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.     

Benefit from adjuvant tamoxifen therapy in primary breast cancer patients according oestrogen receptor, progesterone receptor, EGF receptor and HER2 status.

BACKGROUND: Most women with oestrogen receptor (ER) positive primary breast cancer receive adjuvant tamoxifen after surgery. The measurement of tumour biomarkers should allow better selection of patients for such treatment or for therapies such as aromatase inhibitors. PATIENTS AND METHODS: Histopathological blocks of primary breast cancer patients who had been randomized to receive 2-years tamoxifen or no adjuvant therapy in two mature randomised clinical trials were retrieved. Immunohistochemical staining for ER, progesterone receptor (PgR), HER2 and epidermal growth factor receptor (EGFR) was undertaken. The primary endpoint was relapse free survival. RESULTS: 813 patients were included in the study. Benefit from tamoxifen was seen in ER-positive patients [Relative risk (rr) 0.77, ci 0.63-0.93]. ER-negative patients also showed a strong trend to benefit from tamoxifen (rr 0.73, ci 0.52-1.02) which was largely confined to the PgR-positive group. Amongst the ER-positive group, PgR-positive and PgR-negative patients showed similar benefit (rr 0.81; ci 0.65-1.02 and 0.70; ci 0.49-0.99, respectively). Patients positive for HER2 did not benefit significantly (rr 1.14; ci 0.75-1.73) but this group was small. CONCLUSIONS: Measurement of PgR status in ER-negative patients defines a group of patients that benefit from tamoxifen but would be excluded from tamoxifen therapy on the basis of ER status alone. The data are consistent with HER2 positive tumours being resistant to tamoxifen.     

Prognostic value of hormone receptors in breast cancer

The aim of this study was to establish the role of estrogen receptor (ER) and progesterone receptor (PgR) as prognostic indicators for early recurrence and survival. In all, among breast cancer patients, 166 patients who had undergone radical or extended radical mastectomy were studied. These patients were treated with adjuvant chemotherapy alone for 2-3 years after surgery. No patients had adjuvant endocrine therapy. Local recurrence and/or distant metastases were treated by endocrine therapy and/or chemotherapy. The relapse-free interval was not different between the ER-positive and ER-negative patients. The postrelapse survival curve was significantly different between the two groups. There was no significant difference in the relapse-free interval and the postrelapse survival curve between the PgR-positive and PgR-negative patients. These results suggest that ER is a good predictor of the response to endocrine therapy given after relapse, but not of early recurrence.     

Distribution of estrogen and progesterone receptors in primary tumor and lymph nodes in individual patients with breast cancer

Primary breast cancer tissue and lymph nodes were obtained from 48 patients. Estrogen receptors (ER) and progesterone receptors (PgR) were determined by a dextran-coated charcoal assay. ER were present in 72.9% of the primary tumors and in 62.4% of the malignant lymph nodes, whereas PgR were present in 73.0% and 50.0% of the cases, respectively. The primary tumor and the corresponding malignant lymph nodes showed an identical ER and PgR status, i.e., both tumor sites were receptor positive or both receptor negative in 89.6% and 77.1%, respectively. However, 10.4% of the patients had ER-positive tumors but ER-negative lymph nodes and 22.9% had PgR-positive primaries with PgR-negative lymph nodes. No receptor-positive lymph nodes showed a combination with receptor-negative primary tumor. This preliminary data shows that receptor-positive malignant lymph nodes mostly display the same receptor status as the corresponding primary tumor, whereas receptor-negative lymph nodes may have a receptor-positive primary tumor.     

Hormone receptors and disease-free survival in breast cancer: impact of increasing threshold levels

