Citations

529 Background: Multiple prognostic models exist to predict late relapse risk in early stage hormone receptor-positive (HR+) breast cancer (BC). The CTS5 is one such model that has been validated in HR+ HER2-negative BC. The value of this model in HR+ HER2+ has not been established. Here, we assessed CTS5 in patients (pts) with early stage HER2+ BC treated in the NCCTG N9831 (Alliance) trial. Methods: Pts with stage I-III HER2+ HR+ BC who survived ≥ 5 years were included. The online CTS5 calculator was used to determine CTS5 score and risk group (low, intermediate, and high) based on age, tumor size, grade, and number of involved nodes. Kaplan-Meier (KM) estimates, Cox regression models, and C index were used for analysis. Results: From 3,130 pts, 1,204 pts met the criteria and were included. Median age was 49 (22-79) years and median tumor size was 2.4 (0.1-12) cm. 63.6% had grade 3 tumors, 33.6% grade 2, and 2.8% grade 1. Median follow up was 10.89 (5.01-15.32) years. Based on CTS5, 821 (68.2%) pts were classified as high risk, 289 (24%) as intermediate risk, and 94 (7.8%) as low risk. Overall, using univariate Cox regression analysis, there was no statistically significant difference in recurrence free survival (RFS) among pts with intermediate vs. low (HR 0.47 95%CI 0.18-1.22, p = 0.12) and high vs. low (HR1.23 95%CI0.57-2.67, p = 0.6) with the C index of 0.58. Among pts who received concurrent trastuzumab (H) with HR+ BC, there was also no statistical difference in RFS between high vs. low (HR 0.68 95%CI0.24-1.97, p = 0.48) with the C index of 0.55. Paradoxically, pts with intermediate risk had better RFS than low risk (HR 0.18 95%CI0.03-0.97, p = 0.05). As a continuous variable, there is also no significant improvement in RFS per 1 unit increase in CTS5 score (HR 1.19 95%CI 0.73-1.96, p = 0.49) with the C index of 0.54. After 5 years, 7.06% (n = 30/425) of HR+ pts treated with concurrent H recurred. Conclusions: The CTS5 model is not prognostic in pts with early stage HR+ HER2+ BC receiving adjuvant H. While most HR+ HER2+ pts are classified as high risk by CTS5, the recurrence between years 5-10 was low in pts who received adjuvant H. This study highlights the need to develop a new predictive model for risk of late relapse in this specific group of pts to enable clinicians to determine which pts would benefit from extended adjuvant endocrine therapy. Support: BCRF-19-161, U10CA180821, Genentech. https://acknowledgments.alliancefound.org Clinical trial information: NCT00005970 .

Abstract Background: Previous studies have proposed combination of various factors that predict poor mobilization after GCSF stimulation. However, there is no single clinical or laboratory test that reliably correlates with bone marrow reserve and PBPC mobilization. Peripheral blood CD34+ cell count (pCD34) reliably correlates with PBPC mobilization and yield but only after GCSF administration. Methods: We have prospectively followed 36 autologous PBPC transplant candidates, from the time of initial evaluation to transplant, to evaluate factors the correlate with bone marrow reserve and autologous PBPC mobilization. Results: The patients median age was 63 (range 26 – 76). 21 of the 36 patients were diagnosed with dysproteinemia, primarily multiple myeloma, 10 patients had non-Hodgkin’s lymphoma while the remaining 5 had other form of hematological malignancies. Our evaluation shows baseline platelet count prior to growth factor administration significantly correlate with total CD34+ cell yield (spearman: r = 0.64, p <0.001, Figure 1). In addition, daily platelet count during PBPC harvest correlate with CD34+ cell yield for the day (spearman: r = 0.6, p <0.001). Using multiple linear regression model (F = 19.1, p <0.001, R2 = 0.64), we have determined patients’ age (p = 0.03) and type of disease (p <0.001), in addition to platelet count (p<0.001), significantly correlate with total CD34+ cell yield. Further analysis showed low baseline platelet count predicts poor PBPC mobilization. Using Receiver Operating Curve (ROC), we have determined that platelet count of 174,000/ul was the best cut-off for collecting at least 2 million/Kg CD34+ cells with sensitivity of 81% and specificity of 78% and estimated correct classification of 81%. Even though pCD34 counts were slightly more sensitive and were better at identifying poor mobilizers in our cohort (best cut-off 10/ul, sensitivity 96%, specificity 67%, correct classification 89%), their clinical utility were diminished since the values were only known after GCSF administration. Conclusion: Baseline platelet count is a sensitive predictor of bone marrow reserve and can be used prior to growth factor administration to predict poor mobilization. Figure 1: Correlation of baseline platelet count and total CD34+ cell yield Figure 1:. Correlation of baseline platelet count and total CD34+ cell yield

