Metastatic Breast Cancer Disease Research Articles

Real-world data of efficacy and safety of denosumab on patients with breast cancer with bone metastasis: Results from Chinese clinical experience.

e13103 Background: Bone is the most common metastasis site in advanced metastatic breast cancer disease. Denosumab is advocated by various guidelines with high-quality of evidence for the treatment of breast cancer patients with bone metastases (BM) to delay or reduce the occurrence of skeletal related events (SRE). Data for bone lesion repair after treatment on image is still needed in real world. This retrospective study aims to evaluate the efficacy of denosumab on breast cancer with BM by MD Anderson (MDA) criteria which is specific to BM and its safety in real world. Methods: Data of patients age ≥18 years diagnosed with advanced breast cancer with BM and treated with denosumab from June 1st 2020 to Dec 31st 2022 were retrospectively analyzed. The primary endpoint was the objective response rate (ORR) for bone lesions by MDA criteria in evaluable patients. Secondary endpoints include disease control rate (DCR) for bone lesions, risk of SRE occurrence and safety in total population. Subgroup analysis investigated the impact of the time of denosumab treatment initiation post-diagnosis of BM as well as the duration of treatment with denosumab on efficacy. Comparative analysis was performed using Chi-squared test and a p value of <0.05 was considered statistically significant. Results: Atotal of 185 patients were enrolled with median age of 52.45 (SD: 12.02) years. The median follow-up time was 25.2 months. 49 out of the 130 evaluable patients achieved partial response, resulting in an ORR of 37.69% (95% CI: 0.29-0.47), and a DCR of 90% (95% CI: 0.84-0.95). 16 out of 185 (8.65%) patients developed SRE after denosumab treatment with the median time to the first occurrence of SRE not reached. The ORR and DCR for bone lesions of starting denosumab after diagnosis of BM in ≤3 months vs. >3 months were 31.54% vs. 6.15% (p<0.001) and 68.46% vs. 21.54% (p<0.001), respectively. The ORR and DCR for bone lesions of the duration of denosumab treatment <6 months vs. ≥6 months were 4.62% vs. 33.08% (p<0.001) and 37.69% vs. 76.92% (p<0.001), respectively. Renal function impairment decreased from 33 patients before treatment to 8 patients post-treatment, while hypocalcemia increased from 1.62% to 11.35%. Osteonecrosis of the jaw occurred in one patient (1/185,0.54%) post-treatment. Conclusions: Denosumab was found to be effective and safe for breast cancer patients with BM in this large retrospective study. Early initiation and longer duration of denosumab treatment may generate better clinical outcomes for bone lesions by MDA criteria.

Changing practice in the assessment of distant metastatic disease in breast cancer: The development of a staging protocol

Changing practice in the assessment of distant metastatic disease in breast cancer: The development of a staging protocol

Evaluating HEmopatch® in Reducing Seroma-Related Complications following Axillary Lymph Node DIssection: A Pilot Study (HEIDI)

Purpose: Axillary lymph node dissection (ALND) is performed to treat locoregional metastatic disease in breast cancer and melanoma patients. However, it is notorious for its complications, most commonly seroma formation and its sequelae. Ample research has been done to evaluate seroma formation after ALND; these results, however, have not been conclusive. Hence, this pilot study aimed to evaluate a readily available haemostatic patch, Hemopatch®, to assess its effect on seroma formation following ALND. Methods: In this pilot study, a prospective cohort of 20 patients receiving Hemopatch® following ALND was compared to a retrospective cohort of patients who underwent ALND between 2014 and 2019. The primary outcome measure was the number of patients developing clinically significant seroma (CSS) after ALND. Additionally, the number of wound complications, subsequent interventions, additional outpatient clinic visits, and drain output was assessed. Differences between groups were deemed clinically relevant if the proportions differed >50% between groups. Results: In total, 20 prospective and 42 retrospective patients were included. In the Hemopatch® group, 30% of the patients developed CSS, compared to 43% in the control group. Three patients in both groups developed a surgical site infection . Thirty-five percent of patients in the Hemopatch® group required additional unscheduled visits versus 62% of patients in the control group. Conclusion: The application of Hemopatch® after ALND did not lead to a clinically relevant reduction of CSS and wound complications. However, fewer Hemopatch® patients required additional outpatient clinic visits. Due to the limited amount of participants, the true value of Hemopatch® in ALND remains unclear.