Laboratory data from Milan and Houston were evaluated to determine the extent to which the distribution of estrogen receptor (ER) and progesterone receptor (PgR) has changed with time. Results from over 11,500 ER and over 8,200 PgR determinations (6,194 ER and 3,127 PgR from Milan) were analyzed. All assays in Milan were performed by a dextran-coated charcoal method and in Houston by a sucrose density-gradient method. The data demonstrate a time-dependent, upward drift in the amount of ER and PgR detected, with the effect most pronounced at the lower end of the distribution curves. We attribute this change to optimization of all facets of the receptor assay procedures (tissue harvesting and storage) as well as to a change in breast cancer biology. These results suggest that studies correlating certain biological parameters with receptor status (whether using qualitative or quantitative scales) need to be re-examined. For example, a population of 349 node-negative patients who did not receive any adjuvant treatment was studied in Milan to determine any association between disease-free survival (DFS) and receptor status. If the "historical" threshold values (10 fmol/mg protein) were used to determine receptor status, no significant difference in DFS at 5 years was detected. Even the combination of ER and PgR did not improve the predictive power of receptor status. In the premenopausal subgroup, ER status did predict the 5-year DFS. However, if the threshold value for PgR was adjusted to 25 fmol/mg protein, patients with ER-positive, PgR-positive tumors had significantly better 5-year DFS than patients with ER-negative, PgR-negative tumors. In addition, PgR status alone was associated with significantly improved 3-year DFS if the subgroups of PgR less than 5 fmol/mg protein and PgR greater than 100 fmol/mg protein were compared. We conclude from these data that: 1) historical threshold values for receptor positivity should be re-examined in all laboratories; 2) studies involving receptor results determined over an extended period of time should attempt to "normalize" these results; and 3) the quantitative assessment of receptor status should be used whenever possible.     

Tumor-proliferative activity, progesterone receptor status, estrogen receptor level, and clinical outcome of estrogen receptor-positive advanced breast cancer

The relations among pretreatment tumor-proliferative activity, progesterone receptor (PgR) status, estrogen receptor (ER) level, and clinical outcome were analyzed in a series of 45 ER-positive advanced breast cancer postmenopausal women treated with tamoxifen (20 mg/day) until disease progression. Tritiated thymidine ([3H]dThd) Labeling Index (LI) by autoradiographic assay was utilized for proliferative activity analysis, whereas the dextran-coated charcoal method was used for ER and PgR evaluation (cutoff value, 10 fmol/mg of protein cytosol). The median [3H]dThd LI value was 1.8%; 73% of cases were PgR positive, and 53% were highly ER positive (greater than 100 fmol/mg of protein cytosol). Clinical responses were more frequently observed in slowly than in quickly proliferating tumors (86% versus 60%; P less than 0.05) but were similar for PgR-positive and -negative cases, as well as for those with high and low ER positivity. Only [3H]dThd LI was found to individualize patients with different survival rates (at 40 mo of follow-up, 78% versus 40% in slowly and quickly proliferating tumors, respectively). The [3H]dThd LI, monitored in ten patients by a second tumor biopsy after 14 days of tamoxifen therapy, was found to have a significantly lower median value (P = 0.03). These data indicate that pretreatment [3H]dThd LI provides information, which is not available in a study of PgR and ER status, on the clinical outcome of ER-positive advanced breast cancer patients treated by hormone therapy.     

Immunohistochemical evaluation of hormone receptor status for predicting response to endocrine therapy in metastatic breast cancer

BACKGROUND: The importance of establishing hormone receptor status of tumors for the treatment of women with hormone receptor-positive breast cancer has been emphasized, however, there is no general agreement as to how immunohistochemical assays should be evaluated. It is critical to evaluate hormone receptor status when considering response to endocrine therapy. METHODS: Estrogen receptor (ER) and progesterone receptor (PgR) expression was examined by immunohistochemistry using Allred's score for primary breast tumors from 75 metastatic breast cancer patients who received first-line treatment with endocrine therapy (56 patients received tamoxifen, 11 patients received aromatase inhibitors, and 8 patients received LH-RH agonist or other endocrine reagents) on relapse. Correlation between hormone receptor status and response to endocrine therapy as well as post-relapse survival was analyzed. RESULTS: The most significant correlation between positive ER expression and response to any endocrine therapy (p = 0.011) or tamoxifen only (p = 0.030) occurred when the cutoff score was set at 10%. When the evaluation was based on Allred's score (TS), a cutoff point of TS>or=4 showed a more significant association between positive ER expression and response to all kinds of endocrine therapy (p = 0.020) or tamoxifen only (p = 0.047). When evaluated at a cutoff point of 1% positive cells, there were fifteen patients with both ER- and PgR-negative tumors, and three patients (20.0%) responded to the therapy. Patients with 1% or more ER or PgR positive cells had better survival after relapse (p = 0.0005 and p = 0.0008, respectively). CONCLUSIONS: The proportion score alone might be enough to predict hormone responsiveness and post-relapse survival in metastatic breast cancer. The cutoff might be set low, for example 1%, especially for metastatic disease.     

