Changes In Estrogen Receptor Status Research Articles

Alterations in three biomarkers (estrogen receptor, progesterone receptor and human epidermal growth factor 2) and the Ki67 index between primary and metastatic breast cancer lesions.

In recurrent breast cancer, the tumor phenotype, as assessed by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 (HER2) status, occasionally changes. This change, in addition to the Ki67 index were evaluated at sites of recurrence and the correlation between changes in tumor phenotype and survival were assessed in breast cancer patients. Comparisons in pathological parameters between primary and metastatic lesions were drawn between ER, PR, HER2, and the Ki67 index in 70 patients with recurrent breast cancer. The association between changes in tumor phenotype and patient survival was assessed. The hormone receptor status changed from positive, in the primary lesions, to negative, in the metastatic lesions in 19.8% (ER) and 39.5% (PR) of patients, respectively. Conversion from negative to positive status was confirmed in 27.2% (ER) and 31.2% (PR) of patients, respectively. A change in HER2 status from negative (primary lesion) to positive (metastatic lesion) occurred in seven patients (10%). The mean Ki67 index of primary lesions with positive hormone receptor status was significantly lower than at sites of recurrence with any hormone receptor status, from 10.9±9.8 standard deviation (SD) to 22.9±18.6 (P=0.031) and 12.2±10.5 SD to 27.4±20.9 (P=0.023), for ER and PR, respectively. The mean overall survival of patients with ER status conversion from positive to negative was 7.4±1.2 standard error (SE) years, and 14.8±1.4 SE years for patients who retained positive ER status (P=0.005, log-rank), with a hazard ratio of 3.44 (95% confidence interval, 1.36-8.33). This difference in survival based upon change in ER status was similarly observed in patients with PR status conversion in the same direction. Thus, ER and PR status conversion at the time of recurrence strongly impact survival, particularly if the change is from positive (primary lesion) to negative (metastatic lesion). Monitoring the biological behavior of breast cancer may benefit a patient by allowing for a novel personalized treatment strategy.

Breast Cancer Estrogen Receptor Status According to Biological Generation: US Black and White Women Born 1915-1979.

Evidence suggests that contemporary population distributions of estrogen-receptor (ER) status among breast cancer patients may be shaped by earlier major societal events, such as the 1965 abolition of legal racial discrimination in the United States (state and local "Jim Crow" laws) and the Great Famine in China (1959-1961). We analyzed changes in ER status in relation to Jim Crow birthplace among the 46,417 black and 339,830 white US-born, non-Hispanic women in the Surveillance, Epidemiology, and End Results (SEER) 13 Registry Group who were born between 1915 and 1979 and diagnosed (ages 25-84 years, inclusive) during 1992-2012. We grouped the cases according to birth cohort and quantified the rate of change using the haldane (which scales change in relation to biological generation). The percentage of ER-positive cases rose according to birth cohort (1915-1919 to 1975-1979) only among women diagnosed before age 55. Changes according to biological generation were greater among black women than among white women, and among black women, they were greatest among those born in Jim Crow (versus non-Jim Crow) states, with this group being the only group to exhibit high haldane values (>|0.3|, indicating high rate of change). Our study's analytical approach and findings underscore the need to consider history and societal context when analyzing ER status among breast cancer patients and racial/ethnic inequities in its distribution.

Abstract P1-06-03: Serial evolution of hormone receptor status and mutational profile among patients with metastatic breast cancer