Abstract Most common abnormalities in MDS involve the loss of chromosomal material resulting from the loss of an entire chromosome or a part of it, due to deletions or unbalanced translocations. Among partial chromosome losses, del (5q) was found to be the most common followed by del (20q). MDS can also be associated with multiple morphologic RBC abnormalities including macrocytes, ovalocytes, dacrocytes, fragmented cells and basophilic stippling. Limited cases of MDS with elliptocytosis have been reported in the literature. Elliptocytosis encompasses a heterogeneous group of erythrocyte disorders. Although acquired cases of elliptocytosis have been reported, these are most often hereditary disorders with a variable clinical presentation from asymptomatic carriers to patients with severe hemolytic anemia. This disorder is quite rare in the Unites States (US). Mutations in protein 4.1, alpha spectrin, beta spectrin, glycophorin C and band 3 have been reported in hereditary elliptocytosis. Only 7 well reported cases of marked elliptocytosis associated with MDS have been reported in the literature. Of those 7 cases, 4 of them were associated to del(20q). All of them were elderly males and all of them had ≤ 5% bone marrow blasts. Anemia is usually moderate (median 9.4 g/dL; range 8.1–12) and thrombocytopenia is mild to moderate (median platelet count 116 x 109/L; range 46–149 x 109/L). All cases were described either in Europe (n= 1; Rummens et al. Acta Haematologica1986; 75:174–177) or in Asia (n= 3; Ideguchi et al. Br J Haematol.1993, 75:387–92; Ishida et al. Cancer Genetics and Cytogenetics1997, 108:162–165; Hur et al. Clin Lab Haematology, 2004, 26: 69–72). Of these 7 cases, 3 of them were associated with protein 4.1 deficiency. To the best of our knowledge these are the first 2 cases of patients with marked elliptocytosis and MDS with del 20q abnormality reported in the US: Patient 1 Patient 2 Age/sex 82/male 79/male FAB classification RA RA Year of diagnosis of MDS 1998 1999 WBC 3.0 x 109/L 11.5 x 109/L Platelets 82 x 109/L 79 x 109/L Hemoglobin 11.8 g/dL 10.7 g/dL Hematocrit 34.4% 31.9% Reticulocyte 4.3% NA LDH 350 u/L NA Direct Coombs Negative NA BM Cytogenetics 46 XY, del (20)(q11.2) 46 XY, del (20)(q11.2) Prior Therapy supportive care only Erythropoeitin Evaluation for protein 4.1 deficiency in one of these 2 patients is currently pending. The elliptocytosis noted in these MDS patients were most likely derived from acquired clones with abnormal development of the erythroid lineage and were associated with deletion of chromosome 20q. Patients with acquired elliptocytosis and associated MDS with del 20q chromosomal abnormality seem to have an indolent course with prolonged history of mild to moderate blood cytopenias and low risk to transformation to acute leukemia. Further research is needed to deduce the clinical significance of this subtype of MDS with this unusual RBC morphology

Abstract Background: IgM multiple myeloma (MM) are very rare plasmaproliferative disorders representing 0.5–1.2% of all cases of MM and < 0.2% of all IgM monoclonal gammopathies. Clinical criterion are not always helpful in differentiating IgM MM from Waldenstrom macroglobulinemia. However, the presence of lytic bone lesions, absence of lymphadenopathy and/or hepatosplenomegaly, presence of translocation of the immunoglobulin heavy chain locus at 14q32 [t(11;14), t(14;16), t(4;14)], and strong expression of CD138 by the plasma cells are useful in the diagnosis of IgM MM. It has been our experience and of others that these cases have an aggressive behavior at presentation, shorter survival than IgG and IgA MM and poor response to therapy for lymphoplasmacytoid lymphomas. We present here 2 cases of IgM MM with a dramatic response to Lenalidomide and low dose dexamethasone (Rev/Dex) Results: Baseline patient characteristics at time of diagnosis of IgM MM and therapy outcome are presented in the following 2 tables: Table 