Estrogen Receptor-positive Invasive Breast Cancer Research Articles

Glucocorticoid Receptor Activation in Lobular Breast Cancer Is Associated with Reduced Cell Proliferation and Promotion of Metastases.

Estrogen receptor-positive (ER+) invasive lobular breast cancer (ILC) comprises about ~15% of breast cancer. ILC's unique genotypic (loss of wild type E-cadherin expression) and phenotypic (small individual round cancer cells that grow in discontinuous nests) are thought to contribute to a distinctive pattern of metastases to serosal membranes. Unlike invasive ductal carcinoma (IDC), ILC metastases often intercalate into the mesothelial layer of the peritoneum and other serosal surfaces. While ER activity is a known driver of ILC proliferation, very little is known about how additional nuclear receptors contribute to ILC's distinctive biology. In ER+ IDC, we showed previously that glucocorticoid receptor (GR) activity inhibits pro-proliferative gene expression and cell proliferation. Here we examined ER+ ILC models and found that GR activation similarly reduces S-phase entry gene expression and ILC proliferation. While slowing tumor growth rate, our data also suggest that GR activation results in an enhanced metastatic phenotype through increasing integrin-encoding gene expression, extracellular matrix protein adhesion, and mesothelial cell clearance. Moreover, in an intraductal mouse mammary gland model of ILC, we found that GR expression is associated with increased bone metastases despite slowed primary mammary tumor growth. Taken together, our findings suggest GR-mediated gene expression may contribute to the unusual characteristics of ILC biology.

De-Implementation of Low-Value Care for Women 70 Years of Age or Older with Low-Risk Breast Cancer During the COVID-19 Pandemic

BackgroundOlder women with early-stage estrogen receptor-positive (ER+) invasive breast cancer (IBC) are at risk for overtreatment. Guidelines allow for sentinel lymph node biopsy (SLNB) and radiotherapy omission after breast-conserving surgery (BCS) for women 70 years of age or older with T1, clinical node negativity (cN0), and ER+ IBC. The study objective was to evaluate radiotherapy and SLNB de-implementation in older women with low-risk IBC after the resource limitations of the COVID-19 pandemic.MethodsAn institutional database was analyzed to identify women 70 years of age or older who received BCS for IBC from 2012 to 2022. The patients were divided into two cohorts: (1) patients with low-risk IBC (pT1, cN0, and ER+/HER2–) who were eligible for radiotherapy and SLNB omission and (2) patients with high-risk IBC (pT2-T4, cN+, ER–, or HER2+) who were ineligible for therapy omission. Clinicopathologic variables in both cohorts were analyzed.ResultsThe study enrolled 881 patients. For the patients with low-risk IBC, the annual rates of radiotherapy were stable from 2012 to 2019. However, radiotherapy utilization decreased significantly from 2020 to 2022 (58% in 2012 vs 36% in 2022; p = 0.04). In contrast, radiotherapy usage among the patients with high-risk IBC was stable from 2012 to 2022 (79% in 2012 vs 79% in 2022; p = 0.95). Among the patients with low-risk IBC, SLNB rates decreased from 86% in 2012 to 56% in 2022, but this trend predated those in 2020. The factors significantly associated with SLNB and receipt of radiotherapy among the patients with low-risk IBC were younger age, larger tumors, grade 3 disease, and involved nodal status (p < 0.01).ConclusionThis study demonstrated appropriate and sustained de-escalation of radiotherapy in older women with low-risk IBC after the COVID-19 pandemic.

Abstract 5354: Prediction of OncotypeDX high risk group for chemotherapy benefit in breast cancer by deep learning analysis of hematoxylin and eosin-stained whole slide images

Abstract Introduction: Breast cancer is the most common cancer in women, with most patients diagnosed with early-stage disease. While adjuvant therapy should be considered in all fit patients, in many low-risk patients drug toxicity may out-weigh the potential benefit, therefore, identifying these patients is desired. Hematoxylin and eosin (H&amp;E) is the basic staining routinely performed for biopsies. It allows visual examination of the tissue and cells. Such manual examination, however, does not provide information about the molecular profile of the cancer, which is essential for diagnosis and guidance of treatment. The OncotypeDX assay is recommended for patients with node-negative, estrogen receptor-positive invasive breast cancer for determining chemotherapy benefit. It is based on RT-PCR gene expression profiling and provides a recurrence score (RS) that enables patient stratification to non-high risk (RS &amp;lt; 26) and high risk (RS ≥ 26). It was shown that high risk patients are likely to benefit from chemotherapy, while non-high risk are not. Unlike H&amp;E staining, the OncotypeDX assay is costly, time consuming, and inaccessible in low-income countries. Here, we sought to evaluate whether analysis of scanned H&amp;E-stained slides by convolutional neural networks (CNNs) could predict the RS risk group (high versus non-high), which determines eligibility for chemotherapy. Methods: 684 H&amp;E-stained slides were collected from 430 invasive breast cancer patients who were assayed for OncotypeDX between 2014 and 2020 at Sheba medical center, Israel. The slides were scanned at 0.25 micron/pixel, and automatically segmented and split to 256 × 256 non-overlapping tiles, resulting in overall 339,986 tile images containing tissue. The patients were randomly split into training (75%) and test (25%) sets, and a CNN model was trained and validated on the training set to classify each tile to non-high risk (RS &amp;lt; 26) versus high risk (RS ≥ 26), in 5-fold cross-validation. The final model was then applied to the held-out test set, and tile scores were aggregated to produce per-patient prediction scores. The final CNN prediction scores on the test set were compared to the ground truth risk group and the AUC performance was calculated. Results: The AUC performance of the model on the held out test set for high-risk versus non-high-risk classification based on the H&amp;E images alone was high (0.798, 95% CI: 0.689 - 0.875, P value &amp;lt; 0.001), showing that the H&amp;E image analysis could predict the high risk group. Conclusions: These results show, for the first time, that CNN-based analysis of H&amp;E images could predict benefit from chemotherapy, thus implying distinct tumor morphologies differing between RS groups. Utilizing such a system may enable physicians in countries that lack genetic profiling capabilities to refine chemotherapy stratification based on H&amp;E images alone. Citation Format: Gil Shamai, Ran Schley, Ron Kimmel, Nora Balint-Lahat, Iris Barshack, Chen Mayer. Prediction of OncotypeDX high risk group for chemotherapy benefit in breast cancer by deep learning analysis of hematoxylin and eosin-stained whole slide images. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5354.

