Citations

Abstract Background: Evidence from randomized trials, including a recent meta-analysis, suggests that adjuvant bisphosphonates can decrease recurrence and death in postmenopausal women with early-stage breast cancer. Bisphosphonates (BP) have been included as adjuvant therapy for postmenopausal breast cancer patients in multiple guidelines. SWOG S0307 compared efficacy of 3 BPs in early stage breast cancer, with no evidence of differences in efficacy on breast cancer outcomes by type of bisphosphonate, either in the overall analysis or subgroups. BPs are generally well tolerated, with a relatively low risk of serious adverse effects. Treatment for hormone sensitive breast cancer frequently includes treatment with an aromatase inhibitor (AI) or ovarian function suppression (OFS), both of which can accelerate bone loss, decrease bone density, and increase fractures. In addition to decreasing breast cancer events, BPs have been shown to decrease fractures in breast cancer patients receiving AIs or OFS. However, concerns have been raised about the risk of atypical femur fractures (AFF), a rare subtype of fragility fractures, which appear to increase with longer BP use (3-100/100,000 person-years) (Shane 2013). This substudy evaluated all fractures occurring in patients enrolled on S0307. Methods: Patients with stage I-III breast cancer who were receiving adjuvant systemic therapy were randomized to receive 3 years of intravenous zoledronic acid (ZA) 4 mg IV given every 4 weeks for the first six months, and then every 3 months for the following 2.5 years, oral clodronate (CLOD) 1,600 mg/day orally, or oral ibandronate (IBAN) 50 mg/day orally. The primary endpoint was disease-free survival (DFS). On-treatment data collection forms specifically queried whether a fracture had occurred during the reporting period, the site of the fracture, and whether or not it was associated with trauma. Results: A total of 6,097 patients were randomized to S0307, with a median age of 53 years. Rates for overall fractures at 7.7 years were higher for CLOD (9.3%) compared to IBAN (7.4%) and ZA (7.1%) (p=0.02), with differences being mostly in the spine. Traumatic fracture differences were not significant (CLOD 2.0%, ZA 1.9%, IBAN 1.7%; p=0.83). Fragility fracture rates were 5.2% with ZA, 7.2% with CLOD, and 5.6% with IBAN. Ankle fractures were the most common fracture site at 2.8% overall. Leg fractures, including femur fractures, were relatively low with a rate of 1.5% overall and not different between agents. AFF were not specifically queried/determined. Conclusion: In S0307, BPs were used in higher doses than is recommended for treatment of postmenopausal osteoporosis. There is limited data comparing the long-term effects across BP drugs used at these higher doses on the skeleton. In S0307, an overall fracture rate of 8% was seen in early stage breast cancer patients despite receiving BPs along with conventional systemic therapy. Fracture rates were slightly higher for CLOD than ZA and IBAN for fragility and overall fractures, but similar for traumatic fractures. This may reflect the potency of CLOD or the dosing schedule. Rates of femur fractures were relatively low in all arms without evidence of excess femur fractures. Funding: NIH/NCI CA180888, CA180819, CA180820, CA180821, CA180868, CA180863, CA196175; BCRF, Komen, Berlex (Bayer), Roche/Genentech, Novartis. Citation Format: Rachel L (MD) Yung, Jieling Miao, Alexander HG Paterson, Mark Clemons, Elizabeth C Dees, James N Ingle, Carla I Falkson, William Barlow, Gabriel N Hortobagyi, Julie R Gralow. Fractures in women with breast cancer receiving high-dose bisphosphonates to prevent breast cancer metastases as part of the SWOG S0307 trial (ClinicalTrials.gov Identifier: NCT00127205) [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 P2-18-02.