1. Case 1 2 Age and sex 72 (F) 73 (F) Serum M-spike (g/dL) 5.3 6.2 Urine M-spike (mg/dl/24 hrs) 72 412 Serum IgM (mg/dL) 8,590 11,000 BM plasma cells percentage 90 20 Plasma cell immunophenotyping CD138+++, partial CD20, CD56− CD138+++, partial CD20, CD56− Cytogenetics (Standard and/or FISH) Standard: normal FISH: not done on initial biopsy. On follow up there were insufficient number of plasma cells to perform test Standard: of 20 metaphases, 6 had a complex hypotetraploid karyotype with relative loss of 13q, 14, 15, 16, 20, and 22, and numerous unbalanced rearrangements. FISH: a plasma cell clone with monosomy 13 and IGH/c-MAF fusion, t(14;16). In addition, approximately 60% of plasma cells had a tetraploid clone with the same anomalies as well as relative loss of p53 Bone lesions Multiple non-traumatic spinal fractures and of stenum Several lytic lesions of long bones Renal insufficiency No No Anemia (Hbg g/dL) Yes (8.7) Yes (8.1) Hypercalcemia (Ca mg/dL) Yes (12.5) Yes (11.4) Beta 2 microglobulin (mg/dL) 5.79 8.51 Serum viscosity (cpoise) 5.9 4.8 Table 2. Best Response to therapy Case Therapy Best Response Comments 1 Rituxan, then Fludarabine based therapy Transient response Rapid progression after partial and transient response to each therapy 1 Lenalidomide + LD-Dex sCR after cycle #6. Currently on CR 18 months later IgM declined from 8,590 to 43 mg/dL after 4 cycles of Rev/Dex. 2 Lenalidomide + LD-Dex VGPR after cycle #2 IgM declined from 11,000 to 463 mg/dL after cycle 3. Complete disappearance of M-spike in serum; BM to be done after cycle #4 Conclusions: This is the first report that we are aware of a rapid and dramatic response to lenalidomide and low dose dexamethasone in these rare cases of IgM MM with poor response to NHL-type treatment. Lenalidomide-based therapy might abrogate poor prognosis cytogenetics in this unusual subtype of MM (case #2), however, follow up for this patient is still very short.

Abstract Introduction: POEMS syndrome is characterized by chronic progressive polyneuropathy (P) with constellation of other symptoms including organomegaly (O), endocrinopathy (E), serum monoclonal protein (M), and skin changes (S). Other features not included in the acronym include sclerotic bone lesions, Castleman disease, papilledema, thrombocytosis, peripheral edema, ascites, fatigue and clubbing. With limited available data, autologous peripheral blood stem cell transplant (APBSCT) is probably the mainstay of therapy in good performance status patients. Case Description: A 37 year old male presented to the Mayo clinic with a three year history of progressive severe peripheral neuropathy leaving him wheelchair bound, as well as lymphadenopathy, hepatosplenomegaly, diabetes, proteinuria, monoclonal gammopathy and hyperpigmentation. Patient also had significant pain from diffuse sclerotic lesions, blurry vision due to papilledema and generalized edema. Based on the above findings, a diagnosis of POEMS was suspected. The diagnosis was confirmed by a biopsy of a left axillary node showing plasma cell Castleman’s disease. Patient’s bone marrow was negative for multiple myeloma and amyloidosis. Patient underwent APBSCT and had a remarkable clinical improvement that persisted over three years. Patient was able to live a normal, active life during those years. After three years, patient developed ascites, massive splenomegaly and pancytopenia. Patient was referred again to our institution for possible splenectomy. On further evaluation, he was found to have significant portal hypertension and underwent TIPS (transjugular intrahepatic portosystemic shunt) procedure with some improvement in his symptoms. Patient remained in observation for another 18 months but returned oxygen dependent with worsening ascites, peripheral neuropathy, and encephelopathy. Further evaluation confirmed worsening POEMS. Patient’s ECOG performance status was poor therefore repeat APBSCT was not considered an option. Lenalidomide was started at 10mg/day for 21 days of a 28 day cycle with once weekly dexamethasone 40mg. The dose of lenalidomide was gradually increased to standard 25mg dose which the patient tolerated well. By the second month patient was on therapy, his performance status improved to ECOG 1, his ascites and encephalopathy resolved, the splenomegaly improved and he no longer required oxygen. Patient has currently completed a total of 10 cycles and feels as good as 10 months post-APBSCT. The only side effect experienced by the patient is weight gain due to chronic dexamethasone therapy. Dexamethasone was weaned and discontinued after which lenalidomide continued as a single agent. Conclusion:: Lenalidomide is a less toxic but effective alternative treatment for POEMS syndrome. The Lazarus response to the use of lenalidomide supports the principle that POEMS is a cytokine-mediated syndrome