Optimizing Preventive Adjuvant Linac-Based (OPAL) Radiation: A Phase 2 Trial of Daily Partial Breast Irradiation

Evidence supports use of partial-breast irradiation (PBI) in the management of early breast cancer, but the optimal dose-fractionation remains unsettled. We conducted a phase 2 clinical trial (OPAL trial) to evaluate a novel PBI dosing schedule of 35 Gy in 10 daily fractions. Patients with close (<2 mm) margins also received a boost of 9 Gy in 3 fractions. Eligible patients underwent margin-negative lumpectomy for ductal carcinoma in situ or estrogen receptor-positive invasive breast cancer, up to 3 cm, pTis-T2 N0. The primary outcome was any grade ≥2 toxic effect occurring from the start of radiation through 6 months of follow-up. Secondary outcomes included patient-reported cosmesis, breast pain, and functional status, measured using the Breast Cancer Treatment Outcomes Scale, and physician-reported cosmesis, measured using the Radiation Therapy and Oncology Group scale. The Cochran-Armitage trend test and multivariable mixed-effects longitudinal growth curve models compared outcomes for the OPAL study population with those for a control group of similar patients treated with whole-breast irradiation (WBI) plus boost. All 149 patients enrolled on the OPAL trial received the prescribed dose, and 17.4% received boost. The median age was 64 years; 83.2% were White, and 73.8% were overweight or obese. With median follow-up of 2.0 years, 1 patient (0.7%) experienced in-breast recurrence. Prevalence of the primary toxicity outcome was 17.4% (26 of 149 patients) in the OPAL trial compared with 72.7% (128 of 176 patients) in the control WBI-plus-boost cohort (P < .001). In longitudinal multivariable analysis, treatment on the OPAL trial was associated with improved patient-reported cosmesis (P < .001), functional status (P=.004), breast pain (P=.004), and physician-reported cosmesis (P < .001). Treatment with daily PBI was associated with substantial reduction in early toxicity and improved patient- and physician-reported outcomes compared with WBI plus boost. Daily external-beam partial-breast irradiation with 13 or fewer fractions merits further prospective evaluation.

Analysis of Sociodemographic, Clinical, and Genomic Factors Associated With Breast Cancer Mortality in the Linked Surveillance, Epidemiology, and End Results and Medicare Database

Understanding interactions among health service, sociodemographic, clinical, and genomic factors in breast cancer disparities research has been limited by a disconnect between health services and basic biological approaches. To describe the first linkage of Surveillance, Epidemiology, and End Results (SEER)-Medicare data to physical tumor samples and to investigate the interaction among screening detection, socioeconomic status, tumor stage, tumor biology, and breast cancer outcomes within a single context. This population-based cohort study used tumor specimen blocks from a subset of women aged 66 to 75 years with newly diagnosed nonmetastatic, estrogen receptor-positive invasive breast cancer from January 1, 1993, to December 31, 2007. Specimens were obtained from the Iowa and Hawaii SEER Residual Tissue Repositories (RTRs) and linked with Medicare claims data and survival assessed through December 31, 2015. Data were analyzed from August 1, 2018, to July 25, 2021. Screening- vs symptom-based detection of tumors was assessed using validated claims-based algorithms. Demographic factors and zip code-based educational attainment and poverty socioeconomic characteristics were obtained via SEER. Molecular subtyping and exploratory genomic analyses were completed using the NanoString Breast Cancer 360 gene expression panel containing the 50-gene signature classifier. Factors associated with overall and breast cancer-specific (BCS) survival were analyzed using Cox proportional hazards regression models combining sociodemographic, clinical, and genomic data. SEER-Medicare data were available for 3522 women (mean [SD] age, 70.9 [2.6] years; 3049 [86.6%] White), of whom 1555 (44.2%) were diagnosed by screening mammogram. In the SEER-Medicare cohort, factors associated with increased BCS mortality included symptomatic detection (hazard ratio [HR], 1.49 [95% CI, 1.16-1.91]), advanced disease stage (HR for stage III, 2.33 [95% CI, 1.41-3.85]), and high-grade disease (HR, 1.85 [95% CI, 1.46-2.34]). The molecular cohort of 130 cases with luminal A/B cancer further revealed increased all-cause mortality associated with genomic upregulation of transforming growth factor β activation and p53 dysregulation (eg, p53 dysregulation: HR, 2.15 [95% CI, 1.20-3.86]) and decreased mortality associated with androgen receptor, macrophage, cytotoxicity, and Treg signaling (eg, androgen receptor signaling: HR, 0.23 [95% CI, 0.12-0.45]). Symptomatic detection (HR, 2.49 [95% CI, 1.19-5.20]) and zip codes with low levels of educational attainment (HR, 5.17 [95% CI, 2.12-12.60]) remained associated with mortality after adjusting for all clinical and demographic factors. Linkage of SEER-Medicare data to physical tumor specimens may elucidate associations among biology, health care access, and disparities in breast cancer outcomes. The findings of this study suggest that screening detection and socioeconomic status are associated with survival in patients with locally advanced, estrogen receptor-positive tumors, even after incorporating clinical and genomic factors.