e13516 Background: Breast cancer affects thousands of women each year. Epithelial to Mesenchymal transition (EMT) has been associated with increased metastatic potential of cancer cells as well as resistance to chemotherapy. Predicatively, presence of EMT leads to worse prognosis. We have recently showed that Aurora-A plays a key role in development of EMT and increased ability of breast cancer cells for self renewal. Therefore we hypothesized that inhibition of Aurora-A will lead to increased sensitivity to chemotherapy. Methods: The hypothesis was tested in vitro. Cellular proliferation was tested using MTT assay and protein levels were determined on Western blots. Results: In ER+ cell line, MCF7, constitutive activation of Raf-1/MAPK signaling pathway leads to aberrant activation of Aurora-A kinase activity. These cells have decreased sensitivity to treatment with paclitaxel when compared to parental MCF7 cells. This effect is even more pronounced with over-expression of Aurora-A. The sensitivity to paclitaxel was restored with inhibition of Aurora-A by novel inhibitor, Alisertib. This was further explored in triple negative cells (MDA-MB-231) and cells expressing Her-2/neu (BT474) which express higher levels of Aurora-A. Combination of Alisertib and paclitaxel was superior when compared to either therapy alone. Similar effect was seen with use of anthracyclines. Inhibition of Aurora-A resulted in decreased SMAD5 expression as well as decreased Akt phosphorylation. Current studies are investigating a role of Aurora-A in developing chemoresistance through activating SMAD5. In vivo experiments evaluating combination therapies in breast cancer animal model are ongoing. Conclusions: Inhibition of Aurora-A by Alisertib resulted in decreased SMAD5 nuclear phosphorylation and increased effectiveness of chemotherapeutic agents in breast cancer cells. These results contribute to better understanding of signaling pathways involved in resistance of breast cancer cells to chemotherapy. This knowledge could be extremely useful in developing more effective treatments for breast cancer patients both in neo-adjuvant, adjuvant and metastatic settings.

2538 Background: Trebananib is a first-in-class peptibody (peptide-Fc fusion protein) that selectively inhibits Angiopoietin 1 and Angiopoietin 2 to inhibit interaction with the Tie2 receptor tyrosine kinase and prevent angiogenesis by a VEGF independent mechanism. A pediatric phase 1 trial was performed to define the dose limiting toxicities (DLT), maximum tolerated dose (MTD) and pharmacokinetics (PK) of trebananib. Methods: Trebananib was administered as a weekly 30 - 60 minute IV infusion. Three dose levels (10, 15 or 30 mg/kg/dose) were evaluated using a rolling-six design. PK sampling and analysis of peripheral blood biomarkers was performed during the first 4 weeks of therapy. Results: Fifteen eligible patients (14 evaluable for toxicity) with a median age of 14 yrs (range, 3 to 20) and diagnoses of neuroblastoma (n=4), rhabdomyosarcoma (n=3), Ewing sarcoma (n=3), osteosarcoma (n=2), other soft tissue sarcoma (n=2), or nasopharyngeal carcinoma (n=1) have been enrolled. There were no DLTs observed at either the 10 mg/kg (n=6 pts) or 15 mg/kg (n=3 pts) dose. 1/6 pts receiving 30 mg/kg/dose developed DLT (venous thrombosis at a central line site). Non-dose limiting grade 3 or 4 toxicities included lymphopenia (n=2) hypertension (n=1), and neutropenia (n=1). Response in evaluable patients after eight weeks of therapy included stable disease (n=6 pts) and progressive disease (n=7 pts). PK were linear over the 3 dose levels, with t1/2 and Clpvalues of 69±18 h and 1.6±0.5 ml/h/kg, respectively. Conclusions: Trebananib is well tolerated in pediatric patients with recurrent or refractory solid tumors with recommended Phase 2 dose of 30 mg/kg. Correlative biology studies will be presented. Further study is planned to evaluate tolerability and changes in vascular permeability in patients with primary CNS tumors. Clinical trial information: NCT01538095.