Abstract Background: Cardiac toxicity (CT) in the form of left ventricular systolic dysfunction is a well-known complication of anti-HER2 therapy. Prior clinical trial data has suggested potential factors associated with increased risk for CT. We sought to develop a clinical risk prediction model from real world patients to better identify patients who may be at higher risk for CT. Methods: Patients treated with anti-HER2 agents at all Mayo Clinic sites from Jan 2008 to July 2015 were reviewed. Patient data including age, race, body mass index, comorbidities, smoking history, baseline ejection fraction (EF), presence of left ventricular hypertrophy (LVH), prior cancer treatments, number of anti-HER2 agents used, and cardiac medication use were recorded. Factors were compared in patients with and without development of CT. Cox regression models were used to identify univariate and multivariate predictors of CT. A risk score was then assigned based on the final multivariable model. Results: 604 patients were included in final analysis. Median follow-up 2.9 yrs; median age: 57 yr; baseline EF: 64%. One yr CT rate was 7%. Independent predictors of CT were age, baseline EF, LVH, and anthracycline use (C index=0.74). Based on model coefficient, scores of 1, 1, 2 and 3 were assigned to age>55, EF <60%, anthracycline exposure and LVH, respectively. Two random samples of 300 patients were created out of the original cohort for internal validation of the risk score model. In each, the risk score was found to be a highly significant predictor for CT with C index of 0.72 {HR 2.13 (95% CI 1.57-2.90), p <0.001} and 0.77 {HR 2.45 (95% CI 1.74-3.44), p <0.001}. Conclusions: Patients with risk factors of older age, lower baseline EF, anthracycline use and LVH are at increased risk for CT when treated with anti-HER2 agents. Using a risk prediction model at therapy initiation may enhance identification of patients who benefit from cardiology referral, closer cardiac monitoring, and/or prophylactic treatment while on anti-HER2 targeted therapy. Table 1. Multivariable Cox regression model predicting cardiac dysfunctionParameterParameter EstimateHR (95%CI)p valueScoreAge >550.909552.48(1.27, 4.84)0.00751EF<600.634361.89(1.01, 3.53)0.04751Anthracycline Exposure1.046132.85(1.48, 5.46)0.00162Baseline LVH1.633565.12(2.04,12.85)<0.0013 Citation Format: Pooja P Advani, Lauren Cornell, Zhuo Li, Jordan Ray, Catalina Sanchez, Armando Villanueva, Taryn Smith, Alvaro Moreno-Aspitia. A validated clinical risk prediction model for cardiac toxicity in patients treated with antiHER2 agents [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 P5-14-14.

Abstract Background: The combination of cyclin dependent 4/6 kinase inhibitors (CDK4/6i) with endocrine therapy (ET) has resulted in clinically significant improvements in progression-free survival (PFS) and overall survival (OS) in hormone-receptor (HR)-positive metastatic breast cancer (MBC). However, most patients’ disease ultimately progresses on CDK4/6i and ET. Therefore, further research is necessary to understand the mechanisms driving primary and secondary resistance. PROMISE is a multicenter prospective cohort study enrolling women with HR-positive MBC commencing treatment with palbociclib + letrozole (1st line) or palbociclib + fulvestrant (2nd Line). The study provides a comprehensive “omic” assessment of blood, tumor, urine and the fecal microbiome to identify molecular or cellular features associated with primary endocrine resistance (e.g. disease progression ≤ 12 months on treatment) and acquired resistance to CDK 4/6i. Additionally, patient derived xenografts and organoids are created to test new drug strategies designed to overcome resistance to CDK 4/6i and ET. Here, we present initial sequencing results from pretreatment biospecimens collected from PROMISE study participants. Methods: On-study tumor biopsies and blood samples were collected for DNA/RNA sequencing (TempusTM). The analyzed biospecimens were all obtained