 1990, the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program has collected data on hormone receptor status among patients with breast carcinoma. In a cohort of 205,736 women with breast carcinoma age > or = 20 years at diagnosis who were entered into the SEER data base between 1990 and 2000, the authors analyzed the association of hormone receptor status with year of diagnosis, patient age, disease stage, tumor histology, tumor grade, race/ethnicity, and metropolitan/statewide residence areas. Kaplan-Meier survival curves were compared according to hormone receptor status, and Cox proportional-hazards regression models were used to assess the association of hormone receptor status with breast carcinoma-specific and all-cause mortality controlling for age, disease stage, tumor grade, tumor histology, race/ethnicity, and SEER region. RESULTS: Women who had tumors that were positive for both estrogen and progesterone hormone receptors had significantly better survival than other women with breast carcinoma in the overall cohort, within each stage, and in the younger and older age groups, although the survival advantage was greater among women age < or = 50 years than among older women. Hormone receptor status was associated with mortality even when patient age, disease stage, tumor grade, tumor histology, race/ethnicity, and metropolitan/statewide residence areas were taken into account. CONCLUSIONS: Hormone receptor status was identified as an independent predictor of outcome in women with breast carcinoma. Data from clinical trials with long follow-up may shed light on whether and how the benefit of hormonal and other treatment varies with hormone receptor status.     

Hormone receptor status of a contralateral breast cancer is independent of the receptor status of the first primary in patients not receiving adjuvant tamoxifen.

PURPOSE: To determine whether the hormone receptor status of the primary breast cancer (PBC) is predictive of the hormone receptor status of the subsequent contralateral breast cancer (CBC). PATIENTS AND METHODS: We identified patients in our database with known estrogen receptor (ER; n = 193) and/or progesterone receptor (PgR; n = 178) status in their PBC and in their subsequent CBC. One hundred twenty-six of these patients had received no adjuvant therapy, 34 had received adjuvant tamoxifen, and 33 had received adjuvant chemotherapy alone. The median interval between the first diagnosis of PBC and the development of the subsequent CBC was 3 years. ER and PgR assays were assessed biochemically in two central reference laboratories using identical quality-controlled ligand-binding methods. RESULTS: Among systemically untreated patients (n = 126), 88% of patients with ER-positive PBC and 75% of patients with ER-negative PBC developed an ER-positive CBC (P = .11). Among the tamoxifen-treated patients, those with an ER-positive PBC were almost equally likely to develop an ER-positive (47%) or ER-negative (53%) CBC (P = .99). PgR status was similar. In the untreated group (n = 112), 59% of patients with a PgR-positive PBC and 66% with a PgR-negative PBC developed a PgR-positive CBC (P = .48). Among tamoxifen-treated patients (n = 33), 50% of patients with a PgR-positive PBC versus 27% of patients with a PgR-negative PBC developed a PgR-positive CBC (P = .28). CONCLUSION: ER and PgR status of the primary tumor does not predict the hormone receptor status of the subsequent CBC in the absence of selective pressure of adjuvant therapy. Thus, other reasons should be considered to clarify the failure of tamoxifen to reduce the incidence of CBC in patients with a receptor-negative PBC.     

Hormone therapy and breast cancer

The nuclear estrogen receptors (ER) are the major targets for endocrine treatment of hormone-dependent breast cancers. Hormone therapy blocked endogenous estrogen activation of ER, either by competitive inhibition of endogenous estrogens (selective estrogen receptor modulators – SERM or selective estrogen receptor down regulators – SERD) or by inhibition of estrogen synthesis (aromatase inhibitors) from adrenal androgens in post-menopausal women. The efficacy of these treatments has been shown on large series of breast cancer patients. However de novo or acquired resistance to treatment occurs. The better knowledge of the mechanism of action of such treatment may help to better understand them, and also for the determinism of adverse side effects of the different class of molecules.     