Abstract Introduction: Tumor heterogeneity presents a significant impediment to identifying appropriate treatments for patients. Genetic mutations and hormone receptors are frequently used as a guide for selecting appropriate targeted or hormonal therapies, however it is possible that these markers may change over time, leading to reduced effectiveness of these treatments. In this study, we review the results of serial and paired biopsies to identify receptor switch in estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status as well as to identify changes in clinically relevant mutations, including spatial and temporal heterogeneity. Methods: We identified a total of 237 patients initially presenting with ER+/HER2 negative breast cancer and who had multiple biopsies during the course of their treatment, including at least one in the metastatic setting. ER, PR, and HER2 status for each of these serial biopsies was gathered from chart reviews. HER2 results by both IHC and FISH were collected. PIK3CA mutations were also assessed by Snapshot utilizing multiplexed PCR of common hotspot mutations using DNA derived from formalin-fixed, paraffin-embedded (FFPE) tissue. Results: From a total of 213 patients with known ER status for multiple serial biopsies, we identified 9.4% (N=20) who had at least one change in ER status over time. From a total of 198 patients who had documented PR status for multiple biopsies, 40.4% (N=80) had at least one change in PR status. Changes in HER2 status were similarly assessed, with 6.7% of patients having at least one change by IHC and 4.4% of patients having at least one change by FISH. Of those patients exhibiting changes in ER status, 6 were noted to have multiple changes over time. Of those with changes in PR status, 18 had multiple changes over time. Changes in hormone receptor status were also noted to occur between serial biopsies in the metastatic setting. A total of 128 patients had ER results available for multiple metastatic specimens, of which 8.6% (N=11) had at least one change in ER status. A total of 116 patients had PR results available for multiple metastatic biopsies, of which 38.8% (N=45) had at least one change in PR status. Changes were also noted in the metastatic setting in HER2 (IHC) with a frequency of 8.7% and in HER2 (FISH) with a frequency of 4.7%. A subset of 108 patients were identified as harboring a mutation in PIK3CA. Within this population, 9.6% of patients had at least one change in ER status over time and 34.1% had at least one change in PR status. 9.0% exhibited at least one change in HER2 (IHC) and 6.5% in HER2 (FISH). Serial changes in genotype, from pre- and post-treatment biopsies, were also detected using NGS based Foundation Medicine platform, including acquired alterations in the ESR1 and PI3K pathway. Conclusion: Serial changes in hormone receptor status and mutation profile are not uncommon among patients initially diagnosed with ER+/HER2 negative breast cancer, and some patients have been noted to have multiple changes over time. Further studies are needed to understand the mechanistic underpinnings governing the emergence of these alterations and their relationship to therapeutic resistance in breast cancer. Citation Format: Henderson L, Brachtel E, Fitzgerald D, Gadd M, Specht M, Thabet A, Gurski J, Sgroi D, Moy B, Isakoff S, Bardia A, Juric D. Serial evolution of hormone receptor status and mutational profile among patients with metastatic breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-06-03.

HER-2, ER, PR status concordance in primary breast cancer and corresponding metastatic lesion in lymph node in Chinese women

Aims and backgroundTo compare the expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER-2) in the primary site and the metastatic lesion of lymph nodes in invasive breast cancer for investigating whether the expression of these biomarkers in the primary site could act as a surrogate to the lymphatic metastatic lesion in the same patient. MethodsIn lymphatic metastatic lesion and corresponding primary lesion of 107 cases of invasive breast cancer, ER and PR statuses were assessed by immunohistochemistry (IHC). HER-2 expression level was evaluated by IHC and/or fluorescence in situ hybridization (FISH). ResultsIn the primary lesions, 43.9% were ER positive; 46.7% were PR positive; 34.6% were HER-2 positive. In corresponding lymphatic metastatic lesions, the HER-2 status was concordant in 90 patients; 9 patients were diagnosed positive in metastatic lesion while negative in primary lesion; 8 patients were negative in metastatic lesion while positive in primary site (agreement, 84.1%; κ=0.647). A change in ER status was observed in 24 cases: 17 cases positive in metastatic site while negative in primary site; 7 cases negative in metastatic site while positive in primary site (agreement, 77.6%; κ=0.534). PR status discordance between the primary lesion and the metastatic regional lymph nodes was reported in 19 cases (agreement, 82.2%; κ=0.640). ConclusionsThis study revealed that there was only a moderate concordance of ER, PR and HER-2 status between primary tumors and metastatic lymph nodes. These results indicate that it was inappropriate to predict the status of ER, PR and HER-2 in metastatic lymph nodes based on the results of evaluation of that in primary lesions.