Abstract 2187: A multiplexed staining method to quantify EMT derived tumor heterogeneity presents a means of predicting patient prognosis based on EMT state

Abstract Intra-tumoral heterogeneity is a key contributor to poor prognosis and metastatic disease in breast cancer. This study seeks to detect and quantify intra-tumoral heterogeneity deriving from the Epithelial-to-Mesenchymal transition using a multi-round, multiplexed immunofluorescence staining approach to delineate EMT states at a single cell resolution in primary tumor specimens to aid in pathological patient diagnosis. Despite major advances in our understanding, the contributions of EMT research to improvements in diagnostic pathology or cancer therapy have been minimal. One reason for this gap stems from our inability to accurately detect and quantify epithelial-mesenchymal heterogeneity in primary tumor specimens. Secondly, the significance of recently identified intermediate or partial EMT states to predicting tumor prognosis and therapy response are unclear. To study the role of various states within the EMT spectrum and their regulatory networks, the heterogeneous breast cancer cell line, SUM149PT, was used to derive six single cell clones encompassing the spectrum of EMT states, from epithelial to mesenchymal. Interrogation of this model system in vivo has revealed increased tumor growth and metastatic potential in the intermediate EMT states when compared to the extreme epithelial and mesenchymal states. To further elucidate EMT states in vivo, we employ a 6-marker multi-round immunofluorescence-based staining approach to identify cells that reside in various states along the EMT spectrum. We subsequently used cell-segmented, entropy-based approach and weighted phenotype analysis on these tumors with the purpose of scoring heterogeneity and overall EMT state. Notably, this analysis segregated stromal infiltrates and their contributions to aggregate EMT scoring, which has been a major hurdle in using EMT as a scoring metric in patient samples. Overall, SUM149 clone-derived tumors held true to the relative EMT states of the starting cell populations; intermediate-derived tumors displayed high heterogeneity while epithelial and mesenchymal clone-derived tumors had lower levels of heterogeneity, despite retaining different EMT scores. Decoupling of heterogeneity and EMT state in this way provides two metrics to assess potential metastatic ability of a tumor. This staining method and analysis has been successfully applied in a preliminary set of patient tumors, showing promise for these two factors, E-M Heterogeneity and EMT score, as a tumor prognostic indicator to inform therapeutic decision-making. In the future, this staining and quantification shows promise as a means of predicting patient prognosis and informing potential treatment options based on targeting EMT states. Citation Format: Meredith S. Brown. A multiplexed staining method to quantify EMT derived tumor heterogeneity presents a means of predicting patient prognosis based on EMT state [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2187.

Interventional oncology procedures for breast cancer metastatic disease: current role and clinical applications.

Worldwide, breast cancer constitutes the most common malignant neoplasm among females, impacting 2.1 million women annually. Interventional oncology techniques have been recently added as an additional therapeutic and palliative alternative in breast cancer metastatic disease, concerning mainly osseous, liver, and lung metastasis. In the current literature, there are reports of promising results and documented efficacy regarding the ablation of liver and lung metastasis from breast carcinoma, transarterial embolization or radioembolization, as well as the treatment of osseous metastatic disease. These literature studies are limited by the heterogeneity of breast cancer disease, the evaluation of variable different parameters, as well as the retrospective nature in most of the cases. Consequently, dedicated prospective series and randomized studies are required to identify the role of minimally invasive local therapies of interventional oncology armamentarium. The present review paper focuses upon the current role of interventional oncology techniques for the curative or palliative treatment of metastatic breast cancer disease. The purpose of this review paper is to present the current minimally invasive procedures in the treatment of metastatic breast disease, including local control rates and survival rates.

Elevated CA 15.3 in Newly Diagnosed Breast Cancer: A Retrospective Study

PurposeTo examine the relationship between baseline elevated CA 15.3 (>30 kU/L) and the prevalence of primary or secondary metastatic disease in breast cancer. MethodsWe performed a retrospective, single-center cohort study on patients with newly diagnosed breast cancer and baseline CA 15.3> 30 kU/L, diagnosed between 2000-2015. Information on tumor characteristics, pre-treatment CA 15.3, staging results, treatment approach, disease recurrence and death were collected from individual medical files. For every tumor subtype, the optimal cut-off value of CA 15.3 for determining primary metastatic disease is determined. ResultsEight hundred ninety-four patients with baseline CA15.3 > 30 kU/L were included of which 38% were diagnosed with primary metastatic disease while 15% subsequently developed secondary metastatic disease, with a median follow-up of 74 months. LuminalHER2 tumors had the highest proportion of primary metastatic disease (48%), Triple Negative tumors had the highest proportion of secondary metastatic disease (24%) (p=0.008). A higher CA 15.3 value corresponds to higher risk of both primary and secondary metastatic disease (p<0.001). For the determination of primary metastatic disease, optimal cut-off values for CA 15.3 range between 44 kU/L (Triple Negative) and 59 kU/L (Luminal B). ConclusionIn patients with newly diagnosed breast cancer and baseline elevated CA 15.3>30 kU/L, 38% presents with primary metastatic disease and 15% develops secondary metastatic disease, with a median follow-up of 74 months. Our results can help clinicians to identify patients at risk of primary or secondary metastatic disease via information on tumor subtype and baseline CA 15.3.

