Bone-dominant Metastatic Breast Cancer Research Articles

Abstract P1-01-07: The role of 18F-Fluoroestradiol (FES) and 18F-Fluorodeoxyglucose (FDG) PET imaging in identification of bone metastases in metastatic breast cancer

Abstract Background: Bone dominant metastatic breast cancer can be difficult to stage using conventional imaging. 18F-FES is an estrogen analogue PET imaging tracer that measures estrogen receptor (ER) expression at multiple tumor sites simultaneously and predicts response to endocrine therapy. We analyzed FES-PET and FDG-PET SUV uptake within bone in patients with metastatic lobular breast cancer from an ER+ primary. Methods: We retrospectively reviewed FES and FDG SUV uptake from scans in women with boney lesions or diffuse marrow uptake (n = 30). Our cohort was obtained from various cross-sectional studies at our institution and the majority received multiple lines of prior endocrine and/or chemotherapy. Up to 10 lesions in each patient were evaluated for a total of 200 lesions in both FES and FDG images. Diffuse marrow uptake was found in 7 women, and we compared this subgroup (bone marrow) vs the others by two-sample t-test for FES/FDG scans. Progression free survival (PFS), from time of earliest scan date to progression or death (whichever came first), and overall survival (OS), from time of earliest scan date to death, was evaluated using Kaplan-Meier curves and the Log-Rank test. Results: Mean (range) SUVmax in FES and FDG respectively for all bone lesions were 3.9 (1.5-9.1) and 4.7 (1.4-9.5). Higher FES and FDG uptake were noted in patients with bone marrow uptake (mean FES SUVmax 5.2 and mean FDG SUVmax 5.7) compared to non-marrow bone uptake (mean FES SUVmax 3.5 and mean FDG SUVmax 4.4), and the average difference for FES SUVmax was statistically significant higher in bone marrow uptake subgroup (p=0.032). Of the 200 lesions identified, 92 (46%) were located in the spine. Bone marrow uptake was visually more pronounced in the FES-PET scans. Compared to bone only uptake, patients with bone marrow uptake had a higher progression free survival (1.3 years vs 0.57 years p = 0.12), but similar overall survival (1.56 years vs 1.63 years, p = 0.69). Conclusions: Amongst patients with metastatic lobular carcinoma involving the bone marrow, there was significant higher uptake in both FES and FDG scans which provides insight in the pattern of spread of lobular breast cancer. Metastatic bone dominant breast cancers have similar FES and FDG avidity, suggesting that both imaging modalities can be used in identification of bone tumor sites. Further prospective trials are needed to confirm the utility of FES to stage extent of disease in bone dominant metastatic lobular breast cancer. Citation Format: Poorni Manohar, Lanell Peterson, Qian (Vicky) Wu, Isaac Jenkins, Brenda Kurland, Alena Novakova-Jiresova, Jennifer Specht, Mark Muzi, Jeanne Link, Kenneth Krohn, Paul Kinahan, David Mankoff, Hannah Linden. The role of 18F-Fluoroestradiol (FES) and 18F-Fluorodeoxyglucose (FDG) PET imaging in identification of bone metastases in metastatic breast cancer [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 P1-01-07.

Abstract P1-18-04: CTCs and SUV to predict the efficacy of the bone-specific radiopharmaceutical agent radium-223 dichloride combined with hormonal therapy for hormone receptor-positive bone-dominant breast cancer metastasis

