Node Negative Estrogen Receptor Research Articles

Relationship of pathological features and a 21 gene expression assay in younger versus older women with node-negative endocrine receptor-positive breast cancer.

Determining the need for adjuvant chemotherapy in estrogen receptor (ER)+ disease can be influenced by pathological characteristics and gene expression assays [i.e., Oncotype Dx recurrence scores (RSs)]. The primary objective of this study is to investigate the relationship between the RSs and pathological markers in younger (< 50) versus older (≥ 50) women with early-stage node-negative ER+ breast cancer. This was a single academic-center retrospective cohort study. Subjects who underwent Oncotype gene expression testing were retrospectively and sequentially identified. 436 Subjects were identified of which 344 were eligible for analysis (133 younger subjects <50years of age, and 211 older subjects ≥ 50years). Pathological data assessed included the progesterone receptor (PR), histological grade (grade), Ki-67, and P53. A multivariable regression analysis was performed using age, PR, and grade as predictor variables for RS. Adjusted R2 was determined. To investigate the primary objective, subjects were stratified based on age, PR, and grade status in that sequence. Within each tumor subtype as determined by PR and grade statuses, the RSs in the younger versus older age group were compared using Student's t-test and the differences in the 95% confidence interval limits in RS means calculated. Age influence on adjuvant chemotherapy recommendation was also assessed by stratifying subjects based on age (< 50 vs. ≥ 50) and then by RS risk group (≤ 10, 11-25, ≥ 26). Subsequently, the proportions of younger versus older subjects within identical RS risk groups who were explicitly advised by their oncologist to proceed with chemotherapy as documented in their electronic health records were compared using χ2 test. Based on the multivariable regression analysis, the adjusted R2 was 0.229232 and RS was found to be independent of age (p = 0.7169). Between younger and older subjects with tumors with similar PR and grade pathological features, the differences in the RS were insignificant (p > 0.05). Chemotherapy was recommended in younger versus older women, in 0% when the RS was ≤ 10, 39% and 40% when the RS was 11-25 (p = 0.82), and 100% and 98% when the RS was ≥ 26 (p = 0.51), respectively. The relationship between pathological features and RS is consistent irrespective of age; therefore, models predicting RS may be applicable irrespective of age.

Abstract P1-09-14: Breast carcinoma with 21-gene recurrence score lower than 18: Rate of distant metastases in a large series with clinical follow-up

Abstract Background: The 21-gene recurrence score (RS) estimates the likelihood of distant recurrence and the benefit from chemotherapy in patients with early-stage node-negative, estrogen receptor (ER)-positive, HER2-negative breast carcinoma. The use of the assay resulted in a substantial reduction in adjuvant chemotherapy usage. In this study, we reviewed the outcome of patients with node-negative, ER+/HER2- breast cancer and low recurrence score treated at our center to further verify the prognostic value of the assay. Design: We identified breast cancer patients treated at our center between 09/2008 and 08/2013 with ER-positive, HER2-negative breast cancer and known RS. We reviewed clinicopathological characteristics, RS, treatment and outcome data. The Institutional Review Board approved the study. Results: We identified 1406 consecutive patients with early stage node negative ER+/HER2- breast cancer and low RS [RS 0-10: 510 (36%), RS 11-17: 896 (64%)] in the study period. The median age at breast cancer diagnosis was 56 years (range 22-90). Sixty-three (4%) patients were &amp;lt;40 years old at breast cancer diagnosis. A total of 1362 (97%) patients received endocrine therapy, and 170 (12%) received chemotherapy. The median follow up time was 46 months (range 1-85). Six (0.4%) of the 1406 patients developed biopsy proven distant metastases within 5 years of breast cancer diagnosis, 5 of which were in the RS 11-17 group (Table 1). Three of the 5 patients with RS 11-17 and distant metastases were younger than 40 years old at breast cancer diagnosis. In the RS 11-17 group, the absolute incidence of distant metastases among patients with breast cancer diagnosed at age younger than 40 years old is 7.1% (3/42), whereas the absolute incidence of distant metastases among patients ≥40 years is 0.2% (2/854). Conclusion: Our results suggest that young age (&amp;lt;40 years old) might be a negative prognostic factor even in patients with low RS. Analysis of data from other studies is necessary to further validate this observation. Table 1. Clinicopathologic characteristics of the 6 patients with ER-positive, HER2-negative, node-negative breast carcinoma of recurrence score &amp;lt;18 who developed distant metastasisPatients#1#2#3#4#5#6Age at diagnosis (years)505437713839Family history of breast/ ovarian cancerNoYesNoNoNoYesPersonal history of breast carcinomaNoIpsilateral DCISNoIpsilateral DCISNoNoTumor typeILCIDCIDCIDCIDCIDCTumor size (cm)2.11.32.72.31.62.1Tumor Grade222223LVINoNoNoNoYesNoER (%)909595959595PR (%)30585757595Oncotype DX RS51212131417SurgeryBTMTMBTMBCSBCSBTMRadiationNoNoNoYesYesNoEndocrine therapyYesYesYesYesNoYesChemoNoNoCMFNoNoNoTime interval to metastasis (months)584125204812Site of metastasisBoneMultipleLungMultipleMultipleBoneFollow-up (months)725359647142SurvivalAWDAWDAWDDODAWDAWDAbbreviations: RS, recurrence score; ILC, invasive lobular carcinoma; IDC, invasive ductal carcinoma; LVI, lymphovascular invasion; BTM, bilateral total mastectomy; TM, total mastectomy; BCS, breast conserving surgery; CMF, cyclofosphamide, metotrexate and 5-fluorouracil. AWD, alive with disease; DOD, died of disease. Citation Format: Wen HY, Krystel-¬Whittemore M, Patil S, Pareja F, Bowser ZL, Dickler M, Norton L, Morrow M, Hudis C, Brogi E. Breast carcinoma with 21-gene recurrence score lower than 18: Rate of distant metastases in a large series with clinical follow-up [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 P1-09-14.

