Unknown Estrogen Receptor Status Research Articles

Long-Term Follow-Up of the Intergroup Exemestane Study.

Purpose The Intergroup Exemestane Study, an investigator-led study of 4,724 postmenopausal patients with early breast cancer (clinical trial information: ISRCTN11883920), has previously demonstrated that a switch from adjuvant endocrine therapy after 2 to 3 years of tamoxifen to exemestane was associated with clinically relevant improvements in efficacy. Here, we report the final efficacy analyses of this cohort. Patients and Methods Patients who remained disease free after 2 to 3 years of adjuvant tamoxifen were randomly assigned to continue tamoxifen or switch to exemestane to complete a total of 5 years of adjuvant endocrine therapy. Given the large number of non-breast cancer-related deaths now reported, breast cancer-free survival (BCFS), with censorship of intercurrent deaths, was the primary survival end point of interest. Analyses focus on patients with estrogen receptor-positive or unknown tumors (n = 4,599). Results At the time of the data snapshot, median follow-up was 120 months. In the population that was estrogen receptor positive or had unknown estrogen receptor status, 1,111 BCFS events were observed with 508 (22.1%) of 2,294 patients in the exemestane group and 603 (26.2%) of 2,305 patients in the tamoxifen group. The data corresponded to an absolute difference (between exemestane and tamoxifen) at 10 years of 4.0% (95% CI, 1.2% to 6.7%), and the hazard ratio (HR) of 0.81 (95% CI, 0.72 to 0.92) favored exemestane. This difference remained in multivariable analysis that was adjusted for nodal status, prior use of hormone replacement therapy, and prior chemotherapy (HR, 0.80; 95% CI, 0.71 to 0.90; P < .001). A modest improvement in overall survival was seen with exemestane; the absolute difference (between exemestane and tamoxifen) at 10 years in the population that was estrogen receptor positive or had unknown estrogen receptor status was 2.1% (95% CI, -0.5% to 4.6%), and the HR was 0.89 (95% CI, 0.78 to 1.01; P = .08). For the intention-to-treat population, the absolute difference was 1.6% (95% CI, -0.9% to 4.1%); the HR was 0.91 (95% CI, 0.80 to 1.03, P = .15). No statistically significant difference was observed in the proportion of patients who reported a fracture event in the post-treatment period. Conclusion The Intergroup Exemestane Study and contemporaneous studies have established that a strategy of switching to an aromatase inhibitor after 2 to 3 years of tamoxifen can lead to sustained benefits in terms of reduction of disease recurrence and breast cancer mortality.

Association of Radiotherapy Boost for Ductal Carcinoma In Situ With Local Control After Whole-Breast Radiotherapy

The use of a radiotherapy (RT) boost to the tumor bed after whole-breast RT (WBRT) for ductal carcinoma in situ (DCIS) is largely extrapolated from invasive cancer data, but robust evidence specific to DCIS is lacking. To compare ipsilateral breast tumor recurrence (IBTR) in women with DCIS treated with vs without the RT boost after breast-conserving surgery and WBRT. This retrospective analysis pooled deidentified patient-level data from 10 academic institutions in the United States, Canada, and France from January 1, 1980, through December 31, 2010. All patients had newly diagnosed pure DCIS (no microinvasion), underwent breast-conserving surgery, and received WBRT with or without the boost with a minimum of 5 years of follow-up required for inclusion in the analysis. Given the limited events after WBRT, an a priori power analysis was conducted to estimate the DCIS sample size needed to detect the anticipated benefit of the boost. Data were uniformly recoded at the host institution and underwent primary and secondary reviews before analysis. Sample size calculations (ratio of patients who received the boost dose to those who did not, 2:1; α = .05; power = 80%) estimated that 2982 cases were needed to detect a difference of at least 3%. The final analysis included 4131 patients (2661 in the boost group and 1470 in the no-boost group) with a median follow-up of 9 years and media boost dose of 14 Gy. Data were collected from July 2011 through February 2014 and analyzed from March 2014 through August 2015. Radiotherapy boost vs no boost. Ipsilateral breast tumor recurrence. The analysis included 4131 patients (median [SD] age, 56.1 [10.9] years; range, 24-88 years). Patients with positive margins, unknown estrogen receptor status, and comedo necrosis were more likely to have received an RT boost. For the entire cohort, the boost was significantly associated with lower IBTR (hazard ratio [HR], 0.73; 95% CI, 0.57-0.94; P = .01) and with IBTR-free survival (boost vs no-boost groups) of 97.1% (95% CI, 0.96-0.98) vs 96.3% (95% CI, 0.95-0.97) at 5 years, 94.1% (95% CI, 0.93-0.95) vs 92.5% (95% CI, 0.91-0.94) at 10 years, and 91.6% (95% CI, 0.90-0.93) vs 88.0% (95% CI, 0.85-0.91) at 15 years. On multivariable analysis accounting for confounding factors, the boost remained significantly associated with reduced IBTR (HR compared with no boost, 0.68; 95% CI, 0.50-0.91; P = .01) independent of age and tamoxifen citrate use. This patient-level analysis suggests that the RT boost confers a statistically significant benefit in decreasing IBTR across all DCIS age groups, similar to that seen in patients with invasive breast cancer. These findings suggest that a DCIS RT boost to the tumor bed could be considered to provide an added incremental benefit in decreasing IBTR after a shared discussion between the patient and her radiation oncologist.