Abstract Background: Radium-223 dichloride (Ra-223) is a targeted alpha particle-based radiotherapeutic that has a localized cytotoxic effect on bone metastases. We sought to determine whether the circulating tumor cell (CTC) count and the presence of CTCs in epithelial-mesenchymal transition (EMT-CTCs) along with the standardized uptake value (SUV) on positron emission tomography-computed tomography (PET/CT) scans predict the efficacy of combined Ra-223 and hormonal therapy in patients with hormone receptor (HR)-positive bone-dominant metastatic breast cancer. Patients and Methods: In this single-center phase 2 study (NCT02366130), 36 patients received Ra-223 (55 kBq/kg intravenously) on day 1 and then every 4 weeks for six cycles. Patients also received a standard care endocrine monotherapy. One non-bone metastatic site was allowed. The number of prior endocrine therapies was not limited and one prior chemotherapy was allowed for metastasis. Response was evaluated using the PET Response Criteria in Solid Tumors (PERCIST) with PET/CT at baseline, 6 and 9 months (mo) later. The CTC count (CellSearch) and the presence of EMT-CTCs (AdnaTest) was determined at baseline, 6 and 9 mo later. Progression-free survival (PFS) time was calculated to evaluate efficacy. Results: Seven patients (20%) had a non-bone metastatic site. The median number of prior therapies for metastasis was 1 (range, 0-4). Six patients (17%) received chemotherapy. The median CTC count at baseline was 4 (range, 0-306). Only four patients (11%) were positive for EMT-CTCs at baseline. The median follow-up time was 14.7 mo (95% confidence interval [CI], 13.2 mo-not reached [NR]). The disease control rate at 9 mo was 46% in 33 patients who reached 9 mo or progressed up to 9 mo. The tumor response rate at 6 mo was 52% (complete/partialresponse rate; 22/30 %) in 27 patients whose disease was evaluable using PERCIST. The SUV on PET/CT decreased significantly at 6 and 9 mo after baseline (average decreases of 1.5 (p=0.0004) and 2.5 (p=0.0054), respectively). The median PFS duration was 7.4 mo (95% CI, 4.8 mo-NR). The median bone PFS was 16 mo (95% CI, 7.3 mo-NR). Patients with bone-only metastasis (N=28, 80%) had a significantly longer median PFS duration than did patients with non-bone metastases at baseline (N=7, 20%) (13.8 mo versus 4.5 mo; p=0.017). Patients without prior treatment (N=12, 34%) tended to have longer median PFS durations than did those who underwent prior treatment (N=23, 66%) (16.8 mo versus 4.8 mo; p=0.1865). Also, patients with <5 CTCs at baseline (N=19, 54%) tended to have longer median PFS durations than did those with ≥5 CTCs (N=16, 46%) (13.8 mo versus 4.8 mo; p=0.1277). EMT-CTCs status did not predict efficacy. Conclusions: Bone-only metastatic breast cancer and SUV suppression by Ra-223 are predictive of efficacy. Patients with baseline <5 CTC count tended to have better outcomes than did those with ≥5 CTCs. Combined treatment with Ra-223 and a hormonal agent is especially effective at controlling bone metastasis in patients with HR-positive breast cancer. Bone-only metastatic disease and CTC count should be factored in future clinical trial designs. Citation Format: Ueno NT, Tahara RK, Reuben JM, Gao H, Saigal B, Fujii T, Lucci A, Ibrahim NK, Damodaran S, Shen Y, Liu DD, Hortobagyi GN, Tripathy D, Lim B, Chasen BA. CTCs and SUV to predict the efficacy of the bone-specific radiopharmaceutical agent radium-223 dichloride combined with hormonal therapy for hormone receptor-positive bone-dominant breast cancer metastasis [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 P1-18-04.

Prospective Study of Serial 18F-FDG PET and 18F-Fluoride PET to Predict Time to Skeletal-Related Events, Time to Progression, and Survival in Patients with Bone-Dominant Metastatic Breast Cancer.

Assessing therapy response of breast cancer bone metastases is challenging. In retrospective studies, serial 18F-FDG PET was predictive of time to skeletal-related events (tSRE) and time to progression (TTP). 18F-NaF PET improves bone metastasis detection compared with bone scanning. We prospectively tested 18F-FDG PET and 18F-NaF PET to predict tSRE, TTP, and overall survival (OS) in patients with bone-dominant metastatic breast cancer (MBC). Methods: Patients with bone-dominant MBC were imaged with 18F-FDG PET and 18F-NaF PET before starting new therapy (scan1) and again at a range of times centered around approximately 4 mo later (scan2). Maximum standardized uptake value (SUVmax) and lean body mass adjusted standardized uptake (SULpeak) were recorded for a single index lesion and up to 5 most dominant lesions for each scan. tSRE, TTP, and OS were assessed exclusive of the PET images. Univariate Cox regression was performed to test the association between clinical endpoints and 18F-FDG PET and 18F-NaF PET measures. mPERCIST (Modified PET Response Criteria in Solid Tumors) were also applied. Survival curves for mPERCIST compared response categories of complete response+partial response+stable disease versus progressive disease for tSRE, TTP, and OS. Results: Twenty-eight patients were evaluated. Higher 18F-FDG SULpeak at scan2 predicted shorter time to tSRE (P = <0.001) and TTP (P = 0.044). Higher 18F-FDG SUVmax at scan2 predicted a shorter time to tSRE (P = <0.001). A multivariable model using 18F-FDG SUVmax of the index lesion at scan1 plus the difference in SUVmax of up to 5 lesions between scans was predictive for tSRE and TTP. Among 24 patients evaluable by 18F-FDG PET mPERCIST, tSRE and TTP were longer in responders (complete response, partial response, or stable disease) than in nonresponders (progressive disease) (P = 0.007, 0.028, respectively), with a trend toward improved survival (P = 0.1). An increase in the uptake between scans of up to 5 lesions by 18F-NaF PET was associated with longer OS (P = 0.027). Conclusion: Changes in 18F-FDG PET parameters during therapy are predictive of tSRE and TTP, but not OS. mPERCIST evaluation in bone lesions may be useful in assessing response to therapy and is worthy of evaluation in multicenter, prospective trials. Serial 18F-NaF PET was associated with OS but was not useful for predicting TTP or tSRE in bone-dominant MBC.