Abstract P3-06-49: Prognostic impact of discordance in hormone receptor status after the neoadjuvant chemotherapy in primary breast cancer

Abstract Background: Hormone receptor (Estrogen receptor (ER), Progesterone receptor (PgR)) is an important biological marker for predicting prognosis and making effective treatment decisions. Discordance in these biomarkers between the primary tumor and recurrent lesions is reported frequently. However, it is not well known whether these biomarkers are affected by neoadjuvant chemotherapy and their impacts on outcomes still remain to be elucidated. The aim of the present study is to evaluate the changes in HR status after neoadjuvant chemotherapy in patients with operable breast cancer and their relationship with response to treatment and prognosis. Patients and Methods: Of 162 patients with stage II/III breast cancer patients receiving neoadjuvant chemotherapy from January 2005 to September 2012 at Keio University Hospital, 140 patients with non-pCR were analyzed. Patients were treated with sequential anthracycline and taxane. ER and PgR were assessed in both CNB performed prior to neoadjuvant chemotherapy and surgical samples. HR status was assessed by immunohistochemistry (IHC). ER/PgR status was determined using the Allred score and defined as positive when score was 3 and more. HR status was considered positive in cases of ER and/or PgR positivity. Pathological response criteria were classified as grade 0, 1, 2, or 3: grade 0 includes almost no change in cancer cells; grade 1 includes slight or marked changes in less than two thirds of area; grade 2 includes marked changes in more than two thirds of area; grade3 includes necrosis or disappearance of all tumor cells. Results: ER, PgR and HR positive rates before neoadjuvant chemotherapy were 72.9%, 67.1% and 76.4%, respectively. Changes in ER, PgR and HR status between CNB and surgical samples were 12.1% (4.3% gain; 7.8% loss), 17.1% (2.1% gain; 15.0% loss) and 9.3% (2.9% gain; 6.4% loss), respectively. In ER-discordant group, grade 2 rate of pathological response was significantly higher than ER- concordant group (61.1% vs. 30%, p=0.033), whereas there were no significant differences of pathological response between discordant and concordant group in PgR status. In the disease free survival (DFS), there were no significant difference between concordance and discordance group for ER, PgR and HR (p=0.216, 0.859, 0.233) after a median follow-up of 40.4 months. But patients with a loss in ER and/or HR status had a trend to a shorter DFS compared with the concordant ER and/or HR-positive group (p=0.169 and 0.154) Conclusions: After neoadjuvant chemotherapy, discordance of biomarkers was seen in 5-20%. The pathological response was significantly associated with the change in ER status. A loss in ER and/or HR status may affect a prognosis of breast cancer after neoadjuvant chemotherapy, but still need further investigation. Citation Format: Toshiaki Kurihara, Hanako Ueno, Masaru Takemae, Aiko Nagayama, Maiko Takahashi, Tetsu Hayashida, Hiromitsu Jinno, Yuko Kitagawa. Prognostic impact of discordance in hormone receptor status after the neoadjuvant chemotherapy in primary breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-49.

