Hormone-refractory Metastatic Breast Cancer Research Articles

Clinical Experience with Abemaciclib in Patients Previously Treated with Another CDK 4/6 Inhibitor in a Tertiary Hospital: A Case Series Study.

The three approved cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, including abemaciclib, have shown differences in their preclinical, pharmacological, and clinical data. Abemaciclib stands out for its broader target range and more rapid and intense activity. It has demonstrated efficacy as a monotherapy or in combination with tamoxifen in endocrine-refractory metastatic breast cancer (MBC) patients with prior chemotherapy. However, the clinical data on abemaciclib after exposure to previous CDK4/6 inhibitors are limited. In this single-center retrospective case series, we identified all patients who received abemaciclib until February 2022 after experiencing documented progression on palbociclib or ribociclib. The safety profile and clinical outcomes of abemaciclib treatment in this specific patient cohort were evaluated. Eleven patients were included in this retrospective case series, nine receiving abemaciclib with tamoxifen. Eight patients had visceral involvement, and the median age was 69 (ranging from 42 to 84). The median time from the end of prior CDK4/6 inhibitor treatment to abemaciclib initiation was 17.5 months (ranging from 3 to 41 months). Patients had undergone a median of three prior therapies (ranging from 1 to 7), including chemotherapy in 54.5% of cases. The median follow-up time was six months (ranging from 1 to 22 months). The median progression-free survival (PFS) was 8 months (95% CI 3.9-12). Five patients continued abemaciclib treatment, and one patient with liver metastases achieved a complete hepatic response. The most common adverse events were diarrhea (72.7%, no grade ≥ 3) and asthenia (27.3%, no grade ≥ 3). Our preliminary findings suggest that abemaciclib could be an effective and safe treatment option for MBC patients who have previously received palbociclib or ribociclib.

An open label phase II study of safety and clinical activity of naltrexone for treatment of hormone refractory metastatic breast cancer

SummaryThe opioid receptor (OR) antagonist naltrexone inhibits estrogen receptor-α (ER) function in model systems. The goal of this study was to determine the clinical activity of naltrexone in patients with ER-positive metastatic breast cancer. Patients with hormone receptor positive metastatic breast cancer were enrolled on a phase II study of naltrexone. An escalating dose scheme was used to reach the planned dose of 50 mg daily. The primary objective of the study was to evaluate response to therapy as measured by stabilization or reduction of the tumor Maximum Standardized Uptake Value (SUVmax) at 4 weeks by PET-CT scan. The secondary objectives included safety assessment and tumor SUVmax at 8 weeks. Out of 13 patients we enrolled, 8 patients had serial PET-CT scans that were evaluable for response. Of these 8 patients, 5 had stable or decreased SUVmax values at 4 weeks and 3 had clinical or imaging progression. Median time to progression was short at 7 weeks. Naltrexone was well tolerated. There were no discontinuations due to toxicity and no grade 3 or 4 toxicities were noted. Naltrexone showed modest activity in this short study suggesting the contribution of opioid receptors in ER-positive breast cancer. Our data do not support further development of naltrexone in hormone refractory breast cancer. It is possible that more potent peripherally acting OR antagonists may have a greater effect. (ClinicalTrials.gov Identifier: NCT00379197 September 21, 2006).

202P Abemaciclib in HR+/Her2- metastatic breast cancer patients after previous progression on palbociclib or ribociclib: Clinical experience in a tertiary hospital in Madrid, Spain