Abstract PD4-02: Sentinel node biopsy should not be routine in older patients with ER positive breast cancer

Abstract Background:Based on randomized controlled trials demonstrating no survival benefit of axillary dissection in elderly breast cancer patients, the SSO/Choosing Wisely campaign recommended against the routine use of sentinel lymph node biopsy (SLNB) in clinically node negative patients aged ≥70 with estrogen receptor (ER) positive breast cancer in 2016. SLNB is still performed in &amp;gt;80% of such patients and we have previously shown that at our institution, SLNB positivity influences adjuvant therapy decisions in this population. In this study, we sought to validate the association of SLNB positivity and adjuvant treatment in a larger population-based cohort, and to evaluate the impact of this finding on oncologic outcomes. Methods:The Breast Cancer Outcome Unit (BCOU) prospectively collects demographic, pathologic, treatment and outcomes data on all patients referred to BC Cancer with breast cancer in British Columbia, Canada. Female patients aged ≥70 with newly diagnosed estrogen receptor-positive invasive breast cancer who underwent SLNB from 2010-2016 were included. Patients with HER2-positive disease or those treated with neoadjuvant therapy were excluded. Multivariable analysis was used to assess the effect of SLNB positivity on adjuvant treatment. Overall survival (OS) and breast cancer specific survival (BCSS) were assessed using Kaplan-Meier analysis and Cox regression was used to assess contribution of SLNB positivity and adjuvant treatment. A nomogram was created to model the effect of nodal positivity and adjuvant treatment on BCSS. Results:We identified 2580 patients who met study criteria with a median age of 75 and a median tumor size of 15 mm. SLNB was positive in 23%. Sixty-seven percent of patients had breast conserving surgery (BCS) and 62% of patients had RT (BCS 79%, mastectomy 25%). As systemic therapy 5% of patients had chemotherapy (CT) and 78% of patients had hormone therapy (HT). Use of adjuvant therapies was associated with SLNB positivity: Systemic therapy (HR = 2.4, 95% CI: 1.84-3.14, p &amp;lt;0.0001), RT (HR = 4.94, 95% CI: 3.91-6.25, p &amp;lt;0.0001) and nodal RT (HR = 61.4, 95% CI: 26.6-141.7, p &amp;lt;0.0001). The 5-year OS was 86% and BCSS was 96% with a median follow-up of 4.33 years (95% CI 4.21-4.47 years). There was improved BCSS with receipt of HT (HR 0.51 95% CI 0.301-0.875, p=0.0142) and worse BCSS with grade 3 vs grade 1 disease (HR 4.09, 95% CI 2.06-8.10, p&amp;lt;0.0001). Age, tumor size, status of SLNB and use of RT were not significant prognostic variables. Patients with a positive SLNB who did not receive any adjuvant therapy had lower BCSS (HR 3.22 95% CI 1.235-8.418, p=0.0168) than those with a negative SLNB. However, amongst those who received any combination of CT, HT and RT, there was no significant difference in BCSS regardless of nodal status. A nomogram was developed incorporating tumor size, grade, SLNB status and adjuvant treatment. Using the nomogram, patients aged 75-79 with T1, grade 1-2 tumors, with or without positive SLNB and treated with or without adjuvant therapy had 5-year BCSS ≥95%. The nomogram also indicated that 5-year BCSS was similar for patients with positive and negative SLNB for all combinations of tumor features when patients received HT. Conclusions:In this modern, population-based cohort of patients over 70 with ER-positive breast cancer, 5-year BCSS was excellent at 96%. Although the use of adjuvant treatment was associated with a positive SLNB, BCSS was not changed based on nodal status when patients received HT. Our results support the Choosing Wisely recommendations; SLNB can be safely omitted in elderly patients willing to take HT, and we advocate that SLNB can be omitted in low-risk patients aged ≥75 even in the absence of planned HT. Citation Format: Elaine McKevitt, Rona Cheifetz, Kimberly DeVries, Alison Laws, Rebecca Warburton, Lovedeep Gondara, Caroline Lohrisch, Alan Nichol. Sentinel node biopsy should not be routine in older patients with ER positive breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD4-02.