Measurement of steroid hormone receptors in breast cancer patients on tamoxifen

Summary Estrogen (ER) and progesterone receptor (PgR) positive breast tumors often respond to tamoxifen, but ultimately progress as they become tamoxifen resistant. An accurate assessment of receptor status in specimens from tamoxifen-resistant patients could help to understand potential mechanisms of resistance and to predict response to second line hormonal therapies. However, since tamoxifen itself can affect ER and PgR determinations, assay results can be misleading. We measured ER and PgR by both ligand binding (LBA) and immunohistochemical (IHC) assays in 34 tumors from patients on tamoxifen, 30 of whom were displaying resistance to the drug. These tumors were classified into several receptor phenotypes. Eleven patients, 8 of whom were clearly progressing, expressed both receptors while on tamoxifen. ER was significantly less often negative when measured by IHC, suggesting that ER status by LBA was falsely negative in this group due to receptor occupancy by tamoxifen. Six patients had no detectable ER by LBA or IHC but still expressed PgR. The presence of PgR suggests that ER could still be functional, though undetectable, in these tumors, or that PgR is constitutively expressed by them. Finally, 12 patients were ER and PgR-negative by both assays, suggesting hormonal independence as the mechanism for resistance in this group. In a subset of patients with receptor assays both prior to tamoxifen and at the time of progression while taking the drug, we found that most ER-positive tumors converted to an apparent ER-negative status when assayed by LBA, while PgR status frequently remained unchanged. The continued expression of ER and/or PgR in many patients with tumor progression on tamoxifen indicates that mechanisms for resistance other than receptor loss are common in breast cancer.Deceased     

Which threshold for ER positivity? a retrospective study based on 9639 patients

BackgroundGuidelines for the use of chemotherapy and endocrine therapy recently recommended that estrogen receptor (ER) status be considered positive if ≥1% of tumor cells demonstrate positive nuclear staining by immunohistochemistry. In clinical practice, a range of thresholds are used; a common one is 10% positivity. Data addressing the optimal threshold with regard to the efficacy of endocrine therapy are lacking. In this study, we compared patient, tumor, treatment and survival differences among breast cancer patients using ER-positivity thresholds of 1% and 10%.MethodsThe study population consisted of patients with primary breast carcinoma treated at our center from January 1990 to December 2011 and whose records included complete data on ER status. Patients were separated into three groups: ≥10% positive staining for ER (ER-positive ≥10%), 1%–9% positive staining for ER (ER-positive 1%–9%) and <1% positive staining (ER-negative).ResultsOf 9639 patients included, 80.5% had tumors that were ER-positive ≥10%, 2.6% had tumors that were ER-positive 1%–9% and 16.9% had tumors that were ER-negative. Patients with ER-positive 1%–9% tumors were younger with more advanced disease compared with patients with ER-positive ≥10% tumors. At a median follow-up of 5.1 years, patients with ER-positive 1%–9% tumors had worse survival rates than did patients with ER-positive ≥10% tumors, with and without adjustment for clinical stage and grade. Survival rates did not differ significantly between patients with ER-positive 1%–9% and ER-negative tumors.ConclusionsPatients with tumors that are ER-positive 1%–9% have clinical and pathologic characteristics different from those with tumors that are ER-positive ≥10%. Similar to patients with ER-negative tumors, those with ER-positive 1%–9% disease do not appear to benefit from endocrine therapy; further study of its clinical benefit in this group is warranted. Also, there is a need to better define which patients of this group belong to basal or luminal subtypes.     