Preclinical and pharmacological data of the three approved cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) suggest differences among them. Abemaciclib inhibits other targets (CDK2/Cyclin A/E and CDK1/Cyclin B) causing cell cycle arrest in phases G1 and G2. In preclinical models, both senescence and apoptosis occurred earlier and at lower concentrations of Abemaciclib, compared to treatment with either palbociclib or ribociclib. Abemaciclib monotherapy or combined with tamoxifen has demonstrated activity in endocrine refractory metastatic breast cancer (MBC) who had received prior treatment with chemotherapy. There are limited clinical data of abemaciclib after a prior CDK4/6i exposure. To assess the safety profile and clinical outcomes of a consecutive cohort of HR+/HER2- MBC patients treated with abemaciclib beyond a previous progression on palbociclib or ribociclib at our institution. From April, 2020 until February, 2022, 11 women met inclusion criteria and were included. 9 out 11 received abemaciclib combined with tamoxifen. 8 patients had visceral involvement, none had brain metastasis. Median age was 69 years (range 42-84 years). Median time to abemaciclib from the end of previous CDK4/6i was 17.5 months (range 3-41 months). Median number of therapies until rechallenge was 3 (range 1-7) including chemotherapy in 54.5% of patients. Median time of follow-up was 6 months (range 1-22 months). The median progression-free survival (PFS) was 6 months (95%CI 3.5 – 10). 5 patients still continue on abemaciclib. Of these, 1 patient with hepatic metastases achieved complete response. Clinical benefit rate (CBR) at 24 weeks was seen in 5 patients out of 8 evaluable patients. Most common adverse events (AEs) were diarrhea (72.7%, no grade ≥ 3) and asthenia (27.3%, no grade ≥3). Neutropenia grade 4 was seen in a heavily treated patient with previous episodes on other therapies. Abemaciclib may result an effective and safe treatment option in MBC patients previously treated with palbociclib or ribociclib. Further prospective studies to confirm this hypothesis are required.

Endoxifen, an Estrogen Receptor Targeted Therapy: From Bench to Bedside.

The selective estrogen receptor (ER) modulator, tamoxifen, is the only endocrine agent with approvals for both the prevention and treatment of premenopausal and postmenopausal estrogen-receptor positive breast cancer as well as for the treatment of male breast cancer. Endoxifen, a secondary metabolite resulting from CYP2D6-dependent biotransformation of the primary tamoxifen metabolite, N-desmethyltamoxifen (NDT), is a more potent antiestrogen than either NDT or the parent drug, tamoxifen. However, endoxifen's antitumor effects may be related to additional molecular mechanisms of action, apart from its effects on ER. In phase 1/2 clinical studies, the efficacy of Z-endoxifen, the active isomer of endoxifen, was evaluated in patients with endocrine-refractory metastatic breast cancer as well as in patients with gynecologic, desmoid, and hormone-receptor positive solid tumors, and demonstrated substantial oral bioavailability and promising antitumor activity. Apart from its potent anticancer effects, Z-endoxifen appears to result in similar or even greater bone agonistic effects while resulting in little or no endometrial proliferative effects compared with tamoxifen. In this review, we summarize the preclinical and clinical studies evaluating endoxifen in the context of breast and other solid tumors, the potential benefits of endoxifen in bone, as well as its emerging role as an antimanic agent in bipolar disorder. In total, the summarized body of literature provides compelling arguments for the ongoing development of Z-endoxifen as a novel drug for multiple indications.

P056 - Efficacy of fulvestrant in hormone refractory metastatic breast cancer (mBC): a Canadian province experience

P056 - Efficacy of fulvestrant in hormone refractory metastatic breast cancer (mBC): a Canadian province experience

NextMONARCH: Abemaciclib Monotherapy or Combined With Tamoxifen for Metastatic Breast Cancer

BackgroundAbemaciclib is a selective cyclin-dependent kinase 4 and 6 inhibitor administered continuously for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer. Abemaciclib is associated with dose-dependent early-onset diarrhea. nextMONARCH evaluated abemaciclib monotherapy (with or without prophylactic loperamide) and combined with tamoxifen for endocrine refractory metastatic breast cancer (MBC) after chemotherapy. Patients and MethodsnextMONARCH is an open-label, controlled, randomized, phase II study of women with endocrine-refractory HR+, HER2− MBC previously treated with chemotherapy. Patients received abemaciclib 150 mg plus tamoxifen 20 mg (A+T), abemaciclib 150 mg every 12 hours (A-150), or abemaciclib 200 mg plus prophylactic loperamide (A-200). The primary objective was progression-free survival (PFS). PFS analyses tested superiority of A+T to A-200 and informal noninferiority of A-150 to A-200. The secondary objectives included the objective response rate (ORR), safety, and pharmacokinetics. ResultsThe median PFS was 9.1 months for A+T versus 7.4 months for A-200 (hazard ratio, 0.815; 95% confidence interval, 0.556-1.193; P = .293). The A-200 PFS was comparable to that with A-150 at 6.5 months (hazard ratio, 1.045; 95% confidence interval, 0.711-1.535; P = .811). The ORR was 34.6%, 24.1%, and 32.5% for A+T, A-150, and A-200, respectively. No new safety signals were identified. The incidence and severity of diarrhea (62.3%; grade 3, 7.8%) with A-200 was similar to that with A-150 (67.1%; grade 3, 3.8%). The pharmacokinetics were comparable to previous observations. ConclusionsThe addition of tamoxifen to abemaciclib did not significantly improve PFS or ORR compared with abemaciclib monotherapy but confirmed the single-agent activity of abemaciclib in heavily pretreated HR+, HER2− MBC. Dose reductions and antidiarrheal medication generally managed diarrhea while maintaining efficacy.