Imputing estrogen receptor (ER) status in a population-based cancer registry: a sensitivity analysis.

Breast cancers are clinically heterogeneous based on tumor markers. The National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program provides baseline data on these tumor markers for reporting cancer burden and trends over time in the US general population. These tumor markers, however, are often prone to missing observations. In particular, estrogen receptor (ER) status, a key biomarker in the study of breast cancer, has been collected since 1992 but historically was not well-reported, with missingness rates as high as 25% in early years. Previous methods used to correct estimates of breast cancer incidence or ER-related odds or prevalence ratios for unknown ER status have relied on a missing-at-random (MAR) assumption. In this paper, we explore the sensitivity of these key estimates to departures from MAR. We develop a predictive mean matching procedure that can be used to multiply impute missing ER status under either an MAR or a missing not at random assumption and apply it to the SEER breast cancer data (1992-2012). The imputation procedure uses the predictive power of the rich set of covariates available in the SEER registry while also allowing us to investigate the impact of departures from MAR. We find some differences in inference under the two assumptions, although the magnitude of differences tends to be small. For the types of analyses typically of primary interest, we recommend imputing SEER breast cancer biomarkers under an MAR assumption, given the small apparent differences under MAR and missing not at random assumptions. Copyright © 2016 John Wiley & Sons, Ltd.

Impact of Primary Tumor Surgery in Stage IV Male Breast Cancer

BackgroundPrimary tumor surgery (PTS) is not a standard treatment modality in stage IV breast cancer. Retrospective studies in female breast cancer show improved survival in women undergoing PTS; however, data regarding the impact of surgery in male breast cancer are lacking. The objective of this study was to analyze the impact of PTS on survival among men with metastatic breast cancer. MethodsA retrospective study was conducted of men diagnosed with metastatic breast cancer at diagnosis were identified from the Surveillance, Epidemiology, and End Results (SEER) database from 1988 to 2011. Cox proportional hazards regression models were used to compare the differences in survival in men who did and did not undergo PTS. ResultsA total of 439 men with stage IV breast cancer at diagnosis were identified, of which 222 (51%) underwent PTS, 171 (77%) mastectomy, and 51 (23%) partial mastectomy. The median age was 65 years; 74% of participants were white, 51% had tumors ≤ T2, 65% had estrogen receptor (ER)-positive tumor, and 24% had unknown ER status. Univariate analysis between the surgery and no-surgery arms showed that white race (P = .04), lower T stage and grade (P = .0003, P = .004), ER positivity (P = .0002), and later year of diagnosis (P < .0001) were associated with better survival. PTS was associated with improvement in median overall survival (29 vs. 11 months, P < .0001). On Cox regression analysis, ER negativity (hazard ratio = 2.08; 95% confidence interval, 1.41-3.01; P < .0003) and not undergoing PTS were associated with diminished survival (hazard ratio = 1.81; 95% confidence interval, 1.42-2.31; P < .0001). ConclusionPTS among men with metastatic breast cancer was associated with improved survival in this retrospective analysis.

Abstract C55: Presentation, treatment, and outcomes of Haitian women with breast cancer in Miami and Haiti: Disparities in breast cancer. A retrospective cohort study