Breast carcinoma with an Oncotype Dx recurrence score

A 21-gene expression assay (Oncotype DX recurrence score [RS]) that uses reverse transcriptase-polymerase chain reaction is used clinically in patients with early-stage, estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast carcinoma (ER+/HER2- BC) to determine both prognosis with tamoxifen therapy and the usefulness of adding adjuvant chemotherapy. Use of the assay is associated with reductions in overall chemotherapy use. The current study examined the treatments and outcomes in patients with low RS. The authors reviewed the institutional database to identify patients with lymph node-negative, ER+/HER2- BC who were treated at the study institution between September 2008 and August 2013 and their 21-gene RS results. A total of 1406 consecutive patients with lymph node-negative ER+/HER2- BC and a low RS were identified (510 patients had an RS of 0-10 and 896 patients had an RS of 11-17). The median age at the time of diagnosis of BC was 56 years; 63 patients (4%) were aged <40 years. Overall, 1361 patients (97%) received endocrine therapy and 170 patients (12%) received chemotherapy. The median follow-up was 46 months. Six patients (0.4%) developed distant metastases (1 patient with an RS of 5 and 5 patients with an RS of 11-17). In the cohorts of patients with an RS of 11 to 17, the absolute rate of distant metastasis among patients aged <40 years was 7.1% (3 of 42 patients) versus 0.2% among patients aged ≥40 years (2 of 854 patients). The data from the current study document a 0.4% rate of distant metastasis within 5 years of BC diagnosis among patients with lymph node-negative ER+/HER2- BC with an RS <18. Patients aged <40 years at the time of BC diagnosis were observed to have a higher rate of distant metastases. Analysis of data from other studies is necessary to validate this observation further. Cancer 2017;131-137. © 2016 American Cancer Society.

Abstract P6-06-03: Differing patterns of treatment effect in a trial assessing sequential docetaxel as adjuvant chemotherapy for early breast cancer (TACT)