Phase II study of pembrolizumab and capecitabine for triple negative and hormone receptor-positive, HER2−negative endocrine-refractory metastatic breast cancer

BackgroundResponse rates to single agent immune checkpoint blockade in unselected pretreated HER2−negative metastatic breast cancer (MBC) are low. However, they may be augmented when combined with chemotherapy.MethodsWe conducted a single-arm,...

A phase II study of pembrolizumab and capecitabine for triple-negative (TN) and hormone receptor-positive, HER2-negative endocrine-refractory metastatic breast cancer (MBC).

1096 Background: Response rates to single agent immune checkpoint blockade in unselected MBC are low; however, they may be augmented when combined with chemotherapy. Methods: We conducted a single-arm, phase II study of patients with TN or endocrine-refractory MBC who were candidates for capecitabine. Patients were treated with pembrolizumab 200 mg IV day 1 and capecitabine 1000 mg PO BID days 1-14 of a 21-day cycle. The primary endpoint was progression free survival (PFS) and secondary endpoints were overall response rate (ORR), safety and tolerability. The study had 80% power to detect a 2 month (mo) improvement in mPFS with the addition of pembrolizumab over historic controls treated with capecitabine alone. Results: Thirty patients, 16 with TN and 14 endocrine-refractory MBC, were enrolled from 2017-18. Patients had a median age of 51 years and received a median of 1 prior line of therapy for MBC. Of 29 evaluable patients, the mPFS was 4.1 mo (95% CI, 2.3-8.2 mo) and median overall survival was 15.4 mo (95% CI, 8.2-16.6 mo). ORR was 14% (n = 4), stable disease (SD) was 41% (n = 12), and clinical benefit rate (CBR = PR + SD > 6 mo) was 28% (n = 8). The ORR and CBR were similar between disease subtypes (ORR 13% and 14%, CBR 25% and 29% for TN and endocrine refractory, respectively). The 1-year PFS rate was 20.7% and 3 pts have ongoing responses. The most common adverse events were low grade and consistent with those seen in MBC patients receiving capecitabine, including hand-foot syndrome, gastrointestinal symptoms, fatigue, and cytopenias. Toxicities at least possibly from pembrolizumab included grade 3 or 4 liver test abnormalities (7%), rash (7%), and diarrhea (3%), as well as grade 5 hepatic failure in a pt with liver metastases. Conclusions: Compared to historical controls, pembrolizumab with capecitabine did not improve PFS in this biomarker unselected cohort; however, some patients had prolonged disease control. Future studies of chemo-immunotherapy in MBC with liver metastases require close safety monitoring. Clinical trial information: NCT03044730.

Use of Everolimus and Trastuzumab in Addition to Endocrine Therapy in Hormone-Refractory Metastatic Breast Cancer

BackgroundIncreased signaling through growth factor receptor pathways, including HER2, plays a role in resistance to endocrine therapy (ET) in patients with hormone receptor (HR)-positive metastatic breast cancer (MBC). Inhibition of mechanistic target of rapamycin improves outcomes when used in addition to ET in patients with HR-positive MBC, who previously received ET. We hypothesized that the additional use of trastuzumab (T) or everolimus (E) could restore sensitivity to ET in patients with endocrine-resistant, HR-positive, HER2-negative MBC. Patients and MethodsPatients with endocrine-resistant HR-positive, HER2-negative MBC continued the ET during which they had experienced disease progression, and were randomized to receive T or E. At disease progression, patients could continue the therapy they were receiving and have E or T used in addition. ResultsFifty-four patients were randomized to the additional use of E (n = 30) or T (n = 24) with existing ET. Progression-free survival (PFS) was 5.7 months, and 2.2 months, respectively, and clinical benefit rate at 24 weeks was 48% and 11% for patients receiving E or T, respectively. PFS was 4.5 months and 3.1 months for patients in whom E (n = 16) or T (n = 12) was used post progression, respectively. There were no new safety signals apart from 2 patients who had a decreased ejection fraction while receiving E with ET. ConclusionThese results suggest that E, but not T, can potentially reverse resistance to ET in patients with endocrine-resistant HR-positive, HER2-negative MBC. Further, the additional use of E with an ET to which the cancer has already been exposed might offer the possibility of delaying time to use of chemotherapy.