prior to initiation of palbociclib and ET. We correlated patient clinical characteristics (phenotypes) with molecular data and responses to protocol treatment. The data were analyzed using a series of cutting-edge bioinformatics pipelines for somatic and germline mutations in addition to copy number alterations (CNAs). The study database was locked for analysis on 06/20/2019. Results: We analyzed the somatic single nucleotide variants/INDELs (sSNV/INDEL) profiles across the tumor samples to determine the genes that were least likely to occur as a result of background mutation processes. Twenty-six patients had somatic copy number alterations (sCNA) and/or sSNV/INDEL in at least one of 18 genes with the most significant sSNV/INDEL profiles (p < 0.03) which included clinically and biologically relevant genes. The genes with the most statistically significant sSNV/INDEL mutation profiles were GATA3, PIK3CA, CDH1, and ESR1 (p < 0.0009). We observed a high percentage of tumors with somatic alterations in GATA3 (23% sSNV/INDEL, 15% sCNA), PIK3CA (38%, 12%), CDH1 (19%, 50%) and ESR1 (19%, 58%). ESR1 mutations were more frequent in patients receiving 2nd line treatment. Other frequently altered genes included TP53 (15%, 46%), MAP2K4 (8%, 50%), DNAAF1 (8%, 50%), and CDKN1B (8%, 35%). Further, ZNF317 and F3 were altered in 9 and 7 patients, respectively. Twenty-four samples had alterations in at least one of the CDK4/6 pathway genes (RB1, CCNE2, CCND1, CDK6, ESR1, CDKN2A, CCND3, CDK4, CDK2 and CCNE1). Four patients progressed on therapy; three of the four patients had mutations in PIK3CA, and one had a mutation in ESR1. Results of the RNA sequencing data (N=26) will be presented at the SABCS meeting. Conclusions: This is the first report of a prospective study designed to characterize the genomic landscape of ER+/HER2- MBC prior to palbociclib treatment. We observed high frequencies of known targetable alterations in PIK3CA and ESR1, including in patients that progress, which is consistent with previous reports. RNA sequencing data will be presented at the meeting. Citation Format: Ciara C O Sullivan, Krishna R Kalari, Vera J Suman, Peter T Vedell, Ann Moyer, Erin Carlson, Jason Sinnwell, Tejaswi Alaparthi, Xiaojia Tang, Kevin Thompson, Jaeyun Sung, Alvaro Moreno-Aspitia, Donald Northfelt, Minetta C Liu, Tufia C Haddad, Prema Peethambaram, Saranya Chumsri, Kathryn J Ruddy, Karthik V Giridhar, Roberto A Leon-Ferre, Paula Gill, Mohammad Ranginwala, Asad Javed, Sameer Batoo, Brendan P. McMenomy, Richard Weinshilboum, Liewei Wang, Matthew P Goetz. Comprehensive tumor sequencing to identify biomarkers of palbociclib response: First report of the PROMISE study [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 P2-11-07.

11553 Background: Little is known about the toxicity of trastuzumab (T) or of trastuzumab + lapatinib (T + L), approved in the advanced setting, in older pts. We have performed a sub-analysis of the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALTTO) trial focused on treatment completion and toxicity of T and T+L in older pts (aged ≥65 years (yr)). Methods: The ALTTO trial (NCT00490139, NCCTG N063D) randomised 8381 pts with early HER2+ BC into 4 arms and we included the T and T+L arms in our analysis. Eligible pts for our study were those having received at least one dose of assigned treatment. Treatment completion was evaluated through the rate of temporary treatment interruptions (TTI), permanent treatment discontinuations (PTD) and lapatinib dose reductions (LDR). Toxicity was evaluated via a selected set of adverse events of interest (AEIs). Risk factors for TTI, PTD, LDR and AEIs were assessed, including comorbidities and polypharmacy at baseline (defined as use 5 or more co-medications) and AEIs during treatment. Results: A total of 430 pts≥65-year-old were identified for this sub-analysis, out of a total of 4190 pts with a median age of 68 yrs (range 65-80). Older pts were more likely to have comorbidities (70% vs 38%). Treatment completion was worse among older pts in the T+L arm but not in the T arm (Table). AEIs were more common in the T+L arm in all patients, with older patients having higher AEI rates (78.04% in older vs 63.38% in younger), particularly diarrhea (60.75% vs 38.0%). Identified risk factors (multivariate) for worse treatment completion in the T and T+ L arms included concomitant use of chemotherapy and the occurrence of grade 3 adverse events, among others. Conclusions: T + L has worse treatment completion and is more toxic in older patients, while T was well tolerated. Identifiable risk factors at baseline and during the course of treatment could be used to aid in regimen selection and management for both T and T + L in their respective indications. Support: UG1CA189823, Novartis;https://acknowledgments.alliancefound.org. [Table: see text]