Combined Use of Immunoreactivities of RIG-I with Efp/TRIM25 for Predicting Prognosis of Patients With Estrogen Receptor-positive Breast Cancer

BackgroundWe previously identified estrogen-responsive finger protein (Efp) as an estrogen-induced gene, and showed that the positive immunoreactivity of Efp is a poor prognostic factor for patients with breast cancer. We also demonstrated that Efp has distinctive roles in innate immunity by activating pattern recognition receptor retinoic acid-inducible gene I (RIG-I). The clinical value of RIG-I protein expression in breast cancer had not been evaluated in relationship with patients’ prognosis. Patients and MethodsTissue samples of estrogen receptor-positive invasive breast cancer were obtained from 145 female patients with breast cancer who underwent surgical treatment. Immunoreactivities of RIG-I and Efp were analyzed with the antibodies generated for the present study. ResultsPositive immunoreactivity of RIG-I was correlated with lower disease-free survival (P = .032) and was an independent poor prognostic factor (P = .043). RIG-I immunoreactivity was positively correlated with that of Efp (P = .0004). Patients with positive immunoreactivities of both RIG-I and Efp proteins were associated with a lower disease-free survival rate (P = .005). ConclusionsPositive immunoreactivity of RIG-I has clinical significance as a poor prognostic factor in patients with estrogen receptor-positive breast cancer. A positive correlation of RIG-I and Efp immunoreactivities was observed, and the combination of their immunoreactivities can be used to predict patients’ prognosis.

Quantitative Whole Slide Assessment of Tumor-Infiltrating CD8-Positive Lymphocytes in ER-Positive Breast Cancer in Relation to Clinical Outcome.

There is a need for a reliable and reproducible quantification of the immune infiltrate within the heterogeneous microenvironment of tumors in order to support therapy selection in oncology. Here we present an automated, modular method for whole-slide image analysis of the spatial distribution of tumor-infiltrating CD8-positive lymphocytes. The method uses a deep learning tissue-type classification algorithm on the hematoxylin eosin (HE) stained tissue section to identify the central tumor (CT) and invasive margin (IM) of the tumor. A CD8-positive cell detection algorithm using a deep learning-based nucleus detection is applied to a sequential immunohistochemistry (IHC)-stained tissue section. Image registration then allows obtaining IHC-derived CD8 scores for the HE-derived CT and the IM, respectively. Both, the mean and the standard deviation of the spatial CD8-positive density distributions were determined for the CT and IM in a cohort of post-menopausal, estrogen receptor-positive invasive breast cancer patients who received adjuvant tamoxifen therapy. Spatial density distributions were found to be highly heterogeneous. In contrast to previous studies, CD8 density in the IM and CT correlated positively with clinical outcome. However, statistical significance was only achieved for the standard deviation of the CD8 density distribution. We hypothesize that this is due to the positive contribution of local high-density areas. The IM/CT density ratio did not correlate with outcome. In view of the clinical relevance of our finding, we would like to encourage a study with a larger cohort. Our modular pipeline approach allows a robust and objective scoring of CD8 infiltrate based on routine pathology staining and should contribute to clinical adoption of computational pathology.

Race May Not Impact Endocrine Therapy–Related Changes in Breast Density

Reduction in breast density may be a biomarker of endocrine therapy (ET) efficacy. Our objective was to assess the impact of race on ET-related changes in volumetric breast density (VBD). This retrospective cohort study assessed longitudinal changes in VBD measures in women with estrogen receptor-positive invasive breast cancer treated with ET. VBD, the ratio of fibroglandular volume (FGV) to breast volume (BV), was measured using Volpara software. Changes in measurements were evaluated using a multivariable linear mixed effects model. Compared with white women (n = 191), black women (n = 107) had higher rates of obesity [mean ± SD body mass index (BMI) 34.5 ± 9.1 kg/m2 vs. 30.6 ± 7.0 kg/m2, P < 0.001] and premenopausal status (32.7% vs. 16.7%, P = 0.002). Age- and BMI-adjusted baseline FGV, BV, and VBD were similar between groups. Modeled longitudinal changes were also similar: During a follow-up of 30.7 ± 15.0 months (mean ± SD), FGV decreased over time in premenopausal women (slope = -0.323 cm3; SE = 0.093; P = 0.001), BV increased overall (slope = 2.475 cm3; SE = 0.483; P < 0.0001), and VBD decreased (premenopausal slope = -0.063%, SE = 0.011; postmenopausal slope = -0.016%, SE = 0.004; P < 0.0001). Race was not significantly associated with these longitudinal changes, nor did race modify the effect of time on these changes. Higher BMI was associated with lower baseline VBD (P < 0.0001). Among premenopausal women, VBD declined more steeply for women with lower BMI (time × BMI, P = 0.0098). Race does not appear to impact ET-related longitudinal changes in VBD. Racial disparities in estrogen receptor-positive breast cancer recurrence and mortality may not be explained by differential declines in breast density due to ET.

Radiomics signature on 3T dynamic contrast-enhanced magnetic resonance imaging for estrogen receptor-positive invasive breast cancers: Preliminary results for correlation with Oncotype DX recurrence scores.