Variation of receptor status in cancer of the breast

One hundred and nineteen patients with breast cancer had 2 or more lesions removed for oestrogen (REc) or progesterone receptor (RPc) assay, either synchronously (on 38 occasions) or after an interval (on 91 occasions). In all but 7 both receptors were assayed for each lesion. The assays did not agree on the presence or absence of REc alone, RPc alone or the combination of both receptors in 11, 13 and 16% respectively of the synchronous samples, compared with 23, 30 and 43% of the asynchronous samples. The differences between the synchronous and asynchronous samples were significant for the combined receptors (P = 0.007) but not for REc (P = 0.176) or RPc alone (P = 0.077). Variation between asynchronous biopsies was greater when the earlier lesion contained RPc (18/37 disagreed) than when it did not (8/50) disagreed, P = 0.0023). This was not true for oestrogen receptor. In those remaining receptor positive there was only a weak correlation between the first and second values (Spearman rank correlation coefficient, rho = 0.39 for REc, P less than 0.02, and 0.45 for RPc, 0.05 less than P less than 0.1). Receptor levels and receptor status may change with time. Biopsy is most appropriate at the time when systemic treatment is proposed.     

Dysregulated PTEN-PKB and negative receptor status in human breast cancer

Recent studies demonstrate that abnormalities in PTEN may be one of the most frequent genetic events observed in human cancers. PTEN dysfunction leads to tumorigenesis through unopposed survival signals mediated via activated protein kinase B (PKB), which may also be associated with hormone-independence. We therefore investigated the relationship between PTEN-PKB and receptor status in human breast cancer. Several molecular variables, including immunohistochemical staining for PTEN, PKB (phosphorylated on ser473), p53 and p21 were evaluated. The p53 gene was sequenced from exons 2-11. Seventy-eight participants in a randomised breast cancer trial served as the cohort for our study. Twenty-eight of 77 (36%) patients' tumours demonstrated absent or reduced PTEN expression; 17 of 78 (22%) tumours over-expressed P-PKB. A significant inverse relationship was observed between reduced PTEN and increased P-PKB expression. Reduced PTEN also correlated with reduced ER or PR expression. None of the molecular variables correlated with survival. ER and PR negative tumours, however, experienced a significantly inferior disease-free survival than other ER/PR status tumours. Immunohistochemical analyses of ER expression in mammary carcinomas arising in PTEN heterozygous knockout mice did not demonstrate a reduction in ER immunoreactivity, in comparison to wild-type mice. Our data demonstrate that the PTEN-PKB pathway is abnormal in approximately 1/3 of lymph node negative breast cancer. Dysregulated PTEN-PKB was also associated with reduced ER/PR expression, but this does not appear to be a simple direct causal relationship. These observations support the contention that dysregulation in PTEN-PKB contributes to disease progression and hormone resistance of human breast cancer.     

Hormone supplemented media for cloning human breast cancer: increased colony formation without alteration of chemosensitivity

We tested the ability of hormones and growth factors to enhance the colony formation in soft agarose of breast carcinoma using two human breast carcinoma cell lines, MCF-7 and MDA-MB231, MCF-7 could clone in a basal medium supplemented only by insulin, transferrin, prostaglandin F2 alpha, and fibronectin. Combining oestradiol, dexamethasone, insulin, transferrin, and triiodothyronine with a basal medium supplemented with 5% (v/v) foetal bovine serum (FBS) increased colony forming efficiency (CFE) two-to three-fold over the best obtained in serum supplemented medium without hormones. While optimal CFE was seen in the hormonally supplemented medium plus 5% FBS, clonal anchorage independent growth could also be obtained without serum for both cell lines by substituting 0.5-1% (v/v) bovine serum albumin (BSA) for FBS. Although CFE was enhanced with the addition of hormones, they did not substantially alter the in vitro chemosensitivity patterns of the cell lines to 8 cytotoxic drugs. Hormonally-supplemented medium with 5% FBS increased the CFE of a small number of fresh specimens of human breast cancer compared with medium supplemented with serum alone. The systematic study of requirements for the in vitro growth of human breast cancer may improve drug sensitivity testing by increasing our ability to grow this neoplasm in culture.