Abstract P1-16-02: Phase II study of the feasibility and safety of radium-223 dichloride in combination with hormonal therapy and denosumab for the treatment of patients with hormone receptor-positive breast cancer with bone-dominant metastasis

Abstract Background Radium-223 dichloride (Ra-223) is a therapeutic alpha particle-emitting radiopharmaceutical compound which have antitumor effect targeted on bone metastases. Alpha particles induces double strand DNA breaks and localized cytotoxic effect to cancer cells with limiting harm on normal tissues. We are conducting a phase II clinical trial of combination of Ra-223, hormonal therapy, and denosumab treatment in patients with hormone receptor (HR)-positive bone-dominant metastatic breast cancer (NCT02366130). In this preliminary analysis of the study, we aimed to evaluate the feasibility and safety of this combination therapy. Methods This single-center phase II study seeks to determine the efficacy and safety of Ra-223 in combination with hormonal therapy and denosumab. Major eligibility criteria include HR-positive breast cancer with bone and/or marrow predominant metastases. Patients with two or more visceral metastases were not eligible. There was no limit in the number of prior hormonal therapies in the metastatic setting. Patients received Ra-223 injection (55 kBq/kg intravenously) on day 1 of the study and then every 4 weeks thereafter for 6 cycles. Patients were also administered a single hormonal agent (i.e., tamoxifen, aromatase inhibitor, or fulvestrant at standard doses) daily and denosumab (120 mg subcutaneously) every 4 weeks. For this analysis, adverse events (AEs) were summarized using descriptive statistics. Results A total of 25 patients were enrolled and 22 were evaluable between March 2015 and December 2016. Median age was 58.5 years (range 31-79), and 59% of patients were postmenopausal. ECOG performance status was 0 in 16 patients (73%), and 1 in six patients (27%). HER2/neu was positive in only one patient. Four patients (18%) were de novo metastasis, no patients had visceral metastasis, and multiple bone metastases in 20 patients (91%) vs. focal metastasis in 2 (9%). Median time from diagnosis of bone metastasis was 4.8 months (range 0.5-96.6). Prior therapy for metastatic disease consisted of hormonal therapy in 50% of the patients (eight patients with one line and three patients with two lines), chemotherapy (9%), palbociclib (14%), radiation to bone metastasis (50%), and bone-supportive therapy (27% with zoledronic acid, 27% with denosumab). The median number of cycles of Ra-223 administered was 6 (range 4-6). The median follow-up time was 4 months (range 2-8). There were no grade 3 or 4 AEs. Major non-hematological grade 1 and 2 AEs were bone pain (77%), fatigue (45%), nausea (36%), diarrhea (32%), AST/ALT elevation (23%), hot flashes (23%), and headache (18%). The most common hematological AEs were grade 1 or 2 neutropenia (23%), anemia (14%), and thrombocytopenia (18%). There was no treatment delay or discontinuation due to AEs. Conclusion Our results suggest that the addition of Ra-223 to hormonal therapy and denosumab is a feasible and safe combination therapy in patients with HR-positive breast cancer with bone-dominant metastasis. We continue to enroll patients in the phase II trial to evaluate the efficacy of the treatment. Citation Format: Tahara RK, Fujii T, Saigal B, Ibrahim NK, Damodaran S, Barcenas CH, Murray JL, Chasen BA, Shen Y, Liu DD, Hortobagyi GN, Tripathy D, Ueno NT. Phase II study of the feasibility and safety of radium-223 dichloride in combination with hormonal therapy and denosumab for the treatment of patients with hormone receptor-positive breast cancer with bone-dominant 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 P1-16-02.