Heterogeneity in hormone-receptor status and survival outcomes among women with synchronous and metachronous bilateral breast cancers

To examine whether discordance in the hormone-receptor status predicts clinical outcomes in patients with bilateral synchronous (SBC) or metachronous breast cancer (MBC), we analyzed data from the Surveillance, Epidemiology, and End Results program (1998–2011) using Cox models. After excluding 10,231 patients with missing data on hormone receptors in at least one tumor, 4403 SBC and 7159 MBC were included in the study. Among SBC cases, patients with estrogen receptor (ER)-discordant tumors had higher mortality risk (multivariable-adjusted hazard ratio [HR] = 1.96, 95% confidence interval [CI] 1.60–2.40) than patients with ER concordant-positive tumors, whereas patients with ER concordant-negative tumors had the highest risk (HR = 2.49, 95% CI 2.03–3.07). Among MBC cases, patients with a positive-to-negative change in ER status (HR = 1.32, 95% CI: 1.08–1.62) or ER concordant-negative tumors (HR = 1.48, 95% CI: 1.19–1.85) had worse survival than patients with ER concordant-positive tumors. In conclusion, discordance in the hormone-receptor status was an independent predictor of survival outcomes.

Hormonal Receptor, Human Epidermal Growth Factor Receptor-2, and Ki67 Discordance between Primary Breast Cancer and Paired Metastases: Clinical Impact

Objective: As hormone receptor and human epidermal growth factor receptor-2 (HER-2) expression in primary breast tumors frequently differs from that of paired metastases, we first evaluated the discordance rate (DR) of estrogen receptor (ER), progesterone receptor (PgR), HER-2, and Ki67 in breast cancer patients and then assessed the discordance effect on prognosis. Methods: Of 145 cases reviewed, 120 with samples available from both primary tumors and paired metastases were included in the study. For each receptor, the DR was calculated as the proportion of discordant cases with respect to the total number of patients. Results: A change in ER status was observed in 19 cases (DR 16.4%), while PgR status was modified in 48 cases (DR 41.7%). HER-2 was altered in 21 cases (DR 17.5%), and Ki67 in 33 patients (DR 38.8%). Patients with Ki67 <20% had a significantly higher postrecurrence survival (PRS) compared to patients with Ki67 ≥20% (p = 0.0006). Patients with ER-positive tumors showed a trend towards higher PRS (p = 0.064) compared to ER-negative patients. No differences in PRS were seen among patients with altered PgR or HER2 status. Conclusions: Changes in the cell biology of breast cancer metastasis would seem to occur and biopsy could potentially guide the choice of treatment and provide useful information on prognosis.

Should liver metastases of breast cancer be biopsied to improve treatment choice?

BackgroundCurrently, the acquisition of tissue from metastatic deposits is not recommended as a routine practice. Our aim was to evaluate the discordance rate of estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor 2 (HER2) receptor status between primary tumor and liver metastases and its potential impact on treatment choice. Patients and methodsWe retrospectively analyzed a database including 1250 ultrasound-guided liver biopsies carried out at the European Institute of Oncology from August 1999 to March 2009. ER, PgR, and HER2 status were determined by immunohistochemistry and/or FISH. Differences between proportions were evaluated using Fisher’s exact test. ResultsWe identified 255 consecutive patients with matched primary and liver tissue samples. Changes in ER status were observed in 37 of 255 patients (14.5%). Changes in PgR status were observed in 124 of 255 patients (48.6%). Changes in HER2 status were observed in 24 of 172 assessable patients (13.9%). We observed a discordance in receptor status (ER, PgR, and HER2) between primary tumor and liver metastases, which led to change in therapy for 31 of 255 of patients (12.1%). ConclusionsBiopsy of metastases for reassessment of biological features should be considered in all patients, when safe and easy to carry out, since it is likely to impact treatment choice.

Should liver metastases of breast cancer be biopsied to improve treatment choice?