1032 Background: Obesity is a predictor of poor outcomes in women with early-stage breast cancer (BC). Some reports suggest that obesity is associated with aggressive tumor histology. We examined the relationship between BMI at diagnosis and PAM50 subtype, and explored the interaction between BMI and subtype on prognosis in early BC. Methods: CALGB 9741 evaluated dose-density and sequence in node-positive BC. All patients received doxorubicin, cyclophosphamide and paclitaxel dosed by actual body weight without cap or dose adjustment. The primary endpoint was RFS. Height and weight at diagnosis were abstracted from patient records; the PAM50 assay was performed using the Nanostring platform. Association between PAM50 and BMI was assessed by a chi-squared test. The prognostic value of BMI conditional on PAM50 was tested as a continuous variable using Cox models for RFS adjusted for number of involved nodes, tumor size, menopausal status, drug sequence, and dose density. Results: Baseline height and weight were available for 1909 of 2005 enrolled patients; 1272 also had subtype determination by PAM50. Distribution of subtypes differed significantly by BMI (p=0.03), with all weight groups having similar proportions of Basal and HER-2 Enriched subtypes and with obese patients having lower rates of Luminal A (30 vs 35%) and higher rates of Luminal B (39 vs 26%) tumors as compared to normal-weight individuals. In multivariate analyses, BMI and subtype were independent predictors of RFS (p=0.011 and p<0.001, respectively). Exploratory analyses did not show a significant interaction between subtype and the relationship between increased BMI and RFS (p=0.15), although largest differences were seen among Luminal cancers (Table). Conclusions: Biologic subtypes were distributed differently in obese and non-obese individuals. The association between BMI and RFS did not differ significantly by subtype in this study. More work is needed to further explore the interaction of BMI and subtype, especially in a larger cohort of Luminal tumors. [Table: see text]

10586 Background: Teschendorff et al. (Breast Cancer Res 2008) reported a 7-gene, immune response-enriched gene expression classifier using microarrays that was prognostic in women with ER-negative breast cancer. To facilitate further evaluation of the prognostic value of a classifier in archival fixed tumor tissue, we developed two multiplex TaqMan assays to quantify the expression levels of these genes, then trained and validated a 7-gene immune response score (IRS). Methods: RNA was extracted from FFPE sections of 185 ER-negative breast cancer patient samples from Mayo Clinic (n=81), Guy’s Hospital (n=50) and California Pacific Medical Center (CPMC) (n=27). Patients (N+ and N-) did not receive adjuvant therapy and were followed for a minimum of 5 years. Amplification of i) LY9, TNFRSF17, HLA-F, and IGLC2 and ii) XCL2, SPP1, C1QA and two reference genes NUP214 and PPIG were carried out in two multiplex RT-PCR TaqMan reactions and relative expression levels were determined using the DDCT method. The training set, comprised of the Mayo Clinic samples, was used to develop an IRS by using a summation of expression levels of the 7 genes. Association of the IRS with distant metastasis was assessed using a Cox proportional hazards model. The score was subsequently tested in a validation set (Guy’s + CPMC). Results: The amplification efficiency of each gene within the multiplex reactions was comparable to singleplex reactions. Duplicate amplifications showed excellent assay reproducibility and sensitivity (R2=0.98). The hazard ratio for a single standard deviation decrease in the IRS was 1.45 (95% CI 0.99-2.12, p=0.056) in the training set and 2.18 (1.32-3.61, p=0.002) in the validation set. ROC curves of continuous IRS to predict distant metastasis within 5 years had AUC of 0.74, 95% CI = 0.60-0.88. Conclusions: Robust multiplex TaqMan assays for FFPE tissue extracted RNA were developed for a 7-gene IRS. Increases in risk are associated with decreases in the IRS. Immune related gene expression clearly plays an important role in the spectrum of risk of ER-negative tumors. Additional signatures are in development that further support this conclusion.

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.