The relationship between hormone receptor content and the effect of adjuvant tamoxifen in operable breast cancer

The relationship between hormone receptor status and the effect of adjuvant tamoxifen in early breast cancer remains controversial. This article presents the results of a randomized trial of adjuvant tamoxifen (40 mg daily for 2 years) versus no adjuvant endocrine therapy in postmenopausal patients. During 1976 to 1984, 1,407 patients were included in the study. Of these, 427 (30%) had high-risk tumors (pN + or pT greater than 30 mm) and were included in a concurrent randomized comparison of postoperative radiotherapy versus adjuvant polychemotherapy. The mean follow-up time was 61/2 years. Tamoxifen improved the recurrence-free survival (RFS) (P less than .01), but the overall survival difference in favor of the tamoxifen-allocated patients was not significant. Data on estrogen (ER) and progesterone receptor (PgR) content were available in 750 patients. Their mean follow-up time was 41/2 years. The effect of tamoxifen was significantly related to ER level (P less than .01). No benefit with tamoxifen was observed among ER-negative patients. The relation to PgR level was of borderline significance (P = .06). Multivariate analysis indicated that most of the interaction between treatment and receptor content was explained by the interaction with ER (P less than .01). The PgR status appeared to modify the effect of tamoxifen among the ER-positive patients and the greatest effect was observed among patients who were positive for both receptors. However, the additional predictive information provided by the PgR assay did not help to identify an unresponsive subgroup of patients.     

Patterns of recurrence of early breast cancer according to estrogen receptor status: a therapeutic target for a quarter of a century

The current therapeutic strategy in breast cancer is to identify a target, such as estrogen receptor (ER) status, for tailoring treatments. We investigated the patterns of recurrence with respect to ER status for patients treated in two randomized trials with 25 years’ median follow-up. In the ER-negative subpopulations most breast cancer events occurred within the first 5–7 years after randomization, while in the ER-positive subpopulations breast cancer events were spread through 10 years. In the ER-positive subpopulation, 1 year endocrine treatment alone significantly prolonged disease-free survival (DFS) with no additional benefit observed by adding 1 year of chemotherapy. In the small ER-negative subpopulation chemo-endocrine therapy had a significantly better DFS than endocrine alone or no treatment. Despite small numbers of patients, “old-fashioned” treatments, and competing causes of treatment failure, the value of ER status as a target for response to adjuvant treatment is evident through prolonged follow-up.     

Relative effect of steroid hormone receptors on the prognosis of patients with operable breast cancer. A univariate and multivariate analysis of 3089 Japanese patients with breast cancer from the Study Group for the Japanese Breast Cancer Society on Hormone Receptors and Prognosis in Breast Cancer.

In a retrospective multicenter study to investigate the correlation between estrogen (ER) and/or progesterone receptors (PgR) in primary breast cancer with patient prognosis, 3118 patients with operable breast cancer (International Union Against Cancer Stages I, II, and III) were investigated from ten hospitals in Japan who underwent surgery from October 1972 to December 1982; 3089 were evaluable. The ER-positive and PgR-positive cancers were found in 56% and 34% of patients, respectively. The positivities decreased as the tumor size increased but were independent on lymph node metastasis. There were no significant differences in relapse-free survival (RFS) in relation to receptor status (median follow-up, 89 months [ER], 84 months [PgR]). However, in patients with four or more positive nodes, those with PgR-positive cancer had a longer RFS. The patients with ER-positive cancer survived significantly longer than ER-negative ones, with the greatest difference seen in those with four or more positive nodes. There was a significantly longer postrelapse survival (PRS) for patients with ER-positive cancer because of the different distribution of the major metastasis and better responses to first-line and subsequent treatments. Cox's multivariate analysis showed that overall survival but not PRS was affected by ER (and more weakly by PgR) because of the longer PRS in patients with ER-positive cancer.     

Comparative study of estrogen receptor assays between immunocytochemical assay using monoclonal antibody and the dextran- coated charcoal method

Estrogen receptor (ER) was measured by the estrogen receptor-immunocytochemical assay (ER-ICA) using monoclonal antibody in 36 mammary carcinomas. Simultaneously, ER and progesterone receptor (PgR) were measured by the dextran coated charcoal (DCC) method. In ER-ICA, tumor cells with estrogen receptors were histologically observed. The proportion of ER-positive tumor cells among tumor tissues and the levels of staining intensity were also examined. Results were compared to those obtained by the dextran coated charcoal (DCC) method. Tumors were evaluated as ER-ICA-positive when they contained more than 10% ER-positive cells. ER at a level of more than 5.0 fmol/mg protein was evaluated ER-positive and PgR at more than 5.0 fmol/mg protein as PgR-positive by the DCC method. Twenty-one out of 24 ER-ICA-positive tumors were ER-positive by the DCC method, and 11 out of 12 ER-ICA-negative tumors were ER-negative by the DCC method. Correlation of ER-ICA and ER by the DCC method was 88.9%. There were 11 PgR-positive tumors, and all were included among ER-ICA-positive tumors which had a high proportion of ER-positive cells and high staining intensities.     