The tyrosine-kinase inhibitor sunitinib targets vascular endothelial (VE)-cadherin: a marker of response to antitumoural treatment in metastatic renal cell carcinoma

BackgroundVascular endothelial (VE)-cadherin is an endothelial cell-specific protein responsible for endothelium integrity. Its adhesive properties are regulated by post-translational processing, such as tyrosine phosphorylation at site Y685 in its cytoplasmic domain, and cleavage of its extracellular domain (sVE). In hormone-refractory metastatic breast cancer, we recently demonstrated that sVE levels correlate to poor survival. In the present study, we determine whether kidney cancer therapies had an effect on VE-cadherin structural modifications and their clinical interest to monitor patient outcome.MethodsThe effects of kidney cancer biotherapies were tested on an endothelial monolayer model mimicking the endothelium lining blood vessels and on a homotypic and heterotypic 3D cell model mimicking tumour growth. sVE was quantified by ELISA in renal cell carcinoma patients initiating sunitinib (48 patients) or bevacizumab (83 patients) in the first-line metastatic setting (SUVEGIL and TORAVA trials).ResultsHuman VE-cadherin is a direct target for sunitinib which inhibits its VEGF-induced phosphorylation and cleavage on endothelial monolayer and endothelial cell migration in the 3D model. The tumour cell environment modulates VE-cadherin functions through MMPs and VEGF. We demonstrate the presence of soluble VE-cadherin in the sera of mRCC patients (n = 131) which level at baseline, is higher than in a healthy donor group (n = 96). Analysis of sVE level after 4 weeks of treatment showed that a decrease in sVE level discriminates the responders vs. non-responders to sunitinib, but not bevacizumab.ConclusionsThese data highlight the interest for the sVE bioassay in future follow-up of cancer patients treated with targeted therapies such as tyrosine-kinase inhibitors.

Z-endoxifen Is Active in Endocrine-Refractory Metastatic Breast Cancer

Abstract The tamoxifen metabolite Z-endoxifen has acceptable tolerability and antitumor activity.

Evaluation of tumor and circulating cell free (cf) DNA mutations in women with hormone refractory metastatic breast cancer (MBC) enrolled in a phase I study of Z-endoxifen (MC093C).

1043 Background: In estrogen receptor (ER) positive MBC, mutations (e.g. ESR1), identified from tumor biopsies or cfDNA, confer resistance. The concordance between mutations observed in tumor and cfDNA and the implications for response to Z-endoxifen, a potent anti-estrogen, are unknown. Methods: We previously conducted a phase I trial of Z-endoxifen in endocrine refractory, ER positive MBC. Seven dose levels were considered ranging from 20 to 160 mg/day followed by expansion cohorts (EC) of 40, 80, and 100 mg/day. Pretreatment blood samples (all pts) and fresh tumor biopsies (EC) were collected prospectively. Tumor and cfDNA were evaluated by targeted NGS. Results: 41 pts (38 evaluable) were enrolled. Prior endocrine therapy included aromatase inhibitors (37/38, 97%), fulvestrant (22/38, 58%) and tamoxifen (26/38, 68%). Substantial endoxifen exposure without DLTs at doses above 80 mg/day led to a halt in dose escalation and opening of the EC. Overall clinical benefit (stable > 6 months [7 pts.] or partial response by RECIST criteria [3 pts.]) rate was 26.3% (95%CI: 13.4-43.1%). cfDNA was obtained from 36 pts and mutations were identified in 13 (36%) including ESR1 [ Y537N or D538G] (5), PIK3CA [ H1047R or E542K] (8), TP53 [ K132R, R248Q, R267Q, or H179Y] (4), AKT ( Q79K) (1), and KRAS ( G12D) (1). In 5 pts with cf ESR1 mutations, 4 had additional cfDNA mutations including PIK3CA (3), and TP53 (1). PFS was shorter in pts with cfDNA mutations relative to those without (median: 61 vs.132 days; log-rank p = 0.021). Discordance was observed between tumor and cfDNA mutations where 3/7 PIK3CA tumor mutations were detected by cfDNA, 1/2 TP53 tumor mutations were detected by cfDNA, and 0/1 AKT tumor mutations were detected by cfDNA. Conversely, 2 pts had cfDNA mutations (either ESR1, TP53 or AKT) undetected in tumor. Conclusions: The absence of cfDNA mutations in patients with endocrine resistant, MBC treated with Z-Endoxifen was associated with significantly longer PFS. Given the discordance between tumor and cfDNA sequence data, future studies must determine which approach maximizes prognosis and prediction of benefit for estrogen-targeted therapy. Clinical trial information: NCT01327781.