Abstract OT1-04-05: A phase 2 randomized, double-blind, placebo-controlled trial of radium-223 dichloride with exemestane and everolimus in patients with HER2-negative, hormone receptor–positive breast cancer and bone metastases

Abstract Background: Treatment options for bone-dominant metastatic breast cancer (MBC) are limited. Radium-223, a first-in-class α emitter with a targeted antitumor effect on bone metastases (mets), was well tolerated and reduced bone biomarker levels in a phase 2 study in patients with bone-dominant MBC (Coleman et al. Breast Cancer Res Treat. 2014). In patients with HER2- estrogen receptor+ (ER+) bone-dominant MBC, everolimus + exemestane (EVE+EXE) improved progression-free survival (PFS) versus EXE alone. Radium-223 combined with EVE+EXE may improve outcomes in patients with HER2- ER+ bone-dominant MBC; this trial will evaluate efficacy and safety of radium-223 versus placebo in these patients (NCT02258451). Trial design: Patients are randomized to receive (1:1) radium-223 (50 kBq/kg [55 kBq/kg after National Institute of Standards and Technology update] IV) or placebo × 6 cycles q 4 wk + EXE (25 mg PO q d) + EVE (10 mg PO q d) plus best supportive care. EXE+EVE continues until disease progression or unacceptable toxicity. Stratification is by geographic region (EU/N America vs Asia), prior hormone therapy (1 vs ≥ 2), and presence of visceral disease (yes vs no). Eligibility criteria: Eligible patients are pre- or postmenopausal with HER2- ER+ MBC and have ≥ 2 bone mets or have soft tissue and/or visceral mets. Patients must have measurable disease per RECIST v1.1, ≥ 1 prior line of hormone therapy for MBC, and 1-2 prior skeletal-related events; be on bisphosphonates or denosumab; and have an ECOG score of 0-1. Patients must have had no past or current need for chemotherapy for MBC, no unresolved spinal cord compression, and no prior EVE treatment. Specific aims: The primary end point is symptomatic skeletal event–free survival (SSE-FS). Secondary end points are overall survival; times to opiate use, pain progression, and cytotoxic chemotherapy; radiologic PFS; and safety. Safety and efficacy are assessed every 4 weeks. Long-term safety is assessed until study termination. Statistical methods: Assuming a 1-sided α of 0.1, 90% power, ∼ 160 SSE-FS events will be required for the analysis. Efficacy will be analyzed by a stratified log-rank test. Safety analysis will be descriptive. Present and target accrual: Estimated enrollment is ∼ 311 patients. Currently, 74 patients are randomized. Contact Oana Petrenciuc, Bayer HealthCare Pharmaceuticals, oana.petrenciuc@bayer.com, for more information. Citation Format: Rugo HS, Drumea KC, Campone M, Barnadas A, Petrenciuc O, Zhang A, Li R, Coleman RE. A phase 2 randomized, double-blind, placebo-controlled trial of radium-223 dichloride with exemestane and everolimus in patients with HER2-negative, hormone receptor–positive breast cancer and bone metastases [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 OT1-04-05.

A phase 2 randomized, double-blind, placebo-controlled trial of radium-223 dichloride with exemestane and everolimus in patients with HER2–negative hormone receptor–positive breast cancer and bone metastases.

TPS621Background: Treatment options for bone-dominant metastatic breast cancer (MBC) are limited.Radium-223 (Ra-223), a first-in-class α emitter with a targeted antitumor effect on bone metastases (mets), was well tolerated and reduced bone biomarker levels in a phase 2 study in patients with bone-dominant MBC (Coleman et al. Breast Cancer Res Treat 2014). In patients with HER2- estrogen receptor+ (ER+) bone-dominant MBC, everolimus + exemestane (EVE+EXE) improved progression-free survival (PFS) vs EXE alone. Ra-223 plus EVE+EXE may improve outcomes in patients with HER2- ER+ bone-dominant MBC; this trial will evaluate efficacy and safety of Ra-223 vs placebo in these patients (NCT02258451). Methods: Eligible patients are pre- or postmenopausal with HER2- ER+ MBC and ≥ 2 bone or soft tissue mets. Patients must have measurable disease per RECIST v1.1, ≥ 1 prior line of hormone therapy for MBC, and 1-2 prior skeletal-related events; be on bisphosphonates or denosumab; and have an ECOG score of 0-1. Patients...