Abstract Background : Plausible underlying treatment effects were investigated in exploratory analysis of the translational component of TACT, a large adjuvant chemotherapy trial (Lancet 2009:373, 1681). Some breast cancer patients are cured by primary therapy and are therefore not at risk of relapse, potentially confounding treatment comparisons using Cox regression, exploratory comparison of outcomes can be undertaken using parametric cure models (PCM) which estimate the proportion of patients cured and the pattern of events in patients not cured. Methods : TACT compared sequential anthracycline-taxane (FEC-D) adjuvant chemotherapy with an anthracycline regimen of similar duration. As part of TransTACT ER Allred scores were assessed centrally on two cores per patient by two pathologists (CG and SP). PCM was implemented using the CUREREGR command in Stata (Buxton A 2007), a lognormal model for time to relapse being fitted for the category of patients who were not cured. The primary endpoint for the analyses was relapse free interval. Results : 2892 patients had Estrogen Receptor (ER) assessed centrally, 1851 tumors were ER positive and 1041 were ER negative, median follow up was 8 years. The proportion of patients cured was related to established prognostic characteristics such as nodal status. In unselected ER+ patients evidence of cure was weak but it could not be ruled out in some subgroups e.g. in node negative ER+ patients the estimate of the proportion cured was approximately 70% (p = ns). In unselected ER- patients the pattern of relapse implied by PCM was found to differ significantly between taxane treated and control patients (p&amp;lt;0.0001), despite the fact there was no overall evidence of a treatment effect (Hazard ratio 0.98, p = 0.71 by Cox Regression). In taxane treated patients the estimate of the proportion of patients cured was 65% (95%CI:60-69), and the estimated median time to relapse in those not cured was 1.9 years (95%CI:1.7-2.1), in the control group the estimates were 45% (95%CI:29-62) cured and in patents not cured median time to relapse 4.2 years (95%CI:2.1-8.4). Conclusions : The concept of cure is of particular interest in tumour subtypes, such as ER negative tumours, in which event rates are high in early years (1-4) but low subsequently. In ER- patients PCM suggested the model-defined cure rate was about 20% higher in docetaxel treated patients, however this was counterbalanced by worse prognosis in the patients without model defined cure. EBCTCG results examining the taxane effect on recurrence were not directly available to support this finding but breast cancer mortality curves in more than 35,000 women with follow up to 8 years (Lancet 379, 432 Webappendix, p15) showed patterns in ER- patients that were consistent with a higher cure rate in taxane treated patients, in addition there was little evidence of cure in unselected ER+ patients. In this study PCM identified differences in the treatment effect between the randomised groups despite the fact there was no evidence of an overall difference based on the hazard ratio by Cox regression, suggesting PCM may have a useful role in exploratory analysis to look for treatment effects in situations where cure is a possibility. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-06-03.

Genomics of Adjuvant Therapy for Breast Cancer

Therapeutic decision for adjuvant systemic therapy for breast cancer involves assessment of baseline risk and estimated benefit from systemic therapy. Molecular profiling studies have clearly demonstrated heterogeneity of chemotherapy response across different molecular subtypes of breast cancer. Meta-analyses of publicly available data from gene expression profiling studies have demonstrated that breast cancer can be divided into 4 basic categories based on expression levels of estrogen receptor (ER), HER2, and proliferation-associated genes; ER-, HER2+, ER+/HER2-/low proliferation, and ER+/HER2-/high proliferation. Notably ER- or HER2+ tumors are associated with high levels expression of proliferation genes, although there is a wide spectrum of expression levels of proliferation genes among ER+/HER2- tumors. Estrogen receptor-positive/HER2-/low-proliferation tumors are associated with a favorable prognosis. Synthetic lethal screening approach has demonstrated that most of the chemotherapeutic agents do not have specific molecular targets. Therefore, it could be hypothesized that chemosensitivity would be largely dictated by proliferation activity of tumor cells. Therefore, tumors with ER-, HER2+, or ER+/HER2-/high proliferation gene expression profile can be categorized as chemosensitive tumors, whereas ER+/HER-/low proliferation tumors categorized as chemoresistant. Therefore, clinical utility of gene expression profiling is mainly in aiding the chemotherapy decision for ER+ patients. Although evidence from prospective randomized clinical trials are lacking, because of the excellent baseline prognosis of patients with ER+/HER2-/low proliferation tumors when treated with endocrine therapy and because of scientific evidence of chemoresistance of these tumors, a comfort zone has been reached among oncologists to allow clinical use of gene expression tests to identify patients who do not require chemotherapy among node-negative ER+ patients. However, these tools are still probabilistic at best in their performances, and one cannot exactly predict which patient will have recurrence after assigned therapies until the time of recurrence. Therefore, strategies have to be established to identify patients who will fail standard chemoendocrine therapies among high-risk patients (ER+/HER2-/high proliferation, HER2+, or ER-) before recurrence events. Neoadjvant therapy can provide such venue because regardless of regimens used the prognosis of those achieving complete pathological response is excellent. Postneoadjuvant setting can be then used for patients with gross residual disease to test novel therapeutic agents.