Abstract Breast cancer diagnosis and death has risen in low to middle income countries (LMIC) in the past 20 years. Early detection, diagnosis and treatment in the LMIC setting are thought to impact morbidity and survivorship. The population of South Florida is composed of a significant portion of Afro-Caribbean immigrants from LMICs. We compared a cohort of recent Haitian immigrants with residents in Haiti who had a diagnosis of breast cancer to evaluate the effects of geographical location on presentation, treatment and outcomes. Methods: Retrospective cohort study. Participants were Haitian females with breast cancer that were living in Miami and presented to the University of Miami/Jackson Memorial Hospital (UM/JMH) between 2008 and 2014 and patients living in Haiti and presented to the Breast Cancer Treatment program at the Hospital Bernard Mevs Project Medishare (HBMPM) from 2013 to 2015 with a new diagnosis or who had been diagnosed as far back as 2008 and were presenting for continuation of care. The main outcome was the relationship between cohort location and breast cancer characteristics and cancer–specific survival by log-rank. Cox proportional hazards regression was used to compare breast cancer–specific survival overall and analyzed by stage and other significant explanatory factors. Results: 102 patients from UM/JMH and 94 patients from HBMPM were included in the analysis. The cohort in Haiti presented after longer median duration of symptoms (20 vs 3 months, p&amp;lt;0.001) and more advanced stage (31% Vs 20% with locally advance and 27% vs 19% with metastatic disease). The median age of diagnosis was 55 years in Miami compared to 50 years in Haiti (p=0.03). In Miami all patients had estrogen receptor (ER) and her-2 status ascertained at diagnosis, whereas only 52% and 27% of the Haitian cohort had them. Tumor characteristics in Miami vs Haiti in patients with reported status: ER + 74% (n=102) vs 55% (n=49), p=0.02, her-2+ 20% (n=102) vs 28% (n=25), p=0.36, triple negative 27% (n=102) vs 28% (n=25),p=0.49. Treatment modalities and censoring was available for all the patients in Miami and 72 patients in Haiti. In Haiti, radiation therapy was not widely available compared to Miami. Once patients had known ER and her-2 status, there was no difference in treatment with hormonal therapy (p=0.97) but none of the patients in Haiti received her-2 directed therapy (p&amp;lt;0.001). 50% of the patients with unknown ER status in Haiti received Tamoxifen. Twice as many Haitian women died after a median follow-up of 23 months (12% vs 24%), with median survival of 53 months for Haitians in Haiti (not reached for Miami cohort). Breast cancer specific survival was significantly different in the two cohorts (p&amp;lt;0.000). After exploratory analysis, the risk of death was higher for Haitians in Haiti than Haitians in Miami [HR 3.13 (CI 1.50-6.51)] and was higher for more advanced disease [HR 2.58 (CI 1.67-3.99)]. No other variable or interaction reached statistical significance in our model. Conclusion: Haitian women diagnosed with breast cancer in Haiti experience a significantly worse outcome than Haitians living in Miami that appears to be related to a more advanced stage, younger age, more ER negative tumors and lack of timely effective treatments including restricted access to trastuzumab and radiation. In addition there is a difference in the age of breast cancer onset (Caucasian 62, African American 58, Haitian American 55, Haitian 50) and ER positivity (Caucasian 70%, African American 48%, Haitian American 74%, Haitian 55%) depending on race and ethnic group that raises the question of whether there are disparities within subgroups of women of African origin who have breast cancer. Confounding epigenetic-related variables may impact survival and they need further exploration in these populations. Citation Format: Alexandra Gomez, Vincent DeGennaro, Jr., Sophia George, Estefania Santamaria, Gustavo Westin, Gabriel Dieudina, Judith Hurley. Presentation, treatment, and outcomes of Haitian women with breast cancer in Miami and Haiti: Disparities in breast cancer. A retrospective cohort study. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr C55.

The prevalence of estrogen receptor-negative breast cancer in Ethiopia.

BackgroundIn contrast with breast cancers (BCs) in other parts of the world, most previous studies reported that the majority of BCs in sub-Saharan Africa are estrogen-receptor (ER) negative. However, a recent study using the US SEER database showed that the proportion of ER-negative BC is comparable between US-born blacks and West-African born blacks but substantially lower in East African-born blacks, with over 74% of patients Ethiopians or Eritreans. In this paper, we provide the first report on the proportion of ER-negative BC in Ethiopia, and the relation to progesterone-receptor (PgR) status.MethodsWe analysed 352 female patients with ER results available out of 1208 consecutive female BC patients treated at Addis Ababa-University Hospital, Ethiopia, from June 2005 through December 2010. The influences of age, stage, and histology on the probability of ER-negative tumours were assessed by a log-linear regression model.ResultsOf the 352 patients, only 35% were ER-negative. The proportion of ER-negative tumours decreased with advancing age at diagnosis and was not affected by histology or stage. For age, the proportion decreased by 6% for each additional 5 years (stage-adjusted prevalence ratio PR = 0.94, 95% CI: 0.89–1.00). About 31% were ER- and PgR-negative, and 69% were ER- and/or PgR-positive.ConclusionsContrary to most previous reports in other parts of sub-Saharan Africa, the majority of patients in Ethiopia are ER-positive rather than ER-negative. These findings are in line with low proportions of ER-negative BCs from East African immigrants within the SEER database, and they have clinical implications for management of BC patients in Ethiopia and other parts of sub-Saharan Africa where ER-status is not ascertained as part of routine management of the disease. Since the majority of patients showed ER-positive BC, Tamoxifen-therapy should be given to all patients even with unknown ER status.