Steroid hormone receptor activity of primary human breast cancer and pattern of first metastasis

Summary A series of 258 breast cancer patients with known estrogen receptor (ER) status of the primary tumour who subsequently developed metastases were reviewed for site of first metastasis. In 188 cases progesterone receptor (PgR) data were also available.Univariate analysis showed metastatic patterns to differ statistically significantly related to ER status and (less pronounced) PgR status of the primary tumour. Patients with ER-positive tumours had bone metastases three times more often than patients with ER-negative tumours. With respect to PgR-positive and PgR-negative tumours this frequency differed by a factor of two. With regard to visceral metastases ER and PgR status were equally potent prognosticators, patients with receptor negative tumours having a 50% higher frequency of visceral metastasis than patients with receptor positive tumours. Assessment of metastatic patterns in relation to combined receptor status did not substantially enhance the discriminatory value of ER and PgR when assessed separately.Multivariate analysis showed that the observed differences in metastatic patterns were all attributable to differences in the ER status of the primary tumour, and were not influenced by age, menopausal status, axillary lymph node involvement, duration of disease-free interval (DFI), mode of postoperative treatment, or the PgR status of the primary tumour.Including the Departments of Surgery (Th. Wobbes, R.F. v.d. Sluis), Radiotherapy (W.A.J. v. Daal), Pathology (R. Holland), Radiology (J.H.C.L. Hendriks), and Medical Oncology (D. Wagener)     

Human breast cancer: survival from first metastasis

Summary Survival from the detection of first metastasis (SAM) was analyzed in a single center series of 258 patients with advanced breast cancer. During the 15 year period covered by this study 230 patients died, 215 of their disease. The overall median SAM was 28 months.Univariate analysis of SAM stratified by first dominant site of metastasis, estrogen receptor status (ER), progesterone receptor status (PgR), tumor size, axillary lymph node status, patient age, menopausal status, and disease-free interval (DFI) showed the first dominant site of metastasis, ER, PgR, and axillary lymph node status to be significantly associated with SAM. Patients with visceral metastasis as first dominant site of metastasis had significantly shorter survival than those with either bone or soft tissue metastasis, median SAM 16 vs. 34 vs. 41 months respectively (P<0.001). SAM also differed according to the steroid hormone receptor status of the primary tumor: median SAM 34 and 33 months for patients with ER-positive or patients with PgR-positive tumors against 14 months for patients with ER-negative or with PgR-negative tumors (P<0.001). Patients with axillary lymph node involvement at primary disease had a shorter SAM than those without, median SAM 24 vs. 35 months (P=0.006). No association between SAM and either tumor size, patient age, menopausal status, or DFI could be observed.Multivariate analysis including first dominant site of metastasis, ER, PgR, and axillary lymph node status showed the first dominant site of metastasis, ER, and axillary lymph node status to be independently associated with SAM.including the Departments of Surgery (Th. Wobbes, R.F. v.d. Sluis), Radiotherapy (W.A.J. v. Daal), Pathology (R. Holland), Radiology (J.H.C.L. Hendriks) and Medical Oncology (D. Wagener)     

Epidermal growth factor receptor-negative tumors are predominantly confined to the subgroup of estradiol receptor-positive human primary breast cancers