Abstract P3-10-35: Using Automated Image Analysis To Validate Ki67 as a Clinical Prognostic Biomarker for Estrogen-Receptor Positive Breast Cancers

Abstract Background: Ki67, an indicator of proliferation, has been shown to be a useful prognostic and predictive marker for breast cancer. Ki67 can be used to identify two distinct estrogen-receptor positive subtypes: luminal A and luminal B. Luminal A breast cancers have been identified as having a lower proliferation and better outcome compared to luminal B. Furthermore, early clinical trials suggest that Ki67 may be useful in identifying a subset of patients that are sensitive to adjuvant docetaxel treatment. Currently, only estrogen-receptor (ER), progesterone-receptor (PR), and human epidermal growth-factor (HER2) are routinely performed. We have optimized and validated an immunohistochemical (IHC) Ki67 assay and automated computerized image analysis platform for routine clinical testing. Materials and Methods: Immunohistochemical staining was quantitatively assessed using the ACIS® III platform on a cohort (N=761) of tamoxifen treated patients who were diagnosed with breast cancer in Calgary between 1990 and 2001. Tissue microarrays were constructed using three 0.6 mm cores. Ki67 results were available for 510 patients, 461 of which are ER/PR positive and HER2 negative. Staining was performed using the DAKO FLEX ready-to-use system. The percent nuclear area positive was calculated using ACIS III and the maximum value was used in statistical analysis Results: X-tile statistical software was used to identify an optimal Ki67 cut point to distinguish differential overall survival in node negative ER positive cancers of 18.75%. This cut point was then used to categorize the 461 ER/PR positive and HER2 negative breast cancers into luminal A (407; 88.3%) or luminal B (54; 11.7%) subtypes. The 8-year breast cancer specific survival was 85.2% (95% CI = 81.3% - 89.1%) for luminal A and 53.6% (95% CI = 39.3% - 67.9%) for luminal B (P&amp;lt;0.0001). Cox regression showed a hazard ratio of 1.63 (95% CI = 0.99 — 2.67, p=0.055), adjusting for age, tumor size, grade and lymph node status. Discussion: Quantification of Ki67 expression using automated image analysis can be used clinically to distinguish luminal A from luminal B in ER/PR positive and HER2 negative breast cancers. The purpose of this project was to develop a reliable Ki67 assay that can be easily adopted by other testing centers. Using a ready-to-use IHC system — such as DAKO FLEX — allows for consistent results between other clinical laboratories. Additionally, using an automated, quantitative imaging system — such as the ACIS® III — reduces inter-observer variation that can occur by human visual assessment. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-10-35.

The effects of Oncotype DX recurrence scores on chemotherapy receipt in a multi-institutional breast cancer cohort.

669 Background: The use of traditional clinicopathologic features in decision making in early stage estrogen receptor (ER)-positive breast cancer (BC) may lead to over or under treatment. We investigated the effect of the Oncotype Dx (ODX) genomic profile on receipt of chemotherapy (CTX) in two tertiary cancer centers. Methods: 276 cases of node-negative ER positive BC from two tertiary cancer centers had ODX performed on tumor blocks between 2005 and 2009. Age at diagnosis, tumor size, grade, histology, presence of lymphovascular invasion, and PR status were abstracted from records and provided to 2 medical oncologists specializing in breast cancer. The Adjuvant! Online (AO) relapse risk and the Nottingham Prognostic index (NPI) were calculated. Results: Median age was 55 years (range, 29-82). 13% of patients had a negative PR status. Mean tumor size was 1.58 cm. Fifty percent had grade 2 BC, 38% and 12% were grade 1 and 3. The median 10 year AO relapse risk was 23 (range, 13-60). The median NPI was 3.4 with 80% of patients in the excellent or good category. The median ODX recurrence score was 17. 51%, 40%, and 9% of patients were in the low, intermediate, and high risk categories respectively. Prior to obtaining ODX, medical oncologists were more likely to recommend CTX to women who were younger (p < 0.0001), had negative PR status (p < 0.0001), higher NPI (p < 0.012), and tumors greater than 1 cm (p < 0.015). The average tumor size of patients recommended CTX was 2.0 cm versus 1.2 cm in the group not recommended CTX. The mean AO for those recommended CTX was 28.6 versus 18.9 for those not recommended CTX. ODX resulted in a change in management for 38% of individuals. Of 188 total patients who ultimately DID NOT receive CTX, 71 of them had an initial CTX recommendation. Of 88 patients who DID receive CTX, 34 of them did not have an initial recommendation. CTX was administered to 13/142 patients with low ODX, 52/110 with intermediate ODX, and 23/24 with high ODX. Only 3/24 women with high-risk ODX did not have an initial CTX recommendation. Conclusions: In our multi-institutional cohort, the ODX score had a significant impact on adjuvant chemotherapy decisions. No significant financial relationships to disclose.