Omission of radiation therapy after breast‐conserving surgery in the United States

Radiation therapy (RT) after breast-conserving surgery (BCS) is associated with a significant reduction in ipsilateral breast tumor recurrence and breast cancer mortality rates in patients with early stage breast cancer. The authors of this report sought to determine which patients with breast cancer do not receive RT after BCS in the United States. The Surveillance, Epidemiology, and End Results registry was used to determine the rates of RT after BCS for women with stage I through III breast cancer in the United States from 1992 through 2007. A multivariate analysis was performed to identify independent predictors of omission of RT. In total, 294,254 patients with invasive, nonmetastatic breast cancer were identified who underwent surgery from 1992 through 2007. Most patients (57%) underwent BCS; among those, 21.1% did not receive RT after BCS. The omission of RT increased significantly from 1992 (15.5%) to 2007 (25%). The receipt of RT also decreased significantly for patients with increased cancer stage, age <55 years, high-grade tumors, large tumors, positive or untested lymph node status, African American or Hispanic race, and negative or unknown estrogen receptor status. Significant geographic variation was observed in the rates of RT after BCS. The omission of RT after BCS was more common in recent years, especially among women who had an increased risk of breast cancer recurrence. This trend represents a serious health care concern because of the potential increased risk of local recurrence and breast cancer mortality.

Pharmacokinetics of a single dose of fulvestrant prolonged-release intramuscular injection in postmenopausal women awaiting surgery for primary breast cancer

Objective: The aim of this study was to describe the pharmacokinetics of 3 different single doses of fulvestrant—a new estrogen receptor (ER) antagonist that downregulates the ER with no known agonist effects—administered as a prolonged-release IM formulation. Methods: Pharmacokinetic data were obtained in a randomized, partially blinded, placebo-controlled, parallel-group, Phase I/II multicenter trial involving postmenopausal women with primary breast cancer (clinical stages T1–T3, with tumors that were ER positive or of unknown ER status) awaiting curative-intent surgery. Patients received either IM fulvestrant (50, 125, or 250 mg), oral tamoxifen (20 mg, once daily), or oral placebo (once daily). Treatment started 2 to 3 weeks before surgery and blood was taken at various times up to 12 weeks after fulvestrant administration to assess pharmacokinetic variables. Results: A total of 200 patients entered the trial, of whom 58 took part in the pharmacokinetic analysis (50 mg, n = 20; 125 mg, n = 16; 250 mg, n = 22). Following single IM injections of fulvestrant, the median time to maximum concentration was 6.98, 6.98, and 6.96 days in the 50-, 125,- and 250-mg dose groups, respectively, with an overall range of 2 to 19 days). The plasma concentration-time profiles were primarily controlled by the rate of absorption from the injection site; post-peak plasma concentrations declined over time and were measurable up to 84 days after administration of fulvestrant 125 and 250 mg. Plasma

Fluorouracil, Doxorubicin, and Cyclophosphamide Followed by Tamoxifen as Adjuvant Treatment for Patients with Stage IV Breast Cancer with No Evidence of Disease

We conducted a single-institution study to determine whether local therapy plus six cycles of chemotherapy with 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) followed by 5 years of tamoxifen is superior to local treatment alone in terms of disease-free survival (DFS) and overall survival (OS) in patients with stage IV breast cancer with no evidence of disease (stage IV-NED breast cancer). Patients with breast cancer were eligible if they had histologic proof of a locoregional or distant recurrence that had been curatively resected, irradiated, or both and had no other evidence of disease. Patients who had received prior anthracycline therapy were not eligible. All patients received six cycles of intravenous FAC, with cycles repeated every 3 weeks. After completion of chemotherapy, patients whose tumors had not previously demonstrated resistance to tamoxifen and had positive or unknown estrogen receptor status received tamoxifen 20 mg by mouth daily for 5 years. Patients in this study were compared with a historical control population (patients with stage IV-NED breast cancer who never received systemic therapy) as well as with the patients in two previously reported trials of chemotherapy for stage IV-NED disease. Forty-seven patients were registered, but only 45 were evaluable. There was a highly statistically significant difference ( p < 0.001) in OS and DFS among the four groups, with patients in our most recent study having the best OS and DFS at 3 years compared with the control group (84% vs. 55% and 66% vs. 11%, respectively). When patients in all four groups were analyzed together in search of prognostic factors, we found that patients whose primary tumors had negative axillary lymph nodes had a statistically significant improvement in OS and DFS ( p < 0.01) compared with patients with positive axillary lymph nodes. No survival differences were found between patients with positive and those with negative hormone receptor status. This study demonstrates a benefit in terms of OS and DFS for patients with stage IV-NED breast cancer who receive doxorubicin-based adjuvant chemotherapy. The benefit was greater on patients with node-negative primary tumors. In patients with stage IV-NED disease, doxorubicin-based chemotherapy should be considered standard treatment after adequate local control is achieved.