Serial FDG-PET to predict response, time to skeletal related events, and survival in patients with bone-dominant metastatic breast cancer.

11569Background: Response to therapy in bone lesions can be difficult to assess. In this prospective study, FDG-PET was used to assess TTP, SRE and survival (OS) in patients (pts) starting a new th...

Abstract P6-01-02: Flourine-18-fluorodeoxyglucose positron emission tomography for the evaluation of response to therapy in bone-dominant metastatic breast cancer: Examination in patients enrolled on UPCC 17113

Abstract Background: Response of bone-only (BO) and bone-dominant (BD) metastatic breast cancer (mBC) to therapy is difficult to assess by conventional imaging. UPCC 17113 is a single institution prospective cohort study evaluating FDG PET at early and conventional follow up intervals, 4 and 12 weeks respectively, in patients with hormone receptor (HR) positive mBC receiving endocrine therapy. The objective of this study is to assess the relationship between changes relative to baseline in standard uptake values (SUV) of specific bone lesions and progression free survival (PFS). We will also explore change in SUV as it relates to overall survival (OS) and skeletal related events (SRE). We present interim results. Methods: Enrolled patients were ≥18 years with biopsy proven or documented clinically obvious HR-positive BD/BO mBC due to start new endocrine therapy. Any line endocrine therapy was allowed. FDG PET was performed at baseline, 4 and 12 weeks after initiation of new therapy. SUVmax for the 5 most metabolically active osseous lesions, excluding sites previously treated by radiation or surgery, were recorded at baseline, 4- and 12- week time-points. Average index lesion SUVmax (sum SUVmax/#lesions) and % change from baseline were calculated. Decline of ≥30% from baseline was defined as significant. Results: As of 6/1/2015, 11 patients were enrolled. All patients have completed the 4-week scan and 8 have completed the 12-week scan. Five and 6 out of the 11 patients had BO and BD HR-positive mBC respectively. Detectable changes in SUV from baseline were noted in all patients at both 4 and 12 weeks, with a 37% overall decline in average index lesion SUVmax at 4 weeks. 8 of 11 patients had a ≥30% decline, in SUV at 4 weeks averaging 46%. Five of the 6 patients in this group who completed the 12-week scan had a sustained decline averaging 50% from the baseline. Of note, the average decline between 4 and 12 weeks in this group was only 8%. Despite having an overall decline from baseline of 44%, the sixth patient in this group had an increase between 4 and 12 weeks of 22%. Three of the 11 patients had a &amp;lt;30% decline at 4 weeks with an average decline of 12%. Of the two patients in this group with 12 week scans, both had average increase of 25% from 4 weeks to 12 weeks, and an average overall increase from baseline of 12%. Conclusions: There are detectable changes in FDG SUV of osseous lesions at 4 and 12 weeks following initiation of endocrine therapy in patients with BO or BD HR positive mBC. Our interim results demonstrate the emergence of 3 groups of patients: (1) those who have a &amp;lt;30% decline at 4 weeks and increase of SUV at 12 weeks, (2) those who have a ≥30% decline in SUV at 4 weeks with sustained decline at 12 weeks, and (3) those who have a ≥30% reduction in SUV at 4 weeks but who do not have a sustained decline at 12 weeks. These interim results suggest that early FDG PET/CT may provide information on mBC response to endocrine therapy and insight into timing of response and progression. As more patients are enrolled and complete the studies, clearer patterns will emerge which will be correlated with PFS, OS and SRE. Citation Format: Lynch MC, Mankoff D, Bradbury AR, Domchek S, Glick JH, Matro J, DeMichele A, Clark AS. Flourine-18-fluorodeoxyglucose positron emission tomography for the evaluation of response to therapy in bone-dominant metastatic breast cancer: Examination in patients enrolled on UPCC 17113. [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 P6-01-02.