A review on the added value of whole-body MRI in metastatic lobular breast cancer.

Invasive lobular breast carcinomas (ILC) account for approximately 15% of breast cancer diagnoses. They can be difficult to diagnose both clinically and radiologically, due to their infiltrative growth pattern. The pattern of metastasis of ILC is unusual, with spread to the serosal surfaces (pleura and peritoneum), retroperitoneum and gastrointestinal (GI)/genitourinary (GU) tracts and a higher rate of leptomeningeal spread than IDC. Routine staging and response assessment with computed tomography (CT) can be undertaken quickly and measurements can be reproduced easily, but this is challenging with metastatic ILC as bone-only/bone-predominant patterns are frequently seen and assessment of the disease status is limited in these scenarios. Functional imaging such as whole-body MRI (WBMRI) allows the assessment of bone and soft tissue disease by providing functional information related to differences in cellular density between malignant and benign tissues. A number of recent studies have shown that WBMRI can detect additional sites of disease in metastatic breast cancer (MBC), resulting in a change in systemic anti-cancer therapy. Although WBMRI and fluorodeoxyglucose-positron-emission tomography-computed tomography (FDG-PET/CT) have a comparable performance in the assessment of MBC, WBMRI can be particularly valuable as a proportion of ILC are non-FDG-avid, resulting in the underestimation of the disease extent. In this review, we explore the added value of WBMRI in the evaluation of metastatic ILC and compare it with other imaging modalities such as CT and FDG-PET/CT. We also discuss the spectrum of WBMRI findings of the different metastatic sites of ILC with CT and FDG-PET/CT correlation. KEY POINTS: • ILC has an unusual pattern of spread compared to IDC, with metastases to the peritoneum, retroperitoneum and GI and GU tracts, but the bones and liver are the commonest sites. • WBMRI allows functional assessment of metastatic disease, particularly in bone-only and bone-predominant metastatic cancers such as ILC where evaluation with CT can be challenging and limited. • WBMRI can detect more sites of disease compared with CT, can reveal disease progression earlier and provides the opportunity to change ineffective systemic treatment sooner.

Expanded criteria for pretreatment staging CT in breast cancer.

BackgroundThere is wide variation in the approach to staging for distant metastatic disease in breast cancer. This study sought to identify factors predictive of distant metastatic disease at presentation to enable appropriate selection of patients for pretreatment CT.MethodsData were collected retrospectively for all patients with newly diagnosed breast cancer (screening and symptomatic) over 3 years (2014–2017). Detailed demographic, pathological, biological, and management data were recorded at presentation, and outcome data were recorded after follow-up. Binomial logistic regression was used to identify variables independently associated with distant metastatic disease at presentation.ResultsA total of 1377 patients with newly diagnosed breast cancer were identified, of whom 1025 had complete data; 323 staging CT examinations were performed. Distant metastases were identified at presentation in 47 (4.6 per cent). Some 30 of 47 patients with metastatic disease met established criteria for staging (T4, recurrence, symptoms of possible distant metastases), leaving 17 patients with metastatic disease potentially missed by use of these criteria alone. Multivariable analysis showed that tumour size at least 3 cm combined with sonographically abnormal axillary lymph nodes predicted a high probability of distant metastatic disease at presentation (positive predictive value 18.8 per cent, odds ratio 4.83, P < 0.001). Addition of this criterion increased the positive CT rate to 17.1 per cent.ConclusionSelective pretreatment CT staging can be further optimized with the addition of tumour size at least 3 cm with abnormal axillary nodes to established staging criteria.