A total of 725 human primary breast tumor biopsy samples were analyzed for epidermal growth factor receptor (EGFR) content, using a multiple-point EGFR assay standardized in accordance with the recommendations of the European Organization for Research and Treatment of Cancer Receptor Study Group. After the establishment of a lower cell membrane protein threshold of 0.2 mg of membrane protein per ml of assay buffer, the results of 27% (194 samples) of the EGFR determinations were excluded from the study because of insufficient assay membrane protein content. Of the remaining 531 breast tumor biopsy samples, 57% (302 samples) were shown to be EGFR positive by Scatchard analysis, with a median value of 40 fmol/mg of membrane protein. Of the breast tumor biopsy samples, 72% (380 samples) were estrogen receptor (ER) positive, and 65% (344 samples) were progesterone receptor (PgR) positive. EGFR positivity was found in 46% (173 of 380) of ER-positive and in 85% (129 of 151) of ER-negative breast tumor biopsy samples (P less than 0.0001), as well as in 49% (168 of 344) of PgR-positive and in 72% (134 of 186) of PgR-negative breast tumor biopsy samples (P less than 0.0001). Mean EGFR levels in ER-positive breast tumor biopsy samples were lower than they were in ER-negative ones, 40 +/- 31 (SD) against 72 +/- 55 fmol/mg of membrane protein (P less than 0.0001). Similarly, mean EGFR levels in PgR-positive breast tumor biopsy samples were lower than they were in PgR-negative ones, 41 +/- 29 against 70 +/- 56 fmol/mg of membrane protein (P less than 0.0001). Both EGFR positivity and EGFR levels decreased with increasing steroid hormone receptor levels. A multivariate analysis showed only ER to be independently associated with EGFR.     

Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer.

PURPOSE: Immunohistochemistry (IHC) is a newer technique for assessing the estrogen receptor (ER) status of breast cancers, with the potential to overcome many of the shortcomings associated with the traditional ligand-binding assay (LBA). The purpose of this study was to evaluate the ability of ER status determination by IHC, compared with LBA, to predict clinical outcome-especially response to adjuvant endocrine therapy-in a large number of patients with long-term clinical follow-up. PATIENTS AND METHODS: ER status was evaluated in 1,982 primary breast cancers by IHC on formalin-fixed paraffin-embedded tissue sections, using antibody 6F11 and standard methodology. Slides were scored on a scale representing the estimated proportion and intensity of positive-staining tumor cells (range, 0 to 8). Results were compared with ER values obtained by the LBA in the same tumors and to clinical outcome. RESULTS: An IHC score of greater than 2 (corresponding to as few as 1% to 10% weakly positive cells) was used to define ER positivity on the basis of a univariate cut-point analysis of all possible scores and disease-free survival (DFS) in patients receiving any adjuvant endocrine therapy. Using this definition, 71% of all tumors were determined to be ER-positive by IHC, and the level of agreement with the LBA was 86%. In multivariate analyses of patients receiving adjuvant endocrine therapy alone, ER status determined by IHC was better than that determined by the LBA at predicting improved DFS (hazard ratios/P = 0.474/.0008 and 0.707/.3214, respectively) and equivalent at predicting overall survival (0.379/.0001 and 0.381/.0003, respectively). CONCLUSION: IHC is superior to the LBA for assessing ER status in primary breast cancer because it is easier, safer, and less expensive, and has an equivalent or better ability to predict response to adjuvant endocrine therapy.     

Significance of immunohistochemical assessment of steroid hormone receptor status for breast cancer patients

The assessment of steroid hormone receptors in resected breast cancer tissues is essential to decide whether endocrine therapy is indicated and to select the best treatment for each patient on the basis of receptor status. Both enzyme immunoassay (EIA) and immunohistochemistry (IHC) have been generally used as methods for examination of estrogen receptor (ER) and progesterone receptor (PgR). In some patients, receptor status cannot be examined for various reasons. A questionnaire survey in Japan clarified that ER status is not examined in approximately 40% of patients receiving breast conserving surgery. To eliminate "receptor unknown" cases, IHC examination on paraffin-embedded tissue is useful to assess the in situ receptor status. The concordance rate of ER and PgR status between EIA and IHC is very high and a study of 88 cases revealed a 97.7% concordance for ER and 92.0% for PgR at a cutoff point of 10%. The cutoff point of IHC is controversial and some studies demonstrated that patients showing 1% ER positive cancer cells would benefit from endocrine therapy. On the other hand, immunohistochemical expression of receptors is heterogeneous and some patients with ER negative invasive tumors have ER positive intraductal components. A study of 65 breast cancers demonstrated that ER positive intraductal components were detected in 3.1% cases of ER negative invasive lesions. According to these results and the recommendation of the St. Gallen International Conference, IHC is thought to be more useful than EIA in the assessment of steroid hormone receptor status for breast cancer patients.     