Abstract P4-01-01: Serial FDG and 18F-fluoride PET predict response to therapy in patients with breast cancer bone metastases

Abstract Background: Assessing response to therapy in patients (pts) with bone-dominant (BD) metastatic breast cancer is challenging by conventional imaging such as CT and bone scintigraphy. In prior retrospective analyses, measures of FDG uptake by FDG PET were predictive of both time to progression (TTP) and the risk of skeletal related events (SRE). Studies have also shown that 18F-fluoride PET improves bone metastasis detection compared to bone scintigraphy and, as a quantitative study, may be better suited to evaluate therapeutic response. We evaluated the utility of serial FDG PET and 18F-fluoride PET to prospectively assess response to therapy in BD metastatic breast cancer. Methods: Pts with BD metastatic breast cancer were evaluated with FDG PET and 18F-fluoride PET prior to starting a new systemic therapy and after approximately 3 months. Serum markers (CA27.29 and CEA) were obtained at baseline and during treatment close to the time of PET imaging. In this analysis, static images from skull base to mid-thighs were analyzed quantitatively using the maximum standardized uptake value (SUV) of up to 5 most prominent lesions. Tumor locations were confirmed by CT and regions-of-interest were drawn on both FDG and 18F-fluoride images. Assessment of clinical endpoints including TTP and time to SRE was determined by independent review of clinical data and analyzed by Cox regression. PET imaging results were reported clinically, but not used to determine endpoints in this analysis. Results: 47 pts (mean age 55, range 39-91) enrolled between 2004 and 2012. Most pts 43/47 (91%) had hormone receptor positive disease (primary or metastatic). 9/47 (19%) of pts had HER2+ disease. Systemic therapy during study was chemotherapy in 20/47 (43%) and endocrine therapy in 31/47 (66%). Most pts 30/47 (64%) received bisphosphonates. Mean time between baseline and follow up FDG and 18F-fluoride PET scans was 4.6 months. 42/47 (89%) pts had disease progression during study follow up (median TTP 5.9 months, 95% CI 4-9.2). Among 24 pts with 2 FDG and 2 18F-fluoride scans, percent change in FDG (&amp;gt;-9% vs ≤-9%) was predictive of TTP, HR = 0.317, p = 0.038. Percent change (&amp;gt;-19% vs ≤-19%) in 18F-fluoride SUV did not predict TTP, HR = 1.05, p = 0.914. Median time to SRE was 48 months. Absolute SUV for baseline FDG and 18F-Fluoride PET were both predictive of time to SRE (FDG SUV &amp;gt;6 vs &amp;lt;6; HR = 4.61, p = 0.002 and 18F-fluoride SUV &amp;gt;25 vs &amp;lt;25; HR = 4.5, p = 0.008). Conclusions: Changes in FDG SUV over the course of treatment were a robust predictor of TTP, while changes in 18F-fluoride PET did not predict response. Both baseline high FDG and 18F-fluoride SUV were associated with earlier SRE occurrence. These results indicate a role for PET, particularly FDG PET, in assessing BD breast cancer and support a role for PET in future clinical trials. Funding support 5R01CA124573-05. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-01-01.

Vorinostat to restore sensitivity to aromatase inhibitor therapy in metastatic breast cancer: A phase II clinical trial with ER imaging correlates.

TPS3109 Background: Endocrine refractory,Indolent, soft tissue, and bone dominant metastatic breast cancer is a clinical problem, for which alternatives to chemotherapy are needed, Histone deacetylace inhibitors (HDACi) have shown pre-clinical promise in estrogen receptor-modulation and restoring sensitivity to endocrine manipulation, suggesting potential clinical benefit. HDACi restore ER expression in ER-negative cells which are then sensitive to AI treatment in xenografts (Sabnis 2011) and are toxic to ER-positive cell lines (Huang 2000). Vorinostat is an FDA approved HDACi for CTCL, and could have a beneficial role in restoring ER-signaling in endocrine-resistant tumors. We hypothesized that HDACi therapy could restore sensitivity to aromatase inhibitor (AI) therapy, in patients with prior progression on AI, and allow continued endocrine therapy. Recent data suggest clinical benefit of Tamoxifen and vorinostat given continuously (Munster 2011) as well as entinostat and an AI (Yardley 2011). Our prior work has shown the feasibility of monitoring regional ER expression and ER-estrogen binding in vivo using [F-18]fluoroestradiol (FES) PET imaging (Linden 2011) providing a biomarker to interrogate the molecular target. Methods: Patients with metastatic breast cancer with prior clinical benefit from endocrine manipulation who progressed on AI therapy are eligible. Patients must be off ER blocking therapies, and functionally postmenopausal. Baseline FES and FDG PET are performed and patients receive investigational vorinostat treatment at 400 mg po BID for 2 weeks followed by serial FES and FDG PET to assess the impact of vorinostat on ER expression and tumor metabolism. Patients are retreated on their prior AI as a single agent for 6 weeks, followed by paired FES and FDG and clinical assessment. Patients with clinical benefit may continue on treatment: 2 weeks of vorinostat followed by 6 weeks of AI in 8-week cycles until progressive disease or toxicity. We have enrolled 4 of a planned 20 patients.