To evaluate the ability of a radiomics signature based on 3T dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) to distinguish between low and non-low Oncotype DX (OD) risk groups in estrogen receptor (ER)-positive invasive breast cancers.Between May 2011 and March 2016, 67 women with ER-positive invasive breast cancer who performed preoperative 3T MRI and OD assay were included. We divided the patients into low (OD recurrence score [RS] <18) and non-low risk (RS ≥18) groups. Extracted radiomics features included 8 morphological, 76 histogram-based, and 72 higher-order texture features. A radiomics signature (Rad-score) was generated using the least absolute shrinkage and selection operator (LASSO). Univariate and multivariate logistic regression analyses were performed to investigate the association between clinicopathologic factors, MRI findings, and the Rad-score with OD risk groups, and the areas under the receiver operating characteristic curves (AUC) were used to assess classification performance of the Rad-score.The Rad-score was constructed for each tumor by extracting 10 (6.3%) from 158 radiomics features. A higher Rad-score (odds ratio [OR], 65.209; P <.001), Ki-67 expression (OR, 17.462; P = .007), and high p53 (OR = 8.449; P = .077) were associated with non-low OD risk. The Rad-score classified low and non-low OD risk with an AUC of 0.759.The Rad-score showed the potential for discrimination between low and non-low OD risk groups in patients with ER-positive invasive breast cancers.

The role of radiotherapy in elderly women with early-stage breast cancer treated with breast conserving surgery.

To analyze the impact of adjuvant radiotherapy (RT) on ipsilateral breast recurrence (IBR) and overall survival (OS) in patients older than 69 years with early-stage breast cancer. From January 2007 to June 2015, we analyzed retrospectively 137 women with estrogen receptor-positive T1-2 invasive breast cancer, with negative axillary lymph nodes, dividing them into 2 subgroups: 70 to 79 years and older than 79 years. After a median follow-up of 43.2 months, the 3-year IBR-free survival in patients treated with surgery plus RT was 98.8% and 92.1% in patients treated with surgery alone, with a significant difference (p = .01). Radiotherapy did not impact overall survival (p = .10). A higher percentage of patients aged between 70 and 79 years received RT after conservative surgery if compared with the older subgroup (p < .01). In elderly women, adjuvant RT reduced the IBR, but did not improve OS.

Abstract P2-05-08: Mucinous breast carcinomas: A genomically distinct subtype of estrogen receptor-positive invasive breast cancers

Abstract Introduction: Mucinous carcinoma of the breast (MCB) is a rare histologic form of estrogen receptor (ER)-positive invasive carcinoma, accounting for up to 2% of breast cancers. MCBs are characterized by clusters of tumor cells floating in lakes of extracellular mucin, and are classified into mucinous A (paucicellular) and mucinous B (hypercellular) subtypes. Some MCBs are found admixed with invasive ductal carcinoma components, and then classified as mixed MCBs. The aims of this study were to determine the repertoire of somatic mutations of MCBs and to ascertain whether these genetic alterations are distinct from those identified in common forms of ER+/HER2- invasive breast cancers (IBCs). We also sought to determine whether the mucinous and ductal components of mixed MCBs would be clonally related. Materials and methods: Thirty MCBs including 25 pure MCBs (n=13 mucinous A, n=12 mucinous B) and five mixed MCBs were microdissected and subjected to whole exome sequencing. Each tumor component of mixed cases was microdissected and analyzed separately. Somatic mutations, copy number alterations and mutational signatures were defined using state-of-the-art bioinformatics methods. The mutational repertoire of MCBs was compared with that of ER+/HER2- IBCs (n = 240) from The Cancer Genome Atlas (TCGA) breast cancer study. Results: The genes most frequently mutated in MCBs were GATA3 (27%, 8/30, all frameshift mutations), KMT2C (13%, 4/30) and MAP3K1 (10%, 3/30). No significant differences were identified in single gene comparisons between mucinous A and mucinous B MCBs or between pure MCBs and the mucinous component of mixed MCBs (Fisher's exact tests, p&amp;gt;0.05). As compared to common forms of ER+/HER2- IBC, MCBs had a lower frequency of PIK3CA mutations (7% vs 42%, p&amp;lt;0.001) and a higher frequency of GATA3 mutations (27% vs 12%, p=0.04). Mucinous B MCBs had a higher frequency of KMT2C mutations than ER+/HER2- IBCs (25% vs 6%, p=0.04). Most MCBs displayed the mutational signature 1 (aging-related; 20/30, 67%), and no differences in the frequency of specific mutational signatures according to the type of MCBs were observed. Concurrent 1q gains and 16q losses, which are the hallmark genetic alterations of low-grade ER+/HER2- breast cancers, were not observed in pure MCBs, but were found in three of the five mixed MCBs analyzed. The mucinous and ductal components of all five mixed MCBs shared a median of 58% of somatic mutations (range 42%-64%), including clonal GATA3 frameshift mutations in two of them, as well as a similar pattern of copy number alterations, supporting their clonal relatedness. Additional somatic mutations found to be restricted to the ductal or mucinous components of all mixed MCBs analyzed were identified, including clonal missense mutations in PIK3C2B and PIK3R2 in the ductal component of one case, and a PIK3R5 missense mutation in the mucinous component of another case. Conclusions: The repertoire of somatic mutations in MCBs is distinct from that of common forms of ER+/HER2- IBCs. These differences include the lack of concurrent 1q gains/16q losses, a lower frequency of PIK3CA mutations and a higher frequency of GATA3 mutations in pure MCBs. Citation Format: Pareja F, Geyer FC, Piscuoglio S, Selenica P, Kumar R, Lim RS, Guerini-Rocco E, Marchio C, Mariani O, Ng CKY, Brogi E, Norton L, Vincent-Salomon A, Weigelt B, Reis-Filho JS. Mucinous breast carcinomas: A genomically distinct subtype of estrogen receptor-positive invasive breast cancers [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-05-08.