Marked lymphovascular invasion,progesterone receptor negativity,and high Ki67 labeling index predict poor outcome in breast cancer patients treated with endocrine therapy alone

Purpose

Whether postoperative chemotherapy should be added to endocrine therapy or not is an important issue in patients with hormone receptor-positive and human epidermal growth factor receptor (HER)2-negative breast cancer. To identify patients who should be treated with additional chemotherapy, prognostic factors were investigated in breast cancer patients postoperatively treated with endocrine therapy alone.

Patients and methods

Tumor samples and clinicopathological data were collected from patients who underwent curative surgery and were postoperatively treated with endocrine therapy alone between 1999 and 2003 in three different institutes. Expression levels of estrogen receptor (ER), progesterone receptor (PgR), and HER2 in primary tumors were centrally retested. Patients with ER-negative and/or HER2-positive tumors and/or with unknown nodal status were excluded from the study subjects. Immunohistochemical analysis of Ki67, HER1, insulin-like growth factor-1 receptor, and aldehyde dehydrogenase-1 was also performed. Prognostic factors were investigated by univariate and multivariate analyses.

Results

A total of 261 patients were the subjects of this study. The median age was 59 years old, the mean tumor size was 1.9 cm, the node-positive rate was 20 %, and 65 % received tamoxifen alone. Distant metastases were observed in 11 patients at a median follow-up of 98 months, and four patients had died of breast cancer at a median follow-up of 99 months. Univariate analysis showed that marked lymphovascular invasion (LVI), PgR negativity, high Ki67 labeling index (LI), and high nuclear grade were significantly worse prognostic factors for distant metastasis. Multivariate analysis revealed that marked LVI [hazard ratio (HR) 21.8] and PgR negativity (HR 10.3) were independently worse prognostic factors for distant metastasis, respectively. Multivariate analysis also revealed that marked LVI (HR 287.3), PgR negativity (HR 25.1), and high Ki67 LI (HR 19.6) were independently worse prognostic factors for breast cancer-specific death, respectively.

Conclusions

The results of this multi-institute cohort study indicated that endocrine therapy alone could not prevent distant metastasis in breast cancer patients with PgR-negative tumors and/or with tumors showing marked LVI or high cell proliferation. These patients may need postoperative adjuvant chemotherapy in addition to endocrine therapy.     

Tamoxifen therapy for primary breast cancer and risk of contralateral breast cancer.

BACKGROUND: Women diagnosed with breast cancer have a twofold to sixfold greater risk of developing contralateral breast cancer than women in the general population have of developing a first breast cancer. Tamoxifen therapy reduces this risk, but it is unclear if this benefit exists for both estrogen receptor (ER)-positive and ER-negative contralateral tumors. METHODS: Using data from a population-based tumor registry that collects information on the ER status of breast tumors, we followed 8981 women residing in western Washington State who were diagnosed with a primary unilateral invasive breast cancer during the period from 1990 through 1998 to identify cases of contralateral breast cancer. We restricted our analyses to women who were at least 50 years old and whose first breast cancer had a localized or regional stage; women who received adjuvant hormonal therapy but not chemotherapy (n = 4654) were classified as tamoxifen users, while those who received neither adjuvant hormonal therapy nor chemotherapy (n = 4327) were classified as nonusers of tamoxifen. By reviewing selected patient abstracts, we estimated that 94% of the subjects were classified correctly with respect to tamoxifen use. The risk of contralateral breast cancer associated with tamoxifen use was estimated with the use of Cox regression. All statistical tests were two-sided. RESULTS: Of the 89 tamoxifen users and 100 nonusers of tamoxifen diagnosed with contralateral breast cancer, 112 had ER-positive tumors, 20 had ER-negative tumors, and 57 had tumors with an ER status that was unknown or had not been determined by an immunohistochemical assay. The risk of developing an ER-positive and an ER-negative contralateral tumor among tamoxifen users was 0.8 (95% confidence interval [CI] = 0.5 to 1.1) and 4.9 (95% CI = 1.4 to 17.4), respectively, times that of nonusers of tamoxifen. This difference in risk by ER status was statistically significant (P<.0001). CONCLUSIONS: Tamoxifen use appears to decrease the risk of ER-positive contralateral breast tumors, but it appears to increase the risk of ER-negative contralateral tumors.