Multimodal Treatment Strategy for Locally Advanced Breast Cancer

Between 1990 and 1995, 87 patients with locally advanced breast cancer were treated with initial chemotherapy consisting of 3-4 cycles of epirubicin and then with surgery, radiotherapy and chemotherapy. All patients with positive or unknown estrogen receptor status were administered tamoxifen. A complete response was observed in 9 patients and a partial response in 64. At a mean follow-up of 29.22 months, 25 patients had died of metastatic disease, and 48 patients are disease-free. 54% patients are alive at 5 years. Statistical analysis confirmed that neither age, menopausal status, size of the primary tumor nor histology seemed to influence the Disease Free and Overall Survival. Improved survival was observed in patients with negative lymph nodes and positive receptor status. The presence of a positive receptor status may be correlated with conserved integrity of hormone sensitivity and with a good response to the hormone therapy.

Aminoglutethimide in patients with metastatic breast cancer

Aminoglutethimide (AG) was administered as palliative therapy in 112 patients with metastatic breast cancer. In 36 patients, the dose level was 1000 mg/day; 76 patients received a dose level of 500 mg/day. Patients with brain or liver metastasis were excluded, as were patients with tumors determined to be negative for estrogen receptors. Objective regression was observed in 35 (31%) patients, with the duration of response ranging from 4 to 36 + months (mean, 12 months; median, 10 months). Response was observed in 11 of 31 (35%) patients with soft tissue metastasis; 16/59 (27%) patients with osseous metastasis; and 8 of 22 (36%) having visceral metastasis. In 93 patients with positive estrogen receptor (ER), 33 responded (35%), whereas in 19 patients with unknown ER status, two responded (11%). Response to previous treatment with tamoxifen (TAM) had occurred in 31 patients; of these, response to AG was noted in 11 (35%). Of 24 patients failing to respond to prior treatment with tamoxifen, four (17%) responded to subsequent therapy with AG. Thirteen patients had previously received combination chemotherapy, and response to AG was noted in two (15%). The side effects observed in this study included skin rash in ten patients, fever in eight, somnolence in three, weakness and dizziness in one, headache in one, insomnia in one, dyspnea in one, and ataxia in one. Treatment had to be discontinued in eight patients, due to the severity of the side effects. As expected, patients receiving AG at the lower dose level of 500 mg/day experienced fewer and less severe side effects than those treated with the higher dose. The response rate in the 1000 mg/day group was 10/36 (28%) and in the 500 mg/day group, it was 25/76 (33%). The lower dosage was better tolerated without apparent compromise in therapeutic efficacy.

Therapeutic oophorectomy in metastatic breast cancer.

One hundred five patients undergoing therapeutic oophorectomy for metastatic breast cancer (n = 105) from 1975 to 1985 were reviewed. There were 54 responders (51%) to oophorectomy, with a median duration of response of 16 months (range, 3 to 129 months). Thirty of 42 (71%) estrogen receptor (ER)-positive patients responded to oophorectomy versus five of 24 (21%) ER-negative patients (P less than 0.001). Of the 39 patients with unknown ER status, 19 (49%) responded to oophorectomy. Osseous, soft tissue, and pulmonary metastases responded at similar rates. Of the 16 patients who had received adjuvant chemotherapy, there were five responders (31%) to oophorectomy. Second-line endocrine therapy was effective in 29 of 53 (55%) patients. Fifteen of 28 (54%) ER-positive patients responded to second-line endocrine therapy while two of six (33%) ER-negative patients responded. Twenty-three of 37 (62%) oophorectomy responders responded to second-line endocrine therapy versus six of 16 (38) nonresponders. Oophorectomy appears to be a valuable palliative treatment for metastatic breast cancer. ER-positive patients have the best chance of responding to this therapy. However, ER-negative patients have a reduced but definite chance of responding with a good duration of response. Response to further endocrine treatments is predicted by response to oophorectomy and to a lesser degree by ER status.