CRA1008 Background: Decision making on systemic treatment of women with metastatic breast cancer is based on features like estrogen receptor (ER), progesterone receptor (PgR), and HER2 status assessed on the primary tumor. We evaluated the concordance of receptor status between primary tumor and liver metastases (mts) and its impact on treatment choice. Methods: We retrospectively analyzed a database including ultrasound guided liver biopsies performed from 1995 to 2008. All tissue samples, both from primary tumor and liver mts, were analyzed for ER, PgR and HER2 status. Clinical and biological data were obtained from medical charts. Differences between proportions were evaluated using the Pearson chi-square test. Results: We identified 255 consecutive patients (pts) with matched primary and liver tissue samples. Median time from primary diagnosis to liver biopsy was 3.4 years (range 0-18.3 years). Changes in ER status were observed in 41/255 pts (16.0%). 16/58 pts (27.6%) changed from ER-negative to ER-positive and 25/197 pts (12.7%) changed from ER-positive to ER-negative (p=0.0066). Changes in PgR status were observed in 76/255 pts (29.8%). 18/91 pts (19.8%) changed from PgR-negative to -positive and 58/164 pts (64.6%) from PgR-positive to PgR-negative (p &lt;0.0001). 12/52 pts (23.1%) changed from ER- and PgR-negative to ER- or PgR-positive (group A) and 27/203 pts (13.3%) changed from ER- or PgR-positive to ER- and PgR-negative (group B) (p=0.087). In the group A the treatment of 4/12 pts (33.3%) was changed after biopsy: 2/4 started endocrine treatment (HT) and 2/4 stopped it. In group B the treatment of 18/27 pts (66.6%) was changed after biopsy: 17/18 stopped HT. Changes in HER2 status were observed in 22/167 pts (13.1%): 6/116 pts (5.1%) changed from HER2-negative to HER2-positive and 16/51 pts (31.4%) changed from HER2-positive to negative (p≤0.0001). In this group pts started and/or stopped a trastuzumab containing treatment after biopsy. Conclusions: There was a discordance in receptor status between primary tumor and liver mts, which led to change in therapy for 48/255 of pts (18.8%). Biopsy of metastases for reassessment of biological features should be considered in all pts when safe and easy to perform, since it is likely to impact treatment choice. No significant financial relationships to disclose.

Should Liver Metastases of Breast Cancer Be Biopsied To Improve Treatment Choice?

Abstract Background: Decision making on systemic treatment of women with metastatic breast cancer is based on features like estrogen receptor (ER), progesterone receptor (PgR), and HER2 status assessed on the primary tumor. We evaluated the concordance of receptor status between primary tumor and liver metastases and estimated the potential change of these pathological features and its impact on treatment choice.Materials and methods: We retrospectively analyzed a database including ultrasound guided liver biopsies performed from 1995 to 2008. All tissue samples, both from primary tumor and liver metastases, were analyzed for ER, PgR and HER2 status. Clinical and biological data were obtained from medical charts (including treatments before and after liver biopsy). Differences between proportions were evaluated using the Pearson chi-square test.Results: We identified 215 consecutive patients with matched primary and liver tissue samples. Median time from primary diagnosis to liver biopsy was 4.1 years (range 0-18.3 years). Changes in ER status were observed in 38/215 patients (17.7%). 15/47 patients (31.9%) changed from ER negative to positive and 23/168 patients (13.7%) changed from ER positive to negative [p= 0.0038]. Changes in PgR status were observed in 111/215 patients (51.6%). 16/74 patients (21.6%) changed from PgR negative to positive and 95/141 patients (67.4%) from PgR positive to negative [p &amp;lt;0.0001]. 11/41 patients (26.8%) changed from ER and PgR negative to ER or PgR positive [Group A] and 25/174 patients (14.4%) changed from ER or PgR positive to ER and PgR negative [Group B] [p=0.054]. In the Group A the treatment of 4/11 patients (36.4%) was changed after biopsy: 2/4 started endocrine treatment (HT) and 2/4 stopped it. In Group B the treatment of 16/25 patients (64%) was changed after biopsy: 15/16 stopped HT. Changes in HER2 status were observed in 19/131 patients (14.5%): 5/93 patients (5.4%) changed from HER2 negative to positive and 14/38 patients (36.8%) changed from HER2 positive to negative [p= &amp;lt;0.0001]. In this group 5/5 patients started a trastuzumab containing treatment after biopsy.Conclusions: There was a substantial discordance in receptor status between primary tumor and liver metastases, which led to change in therapy for 21.8 % of patients. Biopsy of metastases for reassessment of biological features should be considered in all patients when safe and easy to perform, since it might impact treatment choice for many. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6003.