Soluble VE-cadherin in metastatic breast cancer: an independent prognostic factor for both progression-free survival and overall survival

Background:Patients with metastatic breast cancer (MBC) represent a heterogeneous group, with large differences in outcomes from individual patients. VE-cadherin, an endothelial-specific cadherin, was shown to promote tumour proliferation and angiogenesis. Soluble VE-cadherin has been recently associated to breast cancer progression. This study was designed to investigate the prognosis significance of soluble VE-cadherin in hormone-refractory MBC.Methods:Between 2004 and 2007, 150 patients with a fully documented history of hormone-refractory MBC were included in the prospective SEMTOF study. Serum concentrations of VE-cadherin were measured at inclusion for 141 patients and 6 weeks after the beginning of chemotherapy, using a sandwich enzyme immunoassay.Results:The presence of high levels of serum VE-cadherin was significantly correlated to a shorter progression-free (PFS) and overall survival (OS). In a multivariate analysis along with clinical and biologic prognostic parameters, high serum VE-cadherin level was an independent adverse prognostic variable for PFS (median PFS 9.7 (IC95: 8; 11.9) vs 5.8 (IC95: 4.1; 8) months P=0.0008) and OS (median OS 34 (IC95: 26.6; 47.1) vs 14.8 (IC95: 9.3; 21.4) months P=0.0007). Moreover, VE-cadherin decrease during chemotherapy was also associated with good prognosis.Conclusions:Serum VE-cadherin levels correlate to poorer survival in patients with hormone-refractory MBC. As sVE-cadherin reflects tumour angiogenesis, this could have therapeutic implications for antiangiogenic treatment.

A phase II study of afatinib, an irreversible ErbB family blocker, added to letrozole in patients with estrogen receptor-positive hormone-refractory metastatic breast cancer progressing on letrozole.

Phase II, open-label study assessing the efficacy and safety of the ErbB family blocker afatinib combined with letrozole in estrogen receptor-positive metastatic breast cancer (MBC) patients who had progressed on letrozole monotherapy. Adult females (N = 28) received oral afatinib (50 [n = 7], 40 [n = 13] or 30 [n = 8] mg/day) plus letrozole 2.5 mg/day in 28-day cycles until disease progression. Primary endpoint was the progression-free rate at or after 16 weeks of afatinib. At 16 weeks, four patients remained on afatinib without progression; two of these were HER2 negative. Fifteen (54 %) patients had a best response of stable disease according to Response Evaluation Criteria in Solid Tumors. Median progression-free survival was 60, 107 and 79 days with 50, 40 and 30 mg/day afatinib, respectively. Diarrhea, asthenia, rash, mucosal inflammation and nausea were the most frequent adverse events. In this small, exploratory study, afatinib combined with letrozole was able to induce disease stabilization in 54 % of hormone-refractory MBC patients previously progressing on letrozole.Clinical trial registration: NCT00708214

Abstract P1-14-02: Reversing endocrine resistance: A pilot study of estradiol followed by exemestane