Abstract P2-05-36: Clinicopathological predictors for low risk recurrence distinguished by 21-gene recurrence score in estrogen receptor-positive invasive breast cancer patients

Abstract Background: The 21-gene Recurrence Score (RS) (Oncotype DX®; Genomic Health, Redwood City, CA) is the most valid and reliable multigene assay to predict prognosis or response to treatment in hormone receptor-positive invasive breast cancer patients. However, in Japan, the test is expensive (about 4,000 US dollars) and one of the problems is that about 30% of patients will be categorized as having moderate recurrence risk. If clinicopathologic factors can be used to predict patients with low recurrence, many patients can avoid postoperative chemotherapy without testing the RS. Such predictors shall have a substantial impact on medical economics too. The aim of this study was to determine significant clinicopathological predictors for low recurrence risk by RS in patients with estrogen receptor-positive primary breast cancer. Methods: Retrospective cross-sectional study was conducted in tertiary referral hospital in Tokyo, Japan. Two hundreds twenty patients with estrogen receptor-positive invasive breast cancer underwent surgery for breast cancer and tested for RS from November 2009 to March 2016. RS £18 was defined as low recurrence risk. The patients were divided into 2 groups, patients with low recurrence risk (n=143) and with a moderate/high recurrence risk (n=77). Age, menopausal status, histologic type (invasive ductal vs. lobular carcinoma), nuclear grade, progesterone receptor (PR) expression, Ki67 index, tumor size, lymph node status, and lymphovascular invasion were considered as candidate predictors. Student's t test or Wilcoxon-Rank Sum test and Fisher's exact test was used for continuous variables and proportion, respectively. Simple and multiple logistic regression model were used to determine significant predictors. Classification and regression tree analysis (CART) was also conducted. Results: Mean age (SD) of low and moderate/high recurrence patients was 53 years-old (9.4) and 55 years (10.2), respectively. Univariate analyses revealed that the invasive lobular carcinoma, the high PR expression, Ki67 &amp;lt; 24, and the absence of lymphovascular invasion were significantly associated with low recurrence risk. According to multiple logistic regression, The odds ratio (OR) [95%CI] of histological type (invasive lobular), high PR expression, Ki67 &amp;lt; 24, and the absence of lymphovascular invasion was 0.43 [0.08-1.8], 10 [5.4-23.6], 0.95 [0.93-0.97], and 0.57 [0.23-1.18], respectively. The area under the receiver operating characteristic curve was 0.83. CART showed that the probability of low recurrence risk was 79% if with high PR expression, and 92% if with high PR expression and Ki67 &amp;lt; 24. Conclusions: High PR expression and Ki67 &amp;lt; 24 were significant predictors for low recurrence risk by RS in estrogen receptor-positive invasive breast cancer patients. More than 90% of patients with high PR expression and Ki67 &amp;lt; 24 could be classified as low recurrence risk by RS. Citation Format: Tsuchida Y, Hayashi N, Omata F, Yamauchi H. Clinicopathological predictors for low risk recurrence distinguished by 21-gene recurrence score in estrogen receptor-positive invasive breast cancer patients [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 P2-05-36.

Prognostic Impact of Progesterone Receptor Status in Chinese Estrogen Receptor Positive Invasive Breast Cancer Patients.

PurposeEstrogen receptor (ER) and progesterone receptor (PR) have been used as indicators of endocrine system status since the mid-1970s in the clinical management of breast cancer. The predictive role of ER in endocrine therapy is undisputed, but the prognostic value of PR is still debated. The aim of this study was to investigate the clinical characteristics and prognosis of ER positive breast cancer with different PR expression levels.MethodsA population cohort of 3,030 primary invasive ER positive breast cancer patients from a single cancer center underwent surgery and received adjuvant endocrine therapy from 2004 to 2010. The clinical and biological features of these patients with high PR-expressing tumors were compared with those of patients with low PR-expressing tumors. The follow-up data for disease-free survival (DFS), overall survival (OS), and breast cancer specific survival (BCSS) was obtained from 2,778 patients. Cox regression analysis was used to correlate biomarkers and tumor characteristics with DFS, OS, and BCSS.ResultsTumors with low PR expression had more invasive pathological features and biological indexes than those with high PR expression. Low PR expression was an independent poor prognostic factor for DFS (p=0.014; hazard ratio [HR], 0.781; 95% confidence interval [CI], 0.641–0.950), OS (p=0.002; HR, 0.699; 95% CI, 0.560–0.873), and BCSS (p=0.005; HR, 0.714; 95% CI, 0.566–0.902). Furthermore, in low PR expressing tumors, patients who received chemotherapy had better DFS (p=0.002; HR, 0.449; 95% CI, 0.268–0.751), OS (p<0.001; HR, 0.341; 95% CI, 0.192–0.606), and BCSS (p<0.001; HR, 0.292; 95% CI, 0.156–0.549) than patients who did not received chemotherapy.ConclusionPatients with ER positive invasive breast cancer with low PR expressing tumors have a worse prognosis than those with high PR expressing tumors, and these patients can benefit from chemotherapy.

Dynamic contrast-enhanced and diffusion-weighted MRI of estrogen receptor-positive invasive breast cancers: Associations between quantitative MR parameters and Ki-67 proliferation status.