Heterogeneity of Metabolic Response to Systemic Therapy in Metastatic Breast Cancer Patients

Aim The aim of this retrospective study was to describe the intra-individual heterogeneity of the 18F-labelled fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) response among lesions in bone-dominant metastatic breast cancer patients treated with systemic therapies. Patients and methods The metabolic response was analysed by comparing PET/CT scans carried out before and during a new treatment phase ( n = 46) in 25 bone-dominant metastatic breast cancer patients. Patients presented both bone and extra-bone metastases in 48% treatment phases. The metabolic response was analysed according to European Organization for Research and Treatment of Cancer (EORTC) criteria. A heterogeneous response was defined as the coexistence of responding and non-responding lesions within the same patient. Results The lesion-based response analysis showed a heterogeneous metabolic response in 48% of treatment phases. In the subset with both bone and extra-bone metastases ( n = 20), PET/CT showed discordant responses between bone and extra-bone metastases in 6/20 (30%) treatment phases. Considering all the cases included in the study, the time to progression (TTP) was longer in cases with a metabolic response compared with the cases with a metabolic non-response ( P = 0.02). In cases with a PET/CT non-response, TTP seemed to be lower in those with a homogeneous non-response compared with those with a heterogeneous metabolic response ( P = 0.07). Conclusion Whole-body FDG-PET allows frequent heterogeneous responses after systemic therapy to be identified in bone-dominant metastatic breast cancer patients.

Serial 2-[18F] fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) to monitor treatment of bone-dominant metastatic breast cancer predicts time to progression (TTP)

The response of bone-dominant (BD) breast cancer to therapy is difficult to assess by conventional imaging. Our preliminary studies have shown that quantitative serial 2-[(18)F] fluoro-2-deoxy-D: -glucose positron emission tomography (FDG PET) correlates with therapeutic response of BD breast cancer, but the relationship to long-term outcome measures is unknown. Our goal was to evaluate the prognostic power of serial FDG PET in BD breast cancer patients undergoing treatment. We reviewed medical records of 405 consecutive breast cancer patients referred for FDG PET. Of these, 28 demonstrated metastatic BD breast cancer, were undergoing treatment, had at least 2 serial PET scans, and had abnormal FDG uptake on the first scan. Standardized uptake value (SUV) for the most conspicuous bone lesion at the initial scan, absolute change in SUV over an interval of 1-17 months, and percent change in SUV were considered as predictors of time-to-progression (TTP) and time to skeletal-related event (t-SRE). Using proportional hazards regression, smaller percentage decreases in SUV (or increases in SUV) were associated with a shorter TTP (P < 0.006). A patient with no change in SUV was twice as likely to progress compared to a patient with a 42% median decrease in SUV. A higher SUV on the initial FDG PET predicted a shorter t-SRE (hazard ratio = 1.30, P < 0.02). Changes in serial FDG PET may predict TTP in BD metastatic breast cancer patients. However, larger prospective trials are needed to validate changes in FDG PET as a surrogate endpoint for treatment response.

Serial FDG-PET to monitor treatment of bone-dominant metastatic breast cancer predicts time to progression (TTP)

633 Background: The response of bone-dominant breast cancer to therapy is difficult to assess by conventional imaging approaches such as bone scan and MRI. Our preliminary studies have previously shown that quantitative serial [F-18]-2-fluoro-D-glucose positron emission tomography (FDG PET) correlates with therapeutic response of bone-dominant breast cancer, but the relationship to long-term outcome measures is unknown. The aim of this study is to evaluate the prognostic power of FDG PET imaging in bone-dominant breast cancer undergoing treatment. Methods: A retrospective analysis was performed on the medical records of 405 breast cancer patients who were previously referred for FDG PET between January 1999 and December 2003. From this population of patients, 29 patients were selected who demonstrated metastatic bone only +/- nodal breast cancer and were undergoing treatment with at least 2 serial PET scans which had clear uptake. The standard uptake value (SUV) changes for the most conspicuous bone lesio...