Abstract Introduction: Anti-estrogen therapy is highly effective in treating hormone receptor positive breast cancer in both the adjuvant and metastatic settings. However, endocrine resistance frequently develops and strategies to reverse resistance are a high research priority. Pre-clinical data suggest exposure to physiologic or supra-physiologic doses of estrogen induce tumor regression in tamoxifen resistant tumors. Alternating treatment between estrogens and anti-estrogens has also been effective at delaying the development of endocrine resistance in these models. To further test this strategy, we initiated a pilot study of estradiol (E) for reversing endocrine resistance in patients with estrogen receptor (ER+) metastatic breast cancer (MBC) who had failed prior aromatase inhibitor (AI) therapy. Methods: Postmenopausal women with ER+ MBC who had failed at least 1 prior endocrine therapy (including an AI), were eligible for the study. Patients were treated with daily E that was titrated up from 2mg to 6mg/day over the first week of treatment to minimize gastrointestinal side effects. Patients who had not progressed after 3 months of E were switched to exemestane (Ex) to determine if short term E exposure would reverse endocrine resistance and re-sensitize tumors to estrogen deprivation (AI) therapy. The primary objective of the study was the feasibility and toxicity associated with short-term E followed by Ex therapy. Results: 15 patients were screened for enrollment. One patient was ineligible and another patient withdrew from study, leaving a total of 13 patients who were treated with E at 6mg daily. All patients were evaluable for toxicity and response at the end of the 3 month E phase. There were no grade 3 or 4 toxicities observed during the entire study (E and Ex phases). At the end of the E phase, 6 patients (46%) had not progressed (3PR, 3SD) and subsequently were switched to Ex. On Ex, 5 progressed and 1 had SD as their best response. Median PFS for all patients was 4.8 months (0.6 – 9.5 months). After progression on Ex, 4 patients were re-exposed to E and 2 had clinical benefit over 6 and 12 months, respectively. Conclusion: Alternating estrogen with anti-estrogens was not effective at reversing hormone resistance. However, low dose E treatment had significant clinical activity with minimal toxicity and should be considered as a therapeutic option for hormone refractory MBC (Table 1). Table 1: Reported Estradiol Clinical StudiesStudyDrug & DoseNResponse DataCBRTTP/PFSToxicity (grade 3 or 4)Re-exposure to AIEllis MJ et alEstradiol, 30mg321PR,8 SD28%12wks/16 wks34%N = 7,2 PR and 1 SD Estradiol, 6mg343 PR,7 SD29%12wks/16 wks18% Howell S et alEstradiol valerate,2mg195 SD26%2.8m (0.5-29.8)/NR4 stopped treatment due to toxicity, grade 4 hypercalcemia, grade 4 hyponatremiaN = 3,1 PR and 1 SDIwase H et alEthinyl estradiol, 3mg189 PR, 1 SD55%10.6 wks (0-60wks)/NRNo grade 3/4N = 4, 1 respondedOur studyEstradiol, 6mg133 PR, 3 SD46%NR/4.8m (0.6-9.5m)No grade 3/4N = 7, 1 had CBRAll studies 11616 PR, 24 SD34% N = Number of patients, TTP- Time to progression, PFS- progression free survival, PR- partial response, SD- Stable disease, CBR- Clinical benefit rate, NR- not reported Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-14-02.

P4-07-16: Development of Circulating Tumor Cell-Endocrine Therapy Index in Metastatic Breast Cancer Patients.