To explore the association between quantitative parameters derived from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and diffusion-weighted imaging (DWI) and Ki-67 proliferation status in patients with estrogen receptor (ER)-positive invasive breast cancer. We retrospectively reviewed the records of 88 patients with ER-positive invasive breast cancer who underwent preoperative DCE-MRI and DWI on a 3T scanner. Perfusion parameters (Ktrans , Kep , and Ve ) and apparent diffusion coefficients (ADCs) were recorded, and we correlated these data with the Ki-67 status. The Ki-67 proliferation index was categorized as high (≥14%) or low (<14%). In the high-Ki-67 group, the mean Ktrans was significantly higher (P < 0.001) than that of the low-Ki-67 group, and the mean ADC significantly lower (P < 0.001). However, the mean Kep and Ve values did not differ between the two groups (P = 0.248 and P = 0.055, respectively). Univariate analysis showed that a higher Ktrans (>0.274), a lower ADC (≤0.893 × 10-3 mm2 /s), a larger tumor size (>2 cm), a higher histological grade (grade 3), the presence of axillary metastasis, and positive P53 status were significantly associated with high-Ki-67 status (all P values < 0.05). Of these variables, a higher Ktrans (>0.274; adjusted odds ratio [OR] = 9.027, 95% confidence interval [CI] = 1.929-42.245; P = 0.005) and a higher histological grade (grade 3; adjusted OR = 7.510, 95% CI = 1.305-43.205; P = 0.024) independently predicted a high Ki-67 status. Ktrans derived from DCE-MRI is associated independently with the Ki-67 proliferation status in patients with ER-positive invasive breast cancer. 4 J. Magn. Reson. Imaging 2017;45:94-102.

Abstract PD1-03: Cholesterol, cholesterol lowering medication use, and breast cancer outcomes in the BIG 1-98 study

Abstract Background: Cholesterol lowering medications (CLM)—statins in particular—may exert anti-cancer effects. A proposed mechanism involves attenuated signaling through the estrogen receptor by the cholesterol metabolite, 27-hydroxycholesterol, which correlates with systemic total cholesterol. Assessment of cholesterol levels and use of cholesterol-lowering medications among breast cancer patients receiving endocrine treatment may enrich our understanding of factors affecting endocrine therapy effectiveness and the role of statins and cholesterol in cancer survival. Aim: To investigate the prognostic effect of baseline cholesterol level and baseline CLM use, and to study the effect on outcome of concurrent use of CLM and endocrine therapy in the BIG 1-98 study. Design and Methods: The BIG 1-98 study enrolled 8,010 postmenopausal women with early-stage, estrogen receptor-positive invasive breast cancer from 1998-2003. Participants were randomized to five years of tamoxifen, letrozole, or their sequence. Cholesterol levels and use of CLM were assessed at baseline and every six months up to 5.5 years. Multivariable prognostic models of baseline cholesterol or baseline CLM use were adjusted for patient- and tumor characteristics and treatment regimen. Prognostic analyses of baseline cholesterol were restricted to women not taking CLM at baseline. Marginal structural modeling was used to investigate the relationship between initiation of CLM during endocrine therapy and outcome. Median follow-up was approximately 8 years. Endpoints were: disease-free survival (DFS), breast cancer-free interval (BCFI), and distant recurrence-free interval (DRFI). Results: Among 7,963 women who received at least one dose of endocrine therapy, 637 reported use of CLM at baseline, including statins (n=490) and non-statins (n=147). Compared with non-users, women on CLM at baseline were older, more often had a history of diabetes, were more likely to use hormone replacement therapy, and were more often diagnosed with smaller tumors or node-negative disease. During follow-up, 2,005 DFS-events, 1,303 BCFI-events and 1,004 DRFI-events were reported. Among non-users of CLM at baseline, baseline cholesterol levels showed a significant U-shaped association with BCFI and DRFI when grouped according to the quartiles of the distribution; however, these results were not maintained using cardiovascular risk-based cholesterol cut points. Prognostic models also suggested that use of any CLM at baseline was associated with better DFS compared with non-use (HRadj=0.82, 95% CI: 0.68, 0.99); similar, but non-significant associations were seen for BCFI (HRadj=0.83, 95% CI: 0.65, 1.06) and DRFI (HRadj=0.81, 95% CI: 0.61, 1.09). Results from the marginal structural modeling showed no differences in outcomes for women who initiated CLM during endocrine therapy compared with those who did not. Conclusions: In the BIG 1-98 study investigating the use of tamoxifen, letrozole or their sequence as endocrine therapy in the adjuvant setting, use of cholesterol-lowering therapy at baseline was associated with beneficial tumor characteristics. The effects on clinical outcome need further investigation. Citation Format: Borgquist S, Giobbie-Hurder A, Ahern T, Garber JE, Colleoni M, Láng I, Debled M, Ejlertsen B, Coates AS, Goldhirsch A, Price KN, Gelber RD, Regan MM, Thürlimann B. Cholesterol, cholesterol lowering medication use, and breast cancer outcomes in the BIG 1-98 study. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr PD1-03.

Use of Antihypertensive Medications Not Associated with Risk of Contralateral Breast Cancer among Women Diagnosed with Estrogen Receptor-Positive Invasive Breast Cancer.