Genome-scale meta-analysis of breast cancer datasets identifies promising targets for drug development

BackgroundBecause of the highly heterogeneous nature of breast cancer, each subtype differs in response to several treatment regimens. This has limited the therapeutic options for metastatic breast cancer disease requiring exploration of diverse therapeutic models to target tumor specific biomarkers.MethodsDifferentially expressed breast cancer genes identified through extensive data mapping were studied for their interaction with other target proteins involved in breast cancer progression. The molecular mechanisms by which these signature genes are involved in breast cancer metastasis were also studied through pathway analysis. The potential drug targets for these genes were also identified.ResultsFrom 50 DEGs, 20 genes were identified based on fold change and p-value and the data curation of these genes helped in shortlisting 8 potential gene signatures that can be used as potential candidates for breast cancer. Their network and pathway analysis clarified the role of these genes in breast cancer and their interaction with other signaling pathways involved in the progression of disease metastasis. The miRNA targets identified through miRDB predictor provided potential miRNA targets for these genes that can be involved in breast cancer progression. Several FDA approved drug targets were identified for the signature genes easing the therapeutic options for breast cancer treatment.ConclusionThe study provides a more clarified role of signature genes, their interaction with other genes as well as signaling pathways. The miRNA prediction and the potential drugs identified will aid in assessing the role of these targets in breast cancer.

Nanoliposomes as Multidrug Carrier of Gemcitabine/Paclitaxel for the Effective Treatment of Metastatic Breast Cancer Disease: A Comparison with Gemzar and Taxol

AbstractSeveral liposomal drugs have received clinical approval for the treatment of cancer due to the reduced side effects and/or improved therapeutic efficacy in comparison to their respective free drug counterparts. In this study, nanoliposomes are designed as multidrug carriers for codelivering gemcitabine hydrochloride (Gemzar) and paclitaxel (Taxol) and evaluating their anticancer activity in several triple negative human breast cancer cell lines and in a mouse model of metastatic breast cancer. The results demonstrate that the nanoliposomes significantly decrease the cell viability of breast cancer cells compared to combination treatment with the free drugs. Furthermore, the chemotherapeutics coloaded nanoliposomes dramatically decrease the tumor growth and improve survival times, while combination treatment with Gemzar and Taxol has a modest effect on cancer progression. Moreover, pharmacokinetic analysis demonstrates that nanoliposomes increase the half‐life of gemcitabine hydrochloride and paclitaxel 6.3‐fold and 1.7‐fold, respectively. Taken together, the findings indicate that gemcitabine hydrochloride and paclitaxel‐coloaded nanoliposomes can provide an effective treatment strategy for metastatic breast cancer.

P150: Staging for distant metastases in breast cancer: Criteria for pre-treatment CT scans

Introduction: Approaches to staging for distant metastatic disease in breast cancer vary across the UK. This study identifies factors predictive of distant metastases to enable selection of appropriate patients for pre-treatment CT and refine staging guidelines.

Abstract P3-01-13: Association between the histopathological growth patterns (HGP) of liver metastases (LM) and survival after hepatic surgery in patients with oligometastatic breast cancer (BC)

Abstract Background. Liver is the 3rd most common site for metastatic disease in BC. The proportion of patients with BC LM presenting with so-called oligometastatic disease is estimated to be ~10%. Some of these patients have an indolent disease course after hepatic surgery. However, as of today, it is impossible to identify the ideal candidates for hepatic surgery based on standard clinico-pathological characteristics. Two main HGP have previously been identified in LM from colorectal cancer patients1: (i) the desmoplastic HGP with angiogenesis, inflammation and a rim of fibrous tissue that separates the cancer cells from the liver parenchyma, and (ii) the replacement HGP, with vessel co-option, no angiogenesis, and cancer cells growing into the liver parenchyma while replacing the hepatocytes, with minimal inflammation. This replacement HGP was associated with worse survival and lack of benefit from bevacizumab in patients operated for colorectal LM2. Here, we aimed at characterizing HGP of LM from BC patients who underwent hepatic surgery. Patients and methods. We considered a series of 36 consecutive patients with invasive BC from Institut Jules Bordet and Hôpital Erasme, Brussels, who underwent surgical resection of LM. Patients were operated between April 2000 and October 2017, and the median follow-up was 10.7 years. The HGPs of resected LM were scored according to international guidelines on H&amp;E stained section by light microscopy3, by a pathologist (PV) blinded to outcome data. All sections of all LM were evaluated for each patient. Associations between HGP and clinico-pathological characteristics were assessed using the Fisher exact test, and associations with progression-free (PFS) and overall survival (OS) using Cox proportional hazard regressions considering date of hepatic surgery as the starting time. Age at hepatic surgery, ER and HER2 status of the LM, and presence of extra-hepatic metastasi(e)s were considered as adjustment variables and centre as stratification factor. Results. In 16 patients (44%) the LM exclusively presented the replacement HGP (pure-replacement group) while in the remaining 20 patients (56%) the LM were at least partly desmoplastic (any-desmoplastic group). There was no association of HGP with ER or HER2 status of primary BC or LM. LM subtypes were as follows: 2 ER-/HER2- (7%), 11 HER2+ (38%), 16 ER+/HER2- (55%)- information is currently missing for 7 patients. In 10/30 (33.3%) patients, ER-status changed in the LM compared with the primary BC (8 losses, 2 gains). Significantly more patients in the any-desmoplastic group had a primary BC without lymph node metastases (56% versus 21% in the replacement group, p=.02). Survival analyses showed that any-desmoplastic HGP was independently associated with increased PFS after liver surgery when compared with pure-replacement HGP (Hazard Ratio, HR, 0.34; 95% CI: 0.12-0.96; p=.041). All patients with pure-replacement HGP relapsed within the first two years after hepatic surgery. The other factors in the model were not significantly associated with PFS. Similar results were observed for OS (adjusted HR for HGP: 0.26; 0.07-1.01, p=.052). Conclusion. In this study, we showed evidence that the pure-replacement HGP of BC LM is related to worse outcome after hepatic surgery, corroborating our findings in patients with colorectal LM1. These findings, which are currently being validated in additional series, suggest that HGP of LM could represent a promising candidate marker of oligometastatic progression in BC. Refs: 1. doi:10.1007/s10456-019-09661-5; 2. doi:10.1038/s41571-019-0181-9; 3. doi:10.1038/bjc.2017.334. Citation Format: Peter B Vermeulen, Ali Bohlok, Sophia Leduc, François Richard, Lara Botzenhart, Michail Ignatiadis, Philippe Aftimos, Christos Sotiriou, Martine Piccart, Alain Hendlisz, Steven Van Laere, Luc Y Dirix, Jean-Christophe Noël, Valerio Lucidi, Elia Biganzoli, Denis Larsimont, Christine Desmedt, Vincent Donckier. Association between the histopathological growth patterns (HGP) of liver metastases (LM) and survival after hepatic surgery in patients with oligometastatic breast cancer (BC) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-01-13.