Abstract Introduction: Only ∼ 50% of patients (pts) with estrogen receptor (ER) positive metastatic breast cancer (MBC) benefit from endocrine therapy (ET). Currently only clinical judgment can be used to identify pts with endocrine-refractory MBC, who are better palliated with chemotherapy. Circulating Tumor Cells (CTC) are reliably enumerated using an automated immunomagnetic system (CellSearch®; Veridex LLC). High CTC levels predict rapid progression in pts with MBC. We have developed a multi-parameter assay, the CTC-Endocrine Therapy Index (CTC-ETI) using CellSearch® that may identify pts with ER positive MBC who are unlikely to benefit from ET and may be better served with chemotherapy. CTC-ETI scores are assigned based on CTC levels coupled with the relative percent and degree of marker positivity on the CTC. We report preliminary results from a pilot single institutional study. Methods: CellSearch® has 4 fluorescence channels. Three distinguish CTC from WBC (DAPI, anti-cytokeratin, anti-CD45). The 4th “empty” channel was used to measure ER, BCL-2, HER-2, and Ki-67 expression with fluorescent-labeled antibodies. These 4 markers reflect sensitivity (ER, BCL-2) or resistance (HER-2, Ki-67) to ET. Forty ml of blood was drawn into 4 CellSave® tubes from pts with progressive MBC. Whole blood from 4 tubes was pooled and divided into 4 different 7.5 ml aliquots of blood, which were processed and characterized for CTC counts and each of the four molecular markers using the CXC CellSearch® kit. Results: 21 pts have been accrued to the feasibility study. One patient was ineligible. Five of 20 pts had low CTC counts (<5 CTC/7.5ml whole blood), and are expected to have a relatively favorable prognosis. CTC-ETI was successfully determined in 10 pts (50%): 2 pts had low, while 3 had intermediate, and 5 had high CTC-ETI. Technical difficulties precluded accurate CTC-ETI in the remaining 5 patients. Of note, expression of the biomarkers among CTC in single patients was heterogeneous, suggesting that future iterations of the CTC-ETI will have to consider expression variability. Further exploratory results regarding associations between CTC-ETI and outcomes will be presented. Conclusions: ER, BCL-2, HER-2, and Ki-67 can be accurately determined on CTC using the 4th channel in the CellSearch® system to calculate CTC-ETI. We predict that lower CTC-ETI scores (low or no CTC, or CTC with high CTC ER and BCL-2 and low CTC HER-2 and Ki-67) could be associated with favorable response to ET. Successful completion of the feasibility study will lead to a prospective trial to determine if high CTC-ETI at baseline predicts resistance and rapid progression on ET in women starting a new endocrine therapy for MBC. Supported by Veridex, LLC, Fashion Footwear Charitable Foundation of New York/QVC Presents Shoes on Sale ™ (DFH), Associazione Sandro Pitigliani and by a studentship from FIRC (CP). Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-07-16.

Abstract 4154: Multi-parameter molecular characterization of circulating tumor cells (CTC): Development of a CTC-endocrine therapy index (CTC-ETI)

Abstract Introduction. CTC can be reproducibly and reliably enumerated using a commercially-available, automated immunomagnetic system (CellSearch®; Veridex LLC). High levels of CTC predict rapid progression in patients with metastatic breast cancer (MBC). Only ∼ 50% of patients with estrogen receptor (ER) positive MBC benefit from endocrine therapy (ET). Patients with endocrine-refractory MBC are better palliated with chemotherapy. We have developed a multi-parameter assay using CellSearch® that may identify patients with ER positive MBC who are unlikely to benefit from ET and may be better served with chemotherapy. Methods. CellSearch® has four fluorescence channels. Three of these are used to distinguish CTC from WBC (DAPI, anti-cytokeratin, anti-CD45). The 4th “empty” channel was used to measure ER, Bcl-2, HER2, and Ki67 expression with antigen-specific fluorescent-labeled antibodies. These four markers were chosen because of their associations with sensitivity (ER, Bcl-2) or resistance (HER2, Ki-67) to ET. Cultured human breast cancer cells (MCF-7: ER +, BCL-2 +, HER2 -, Ki67 +; MDA-MB-231: ER -, Bcl-2 -, HER2 -, Ki67 +; BT-474: ER +, Bcl-2 +, HER2 +, Ki67 +) were spiked into 7.5 ml human whole blood from normal donors and separated and characterized using the CXC CellSearch® kit. Results. Each cell line stained appropriately for the respective markers, with appropriate negative controls, although staining was heterogeneous, even within a single cell line. Using these preliminary data, we have developed a CTC-ETI in which scores are assigned to the individual categories consisting of cell counts coupled with the relative percent and degree of cell positivity of each marker. We predict that lower scores (low or no CTC, or CTC with high % and intensity of ER and Bcl-2; low HER2 and Ki-67) will be associated with favorable response to ET. Conclusions. CellSearch® can be used to measure the expression of 4 clinically useful and proven breast cancer biomarkers. A clinical trial is underway at U. Michigan to permit calculation of CTC-ETI in patients with MBC, which will lead to a prospective trial to determine if high CTC-ETI predicts resistance and rapid progression on ET. Supported by Veridex, LLC, Fashion Footwear Charitable Foundation of New York/QVC Presents Shoes on Sale ™ (DFH), Associazione Sandro Pitigliani and by a studentship from FIRC (CP) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4154. doi:10.1158/1538-7445.AM2011-4154