Antihypertensive medications are widely used among adults in the United States, and there is some evidence that certain classes may affect the risk of adverse breast cancer outcomes, but their impact on risk of second primary contralateral breast cancer (CBC) is unclear. We used data from a population-based nested case-control study consisting of 359 women diagnosed with both a first primary breast cancer and a second primary CBC and 691 control women diagnosed with only a single breast cancer and individually matched to cases. Multivariate conditional logistic regression was used to estimate ORs and 95% confidence intervals for risks associated with ever, recency, and duration of use for various antihypertensive medications. No class of antihypertensive, including calcium channel blockers, β-blockers, angiotensin-converting enzyme (ACE) inhibitors, and diuretics, was associated with risk of second primary CBC. These results did not change materially in a sensitivity analysis restricted to women with a history of hypertension. Our findings do not support associations between use of various antihypertensives and CBC risk among women with estrogen receptor-positive breast cancer. The present study adds evidence to support the safety of commonly used antihypertensive medications among breast cancer survivors with respect to risk of second primary CBC.

No Surgery for Low-Grade Ductal Carcinoma In Situ?

Since the more widespread use of routine screening mammography, the incidenceofductal carcinoma in situ (DCIS)has increased dramatically and accounts for about 20% to 30%of all newly diagnosed breast cancers.1 Deaths from breast cancer among women with DCISmayoccur fromunidentified invasive disease at the time of diagnosis, progression of inadequately excised DCIS, or the development of an independent recurrent invasive breast cancer.2 Our current inability to accurately predict which women with DCIS are at the greatest risk for developing invasive disease generally necessitates thatallpatientsdiagnosedashavingDCISundergo treatment. Despite the relatively benign course of DCIS, most women undergo aggressive surgical and radiation treatment. The risk of overtreatment has been recognized.2 Sagaraetal3usedapropensityscoreanalysis toevaluate the survivaloutcomesofpatientswithDCIS intheSurveillance,Epidemiology, andEndResultsdatabaseandconcluded that there wasnosurvival benefit for surgical excisionof low-gradeDCIS. Therewasasurvivalbenefit forsurgicalexcisioninpatientswith intermediate-orhigh-gradeDCIS.Therefore,Sagaraetal3questiontheneedandbenefit forsurgicalexcisionof low-gradeDCIS. We urge physicians to exercise cautionwhen generalizing this population-basedcohort analysis to currentpractice.Thereare inherent limitationstopopulation-basedcancerdatawithregard to specificpatient and tumorcharacteristics. For example, 14% of the nonoperative group received radiation therapywithout undergoingsurgicalexcision.This isnotastandardapproachfor DCISandthedetailssurroundingthesediscrepanciesarenotclear withintheSurveillance,Epidemiology,andEndResultsdatabase. Inaddition, it is impossible todeterminehowmanywomenmay havehadan initial diagnosis ofDCISbasedon their coreneedle biopsy but who then had an upgrade to invasion on final excision.Thosepatientswouldhavebeenexcludedfromthisanalysis. Most importantly, we argue that DCIS grade is not an appropriate surrogate for genomic profile and biologic outcomes. Molecular markers that provide prognostic and predictive informationhold themostpromise for tailoring therapy on an individual level. The 21-gene recurrence score for estrogen receptor–positive invasive breast cancer was used as a benchmark for the development of a 12-gene subset that has been used to develop and validate a DCIS score that divides patients into low risk, intermediate risk, and high risk for 10year local in-breast recurrence.4 Multivariable models of risk for ipsilateral breast events both excluding and including the DCIS scorehavebeenperformed.Tumor size,menopausal status, andDCIS scorewere the only factors significantly associatedwith risk for an ipsilateral breast event. Tumor grade and thepresenceof comedonecrosiswerenot associatedwith risk for ipsilateral breast events.4 The ability to profile entire tumor genomes relatively quickly and affordablywill aid our understanding of the relationship between DCIS and invasive disease so that targeted approaches can be taken. We advocate for less treatment in those patients who have a low risk for invasive recurrence and/or progression. That knowledge is unlikely to come from our standard clinicopathologic characteristics. For now, surgeons should hold onto their scalpels.

Breast Cancer Risk after Occupational Solvent Exposure: the Influence of Timing and Setting

Organic solvents are ubiquitous in occupational settings where they may contribute to risks for carcinogenesis. However, there is limited information on organic solvents as human breast carcinogens. We examined the relationship between occupational exposure to solvents and breast cancer in a prospective study of 47,661 women with an occupational history in the Sister Study cohort. Occupational solvent exposure was categorized using self-reported job-specific solvent use collected at baseline. Multivariable Cox regression analyses were used to assess breast cancer risk, adjusting for established breast cancer risk factors. A total of 1,798 women were diagnosed with breast cancer during follow-up, including 1,255 invasive cases. Overall the risk of invasive breast cancer was not associated with lifetime exposure to solvents [HR, 1.04; 95% confidence interval (CI), 0.88-1.24]. Parous women who worked with solvents before their first full-term birth had an increased risk of estrogen receptor-positive invasive breast cancer compared with women who never worked with solvents (HR, 1.39; 95% CI, 1.03-1.86). A significantly elevated risk for estrogen receptor-positive invasive breast cancer was associated with solvent exposure among clinical laboratory technologists and technicians (HR, 2.00; 95% CI, 1.07-3.73). Occupational exposure to solvents before first birth, a critical period of breast tissue differentiation, may result in increased vulnerability for breast cancer. Our findings suggest a need for future studies in this area to focus on exposure time windows and solvent types in different occupational settings.

Ductal Carcinoma In Situ: A Rose by Any Other Name

Ductal Carcinoma In Situ: A Rose by Any Other Name