Examining the evolving utility of 18FDG-PET/CT in breast cancer recurrence.

Many studies have demonstrated the utility of 18fluorodeoxyglucose-positron emission tomography/computed tomography (18FDG-PET/CT) scan in evaluating breast cancer recurrence in subsets of patients based on age, histological subtype and cancer stage to guide response to conventional chemoradiation guidelines during treatment of metastatic breast cancer disease. This literature review focuses on the breakthrough of 18FDG-PET/CT imaging within the paradigm of breast cancer oncology centered toward improving risk stratification and prognostication of disease relapse based on cancer molecular phenotypes, tumor markers, early metabolic activity and response to neoadjuvant chemotherapy (NAC). The authors consider the rapid shift toward biomarker based molecular tracers to quantify treatment response and pathologic complete response with more recent imaging modalities such as dedicated breast positron emission tomography (dbPET), and the advantages afforded by this multisystem approach.

BOMET-QoL-10 questionnaire for breast cancer patients with bone metastasis: the prospective MABOMET GEICAM study

BackgroundBone metastasis (BM) is the most common site of disease in metastatic breast cancer (MBC) patients. BM impacts health-related quality of life (HRQoL). We tested prospectively the psychometric properties of the Bone Metastasis Quality of Life (BOMET-QoL-10) measure on MBC patients with BM.MethodsPatients completed the BOMET-QoL-10 questionnaire, the Visual Analogue Scale (VAS) for pain, and a self-perceived health status item at baseline and at follow-up visits. We performed psychometric tests and calculated the effect size of specific BM treatment on patients´ HRQoL.ResultsAlmost 70% of the 172 patients reported symptoms, 23.3% experienced irruptive pain, and over half were receiving chemotherapy. BOMET-QoL-10 proved to be a quick assessment tool performing well in readability and completion time (about 10 min) with 0–1.2% of missing/invalid data. Although BOMET-QoL-10 scores remained fairly stable during study visits, differences were observed for patient subgroups (e.g., with or without skeletal-related events or adverse effects). Scores were significantly correlated with physician-reported patient status, patient-reported pain, symptoms, and perceived health status. BOMET-QoL-10 scores also varied prospectively according to changes in pain intensity.ConclusionsBOMET-QoL-10 performed well as a brief, easy-to-administer, useful, and sensitive HRQoL measure for potential use for clinical practice with MBC patients.Trial registrationNCT03847220. Retrospectively registered on clinicaltrials.gov (February the 20th 2019).

Factors associated with locoregional and metastatic breast cancer at diagnosis in a Southern Portuguese registry in the period 2005-2012.