Treatment of metastatic breast cancer: looking towards the future

The armamentarium for the treatment of metastatic breast cancer is increasing with the introduction of newer chemotherapeutic agents and the development of molecular targeted therapies. The clinical utility of anthracyclines in advanced breast cancer has been limited by significant adverse events; therefore the taxanes are increasingly used in the metastatic setting. Trastuzumab with a taxane as first-line therapy is now standard of care for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. Other targeted therapies, including the antiangiogenesis agents such as bevacizumab, are being investigated both as monotherapy and in combination regimens. While the number of available agents is growing rapidly, challenges remain concerning appropriate dose, schedule, treatment duration and management of drug resistance. This paper reviews recent data regarding the established and investigational medical treatments for endocrine-refractory metastatic breast cancer, and presents treatment recommendations.

Capecitabine (X) in elderly patients (pts) with hormone-refractory metastatic breast cancer (MBC)

1080 Background: X has demonstrated consistently high single-agent activity and good tolerability in pretreated and chemonaive MBC, and extends survival when added to docetaxel. High activity, minimal myelosuppression and no alopecia make X interesting in elderly pts with hormone-refractory disease. Methods: Between Feb 2004 and Oct 2006, 36 elderly (>65 years) MBC pts previously treated with adjuvant therapy and at least one previous hormonal therapy for advanced disease received X 1,000 mg/m2 twice daily, days 1–14 every 3 weeks. Study objectives were to assess efficacy, safety, and impact on quality of life (QoL), assessed by Clinical Benefit Response (CBR) every third cycle. Results: Median age was 70 years (range 68–73), median ECOG PS was 1 (range 0–2). All pts had visceral metastasis and 19 (53%) had ≥2 metastatic sites. A total of 284 cycles were administered (median 6 cycles per pt). After 3 cycles, 10 pts (28%) showed a partial response, 16 (44%) had stable disease (SD), and 2 (6%) had a minor response, resulting in a disease control rate of 78%. Biochemical response (CEA and/or CA 15.3 reduction) was observed in 20 (56%) pts. SD was maintained in 22 pts (61%) after 6 cycles, 10 pts (28%) after 9 cycles and 2 pts (6%) after 12 cycles. Treatment was well tolerated, the most common grade 3 events being mucositis (6%) and hand-foot syndrome (6%). There were no grade 3/4 hematologic toxicities. All adverse events were easily managed with dose adjustments and supportive therapies as required. As a result, all pts (100%) complied with appreciable benefits in terms of QoL (positive CBR in 56% of pts). Conclusions: These preliminary data indicate that this X dose is active and well tolerated in elderly pts with hormone-refractory MBC. This regimen also warrants study as first-line treatment in pts with less aggressive MBC who might not be suitable for combination therapy. No significant financial relationships to disclose.

Systemic efficacy of oncolytic adenoviruses in imagable orthotopic models of hormone refractory metastatic breast cancer

Conditionally replicating oncolytic adenoviruses represent a promising developmental strategy for the treatment of cancer refractory to current treatments, such as hormone refractory metastatic breast cancer. In clinical cancer trials, adenoviral agents have been well tolerated, but gene transfer has been insufficient for clinical benefit. One of the main reasons may be the deficiency of the primary adenovirus receptor, and therefore viral capsid modifications have been employed. Another obstacle to systemic delivery is rapid clearance of virus by hepatic Kupffer cells and subsequent inadequate bioavailability. In this study, we compared several capsid-modified oncolytic adenoviruses for the treatment of breast cancer with and without Kupffer cell inactivation. Replication deficient capsid-modified viruses were analyzed for their gene transfer efficacy in vitro in breast cancer cell lines and clinical samples and in vivo in orthotopic models of breast cancer. The effect of Kupffer cell depleting agents on gene transfer efficacy in vivo was evaluated. An aggressive lung metastatic model was developed to study the effect of capsid-modified oncolytic adenoviruses on survival. Capsid-modified viruses displayed increased gene transfer and cancer cell killing in vitro and resulted in increased survival in an orthotopic model of lung metastatic breast cancer in mice. Biodistribution of viruses was favorable, tumor burden and treatment response could be monitored repeatedly. Kuppfer cell inactivation led to enhanced systemic gene delivery, but did not increase the survival of mice. These results facilitate clinical translation of oncolytic adenoviruses for the treatment of hormone refractory metastatic breast cancer.