Comparison of immunostaining for estrogen receptor in breast cancer using the rabbit monoclonal antibody SP1 or the mouse monoclonal antibody 6F-11

11562 Background: A high-quality assay to detect estrogen receptor (ER) expression is crucial as ER status guides many therapeutic decisions in breast cancer. Previously the rabbit monoclonal antibody (Ab) SP1 was shown to be more sensitive than the mouse monoclonal Ab 1D5. Results were similar in a comparison of mouse Abs 6F11 and 1D5. This study compares the ER status in breast cancer using SP1 on cases previously interpreted as negative with 6F11. Methods: All low grade (1 or 2), ER negative, invasive breast carcinomas, reviewed at the British Columbia Cancer Agency between 2002 and 2006 were reviewed. Cases that had been stained at the Vancouver site (VCC) with 6F11 were selected and those with available tissue blocks were re-stained with SP1. The patient’s oncologist was notified of any changes in ER status. Results: 123 cases of low grade, ER negative invasive breast tumors were initially selected. 49 of these cases had been stained at VCC with 6F11. Tissue blocks were available for 45/49 (92%) of cases. 5/45 cancers (11%) were grade 1 and 40/45 (89%) were grade 2. With SP1 the ER status changed from negative to positive in 3/45 (6.7%) of the cases. For 2 cases the ER status changed because current scoring criteria regard a test as positive even if only rare cells stain. Review of original 6F11 stained sections revealed these 2 cases would be scored as ER positive using the new criteria. The third case was a core biopsy with scant tumor and only focal staining. Review revealed the change in ER status was likely due to sampling difference in the deeper section. Conclusions: Of 45 previously 6F11 ER negative cases restained with SP1, the ER status changed in 2 because of revised more sensitive scoring criteria and in 1 because of a sampling difference between the original and subsequent sections. The rabbit monoclonal Ab SP1 appears to be as sensitive as the mouse monoclonal Ab 6F11 in detecting ER expression in breast cancer. This highlights the need for good quality ER testing with highly sensitive antibodies. Additional data for grade 3 cases will be presented. No significant financial relationships to disclose.

Estrogen receptor status in BRCA1- and BRCA2-related breast cancer: the influence of age, grade, and histological type.

BRCA1-related breast cancers are more frequently estrogen receptor (ER) negative than are either BRCA2-related or nonhereditary breast cancers. The relationship between ER status and other clinical features of hereditary breast cancers has not been well studied. ER status, grade, and histological tumor type were evaluated in 1131 women with invasive breast cancer, ascertained at 10 centers in North America. There were 208 BRCA1 mutation carriers, 88 BRCA2 carriers, and 804 women without a known mutation. We stratified the patients by mutation status, grade, age, and histological type and calculated the percentage of ER-positive tumors within each stratum. BRCA1 mutation carriers were more likely to have ER-negative breast cancers than were women in other groups, after adjustment for age, grade, and histological subtype (P < 0.001). Only 3.9% of BRCA1-related breast cancers were ER-positive cancers occurring in women in their postmenopausal years. The direction and magnitude of the change in ER status with increasing age at diagnosis in BRCA1 carriers was significantly different from in BRCA2 carriers (P(intercept) = 0.0002, P(slope) = 0.04). Notably, changes in ER status with age at diagnosis for BRCA1 carriers and noncarriers were almost identical (P(slope) = 0.98). The strong relationship between the presence of a BRCA1 mutation and the ER-negative status of the breast cancers is neither a consequence of the young age at onset nor the high grade but is an intrinsic property of BRCA1-related cancers. The ER-negative status of these cancers may reflect the cell of origin of BRCA1-related cancers.