Breast cancer (BC) is the most frequent malignancy in Portuguese women, and more than half of the registered cases live in the south of the country. The main of this study was to characterize patients with locoregional and metastatic incident BC living in the Southern Portuguese and Madeira regions in 2005-2012 according to demographic, clinical and contextual characteristics. Additionally it aimns to find the associations and relative influences of these factors with locoregional or metastatic disease at diagnosis. After a descriptive approach, binary logistic regression models were used to estimate factors related to the presence of metastatic disease at diagnosis. A final multiple regression model was developed and presented graphically as a nomogram. The median age at diagnosis was 60.84 years, being statistically lower in locoregional cases (P < 0.001). Most patients presented a locoregional disease (78.4%) of unspecified location (44.5%) and had a ductal carcinoma (73.1%). The Lisbon region represented 50.5% of the analyzed cases. Metastatic disease significantly decreased over the period under analysis ( ≈ 7%/year). Demographic (age at diagnosis ≥ 50 years), clinical (lobular and 'other' morphologies, unspecified location) and contextual (residence in Portalegre) characteristics were statistically correlated with the presence of metastatic disease at the time of BC diagnosis in univariate logistic regression, with all but the last maintaining their significance in a multivariate model. Cases with metastatic BC disease at diagnosis are decreasing; however, additional information on their characteristics can improve the alignment of public health strategies, thus strengthening this trend, and contributing to the development of a graphically tailored screening tool.

Y90 Clinical Data Update: Cholangiocarcinoma, Neuroendocrine Tumor, Melanoma, and Breast Cancer Metastatic Disease

While the most compelling levels of evidence for the use of Yttrium-90 (90Y) radioembolization are in patients with hepatocellular carcinoma and hepatic metastases from colorectal cancer, a growing body of literature supports its use in other primary and secondary hepatic malignancies. This includes intrahepatic cholangiocarcinoma, as well as hepatic metastases from neuroendocrine cancer, ocular melanoma, and breast cancer. While is it not feasible to conduct prospective, randomized trials for radioembolization in the setting of these malignancies due to the low overall prevalence of liver-only disease, numerous single-arm studies in the last several years make a compelling argument for its use in select situations. This clinical update summarizes those findings.

Abstract PD4-10: 18F-fluoroestradiol (FES) and 18F-fluorodeoxyglucose (FDG) PET imaging in staging extent of disease in metastatic lobular breast cancer

Abstract Background: The histology and pattern of spread in lobular breast cancer has presented challenges in estimating extent of disease and identifying treatment options. 18F-FES is an estrogen analogue PET imaging tracer which measures tumor ER expression at multiple tumor sites simultaneously and predicts response to endocrine therapy. We analyzed FES-PET and FDG-PET SUV uptake in patients with metastatic lobular and ductal carcinoma to identify sites of tumor and responsiveness to therapy. Methods: We retrospectively reviewed FES and FDG SUV uptake between ER+ lobular (n = 36) and ductal (n= 173, including 6 men) metastatic breast cancer patients enrolled in various institutional studies. Up to 3 lesions in each patient were evaluated by FES SUVmax and/or FDG SUVmax for a total of 475 lesions in FES images and 462 lesions in FDG images. Classification into three categories (low FDG, high FDG/high FES, and high FDG/low FES) was generated using recursive portioning with 5-fold internal cross validation. Using a Pearson Chi-squared test, we compared degree of uptake in FES and FDG between lobular and ductal carcinomas. We used linear mixed effects model to assess association of FES SULmean3 (Lean body mass adjusted SUV) and FDG SULmean3 with histology. Overall survival (OS), from time of FES-PET scan to death, and progression free survival (PFS) was evaluated between classification groups in both histologies using Kaplan-Meier curves and Cox model. Results: In patients with metastatic breast cancer, 72 patients had low FDG, 96 had high FES/high FDG, and 41 with high FES/low FDG. Lobular lesions tended to have a higher proportion of patients in the risk group with lower FDG (42% vs 33%) and a lower proportion in the risk group with high FDG/low FES (11% vs 21%) but the difference was not statistically significant (p = 0.32). Mean (range) FES SULmean3 and FDG SULmax3 respectively for ductal was 1.38 (0.10, 6.7) and 3.17 (0.88, 12.26) and for lobular was 1.42 (0.34, 3.43) and 3.13 (1.04, 13.87). There was no significant difference between in FES SULmean3 and FDG SULmax3 between histologies. Following FES-PET imaging, patients with lobular carcinomas and low FDG demonstrated a higher median survival time (7.7 years) compared to high FDG/low FES (4.3 years) and high FDG/high FES (2.6 years). Similarly, patients with ductal carcinomas and low FDG had an improved median survival time (5.6 years) compared to both high FDG/high FES (2.9 years) and high FDG/low FES (2.5 years). However, the interaction between histology and the FDG/FES classifications was not significant (p = 0.86). Across a variety of tumor sites, lobular histology can be detected by both FES and FDG with no difference between the imaging modalities. Conclusions: In the metastatic setting, quantitative FES and FDG can be used to discriminate indolent and aggressive phenotypes in both lobular and ductal breast cancer. A greater proportion of lobular carcinoma lesions had higher FES/lower FDG and would be anticipated to be more sensitive to endocrine therapy. Further prospective trials are needed to confirm the utility of FES to stage extent of disease in metastatic breast cancer. Citation Format: Manohar PM, Peterson LM, Wu V, Jenkins IC, Novakova-Jiresova A, Specht JM, Link JM, Krohn KA, Kinahan PE, Mankoff DA, Linden HM. 18F-fluoroestradiol (FES) and 18F-fluorodeoxyglucose (FDG) PET imaging in staging extent of disease in metastatic lobular breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD4-10.