1037 Background: Folate receptor alpha (FRA the product of the FOLR1 gene) has been identified as a potential prognostic and therapeutic target in a number of cancers. A correlation has been shown between intense expression of FRA in breast tumors and poor prognosis, yet little is known about FOLR1/FRA expression across clinically relevant breast cancer subtypes. Methods: 131 breast cancer tumors including 4 benign, 33 ER+, 26 HER2+, and 68 triple negative (TN) were constructed into tissue microarrays (TMAs). FRA expression was analyzed by immunohistochemistry (IHC) using a high affinity FRA antibody. Tumor membrane staining intensity was scored by a pathologist as negative (0), weak (1+), moderate (2+) and strong (3+). The percent of cells within each tissue core stained at each intensity was recorded to calculate an H-score. The H-score is a weighted score that captured both the proportion of positive staining and intensity for each tumor. H-score values can range from zero (no membrane staining) to a maximum of 300 (100% membrane staining at 3+). H-scores for each patient sample were averaged over 3 TMA cores. The mean H-scores for each tumor subtype and the percentage of 3+ staining in >30% of tumor cells were compared by a Mann-Whitney test. The distribution of FOLR1 mRNA was completed using a TCGA RNA-seq dataset from 691 breast tumors classified as ER+, HER2+ and TN. FOLR1 levels of TN versus ER+ and HER2+ were compared by a Mann-Whitney test. Results: The mean H-score for the benign tumors was 0, ER+ (13.31), HER2+ (39.36), TN (119.02). The median H-score for the benign tumors was 0, ER+ (0), HER2+ (7.5), TN (127.5). The TN tumors mean and median H scores were significantly higher than benign, ER+ or HER2+ (p<0.001). The largest percentage of 3+ staining in >30% of tumor cells was observed in TN tumors (36.7%) and lowest in ER+ tumors (0%) (p<0.001). TN tumors had significantly higher levels of FOLR1 mRNA compared to ER+ and HER2+ subtypes (p<0.0001). Conclusions: Our data indicate that expression of FRA is highly prevalent in TN tumors and is supported by FOLR1 mRNA levels. Anti-FRA therapy may represent an important therapeutic intervention in TNBC who to this point have no active targeted treatment options.

e13501 Background: Loss of estrogen receptor alpha gene expression has been associated with insensitivity to endocrine therapy in human breast cancer patients. Histone deacetylase (HDAC) inhibitors have recently been found to restore sensitivity to the estrogen receptor by modulation of the estrogen and progesterone receptors. This had been shown with both aromatase and tamoxifen refractory and in triple negative cell lines . We performed a Phase I study of the combination of LBH589 (panobinostat) and letrozole to evaluate safety and tolerability in patients with metastatic breast cancer prior to the performance of a phase II trial. Methods: We enrolled postmenopausal women with metastatic breast cancer, ECOG PS 0 or 1, ANC>1500/mm3, platelets>100,000/mm3, normal total bilirubin, and ALT/AST adequate laboratory tests were eligible. Letrozole dose was 2.5 mg/day orally. Dose of LBH589: Level 1, 20 mg orally three times weekly; Level 2, 30 mg orally three times a week. Results: 12 patients (dose level 1:6 patients, dose level 2: 6 patients) have been enrolled. 43 cycles of treatment have been given to these12 patients. Initial cohort of 3 patients at the 20 mg dose level had no dose limiting toxicity (DLT). At the 30 mg dose level 3/6 patients had DLT (thrombocytopenia grade 1: 2 pts; grade 3:1 pt; grade 4: 1 pt; and diarrhea grade 3: 1 pt. One pt at the 30 mg dose level has a confirmed partial response and remains on study after 6 cycles of treatment. Subsequent cohort of 3 patients had 1 dose DLT with doubling of the creatinine. The main DLT was thrombocytopenia in 3/6 pts at the 30 mg dose level. Conclusions: The recommended dose for phase II testing of LBH589 is 20 mg orally 3 times per week in combination with standard dose letrozole.