Profile and Outcome of Supraclavicular Metastases in Patients with Metastatic Breast Cancer: Discordance of Receptor Status Between Primary and Metastatic Site.

Breast cancer is a heterogenous and complex disease. A rare site of metastatic breast cancer disease is the neck. Data about supraclavicular metastases in patients with metastatic breast cancer are still lacking. Hence, our study aimed to analyze histological subtypes of supraclavicular metastases compared to the primary site. This was a retrospective hospital-based cohort study of patients with breast cancer who developed supraclavicular metastases. Diagnosis of supraclavicular metastases was confirmed by biopsy or diagnostic lymph node extirpation. Histological subtypes were analyzed and Kaplan-Meier estimates were calculated for overall survival. A total of 20 patients were included in the analysis. The majority of the patients (12/20) had hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative supraclavicular metastases, disease in 3/20 patients was HR-positive/HER2-positive, HR-negative/HER2-positive in 1/20 patients and basal-like in 4/20 patients. Total discordance rates for estrogen receptor, progesterone receptor and HER2 between primary and metastatic tumors were 20.0%, 36.8% and 29.4%, respectively. The 5-year overall survival was 80%, whereas the 5-year survival after the onset of neck metastasis was 45%. As a rare site of metastatic breast cancer, supraclavicular metastases are associated with a worse median overall survival from their onset. The high rate of discordance of histological subtype stresses the necessity for biopsies in patients with supraclavicular metastasis.

Abstract P1-16-04: Somatic mutations, clinicopathologic characteristics, and survival in patients with untreated breast cancer with bone-only and non-bone sites of first metastasis

Abstract Background: Bone is the most common site of metastasis of breast cancer, and bone metastasis is associated with a high rate of skeletal-related events, all of which contribute to decreased quality of life and poor outcomes. Biological mechanisms of metastasis to bone may be unique, and identification of distinct signaling pathways and somatic mutations may provide biological insight into or rational targets for treatment of and prevention of bone metastasis. The aims of this study were to compare and contrast somatic mutations, clinicopathologic characteristics, and survival in breast cancer patients with bone only versus non-bone as first metastatic site. Methods: Tumor samples were collected from 389 patients who had metastasis and untreated primary breast cancer. In each sample, 46 or 50 cancer-related genes were selectively amplified and analyzed for mutations by AmpliSeq Ion Torrent next-generation sequencing. We used Fisher's exact test to identify somatic mutations associated with bone-only first metastasis and logistic regression models to identify differences in clinicopathologic characteristics, survival, and somatic mutations between patients with bone-only first metastasis and patients with first metastasis in non-bone sites only (“other-only first metastasis”). Results: Among the 389 patients, the first metastasis was located in bone only in 72 patients (18.5%), non-bone sites only in 223 patients (57.3%), and both in 94 patients (24.2%). Of the cancer-related genes analyzed, the most commonly mutated were TP53 (N=103), PIK3CA (N=79), AKT (N=13), and PTEN (N=2). Compared to patients with other-only first metastasis, patients with bone-only first metastasis had higher rates of hormone-receptor-positive disease, non-triple-negative subtype, and low nuclear grade (grade 1 or 2) (all 3 comparisons, p&amp;lt;0.001); had a lower ratio of cases of invasive ductal carcinoma to cases of invasive lobular carcinoma (p=0.002); and tended to have a higher 5-year overall survival (OS) rate (78.2% [95% confidence interval (CI), 68.6%-89.0%] vs 55.0% [95% CI, 48.1%-62.9%]; p=0.051). However, in the subgroup of patients with TP53 mutation and in the subgroup of patients with PIK3CA mutation, OS did not differ between patients with bone-only and other-only first metastasis (p=0.49 and p=0.68; respectively). In univariate analysis, the rate of TP53 mutation tended to be lower in patients with bone-only first metastasis than in those with other-only first metastasis (15.3% vs 29.1%; p=0.051). In multivariate analysis, TP53 mutation was not significantly associated with site of first metastasis (p=0.54) but was significantly associated with hormone-receptor-negative disease (p&amp;lt;0.001). Conclusions: We did not find associations between somatic mutations and bone-only first metastasis in patients with untreated breast cancer. Patients with bone-only first metastasis have longer OS than patients with other-only first metastasis. More comprehensive molecular analysis may be needed to further understand the factors associated with bone-only metastatic disease in breast cancer. Citation Format: Kono M, Fujii T, Matsuda N, Harano K, Chen H, Wathoo C, Aron JY, Tripathy D, Meric-Bernstam F, Ueno NT. Somatic mutations, clinicopathologic characteristics, and survival in patients with untreated breast cancer with bone-only and non-bone sites of first metastasis [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 P1-16-04.

Abstract P2-01-10: Circulating CAF/CTC complexes and breast cancer metastasis

Abstract Background: Metastatic disease in breast cancer (BC) is the leading cause of cancer-related mortality among women worldwide. Synergy between cancer cells and non-cancer cells of the tumor microenvironment (TME) are vital for disease progression. Cancer associated fibroblasts (CAFs) are the major cell type in the stroma of BC and are critical mediators of tumor progression and metastasis. Transport of circulating tumor cells (CTCs) and CTC clusters through the vasculature seeds metastasis and clinical and preclinical studies demonstrate that CTC clusters have a higher metastatic potential than individual CTCs. More recently, circulating cancer stem cells (cCSCs) have been implicated as more metastatic than non-CSC CTCs. In our lab, we have demonstrated that CAFs also circulate (cCAFs). We have observed cCAFs in peripheral blood from breast cancer patients and in murine models of breast cancer. Furthermore, we have observed that cCAFs are present in circulation as both individual cells and as well as in complexes with CTCs. Given the integral role of CAFs in BC metastasis, we hypothesize that cCAFs complex with CTCs/cCSCs to bolster BC metastasis. Methods: cCAF/CTC clusters were identified and enumerated from peripheral blood of patients with BC, and associations with clinical features and disease outcomes were evaluated. Blood was collected by cardiac puncture from PyMT mice from 4 weeks through to the presence of metastases (10 weeks) and cCAF/CTC clusters enumerated. We co-injected CAFs with MCF-7 cellsl into NSG mice, blood collected by cardiac puncture, and cCAF/CTC clusters were enumerated. At time of final sacrifice, tumors were removed and assessed for presence of CSCs. Using our established model of cCAF/CTC clustering in vitro we interrogated cCAF/CTC complexing with both metastatic and poorly metastatic BC cells. Results: Circulating cCAFs/CTCs clusters are significantly increased in the blood of patients with advanced stage BC and associate not only with severity of disease but also with poorer clinical outcomes. In the spontaneous PyMT mouse model, the appearance of circulating cCAF/CTC clusters increased significantly as tumors grew but prior to metastasis. We demonstrate that metastatic BC cells form clusters with CAFs in vitro while non-metastatic BC cells do not form complexes with CAFs in vitro. Enriching for stem cells from MCF7 mammospheres, resulted in CAF/CSC clusters in vitro. In mice that were co-injected with non-metastatic MCF7 cells and CAFs from a TNBC/Basal-like BC (CAF23) we observed disease metastasis, an enrichment for cancer stem cell (CSC)-like CTCs, and the presence of circulating cCAF/MCF7-CSC clusters. Conclusions: Circulating clusters of CTCs and cCAFs are characteristic, and potentially causative, of BC metastasis. Observations of cCAF/CTC clusters from preclinical and clinical samples are corroborated by our determination that the ability of BC cells to form complexes with CAFs in vitro is related to the intrinsic metastatic ability of the breast cancer cells. Both in vitro and in circulation, the BC cells in cCAF/cBC clusters are CSCs, so cCAF/cCSC clusters. Disrupting the formation of cCAF/CTC complexes may be a potential strategy to reduce treat or prevent breast cancer metastasis. Citation Format: Miller P, Sharma U, Medina-Saenz K, Yeasky T, Picon-Ruiz M, Morata-Tarifa C, Seagroves T, Slingerland J, Lippman M, El-Ashry D. Circulating CAF/CTC complexes and breast cancer metastasis [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 P2-01-10.