1006 Background: Patients (pts) with ER-/PR- MBC do not benefit from endocrine treatment (tx). Doane et al (Oncogene 2006;25:3994) described a subset of ER-/PR- BC with a gene expression profile similar to ER+ BC but characterized by AR expression and AR-dependent growth in vitro. Hence, we conducted a multicenter phase II trial (NCT00468715) of the AR antagonist, bicalutamide (B) for pts with AR+ ER-/PR- MBC. Methods: Pts with ER-/PR- (IHC <10%) MBC were consented to AR testing, confirmed centrally at MSKCC. If AR+ (DAKO IHC ≥10%), pts were eligible for tx if ECOG performance status (PS) <2 and normal organ function. No limit on prior tx except prior trastuzumab required if HER2+. Eligible AR+ pts who consented to tx received B 150mg orally daily in 28-day cycles (C). Toxicity assessed q4wks, response q12wks. Primary endpoint = clinical benefit rate (CBR): CR + PR + stable disease (ds) >6mo (SD). B would be considered worthy of further study if ≥4/28 pts have clinical benefit. Results: As of 12/21/11,436 pts consented for AR testing. 24 were ineligible, 12 await testing. 47/400 tested were AR+ (12%). 26 received tx with B (6 ineligible for tx, 15 are eligible for tx with B at progression (POD) if clinically appropriate and study slots remains). Two AR+ pts treated with B were ER+ and removed from study. Three have received tx <12wks. Treated pt characteristics (n=24): median(med)age 64 (41-83), PS 0 (0-1), HER2+ 1, visceral metastases 17. Prior chemotherapy: neo/adjuvant 16; med # regimens for MBC 1 (0-8). Med C# 3 (2-49+). Best response: (21 evaluable pts): CBR 19% (95% CI 5-42%), SD>6mo 4, CR/PR 0, SD<6mo 3, POD 14. Conclusions: ~12% of ER-/PR- MBC pts are AR+. For these pts, AR-inhibition with B is feasible, well tolerated, and has activity based on pre-specified criteria. This study has closed to accrual for AR testing as of 1/2012. These results of the primary endpoint are not expected to change by accrual of the 2 remaining pts. Supported by TBCRC/Breast Cancer Alliance/AstraZeneca. [Table: see text]

1005 Background: We previously reported that in the E5194 clinical trial patients with ductal carcinoma in situ (DCIS) treated with wide local excision (WLE) without radiation (RT), the DCIS Score was significantly associated with 10 year risk of an ipsilateral breast event (IBE - recurrence of in situ or invasive carcinoma), whether evaluated as a continuous or categorical variable (P=0.02 for both). Here we evaluate correlation between DCIS Score and clinicopathologic (CP) features and if DCIS Score provides independent recurrence risk information. Methods: The study population included 327 women with DCIS prospectively selected for treatment with WLE without RT, including low-intermediate grade tumors ≤2.5 cm or high-grade ≤1 cm. CP variables included age, menopausal status, tamoxifen treatment (used in 29%) and expert centrally determined tumor size, grade, comedo necrosis, tumor type, and margin status. The association between DCIS Score and CP variables was examined by spearman rank correlation, and proportional hazards regression models were used to determine variables significantly associated with IBE. Results: Lesion size (p=0.009) and menopausal status (p=0.03) were significantly associated with IBE, while grade (p=0.69) and comedo necrosis (p=0.47) were not. DCIS Score was significantly associated with IBE after adjustment for CP features and tamoxifen use (p=0.02). DCIS Score was moderately correlated with grade (rs=0.46; 95% CI 0.37,0.54), percentage comedo necrosis (rs=0.49; CI 0.41,0.57), and lesion size (rs=0.18; CI 0.08,0.29) but not other features. Exploratory analyses in all CP subgroups, including the multicomponent Van Nuys Prognostic Index, showed a wide range of DCIS Scores in each subgroup. Concordance of the grades among readers was low: local vs parent central, 68%; local vs central nuclear grade, 45%; parent central vs central nuclear grade, 37%. Conclusions: DCIS Score is moderately correlated with grade, comedo necrosis, and tumor size. DCIS Score provides recurrence risk information independent of these features and identifies subjects with DCIS who are at high risk for local invasive and in-situ local recurrence after WLE alone.

564 Background: Our group previously examined if baseline patient/tumor characteristics, or prior treatment affected cause of death in MA.17, a placebo controlled extended adjuvant trial of the aromatase inhibitor (AI) letrozole. We now examine factor effects on all cause mortality in MA.27. Methods: MA.27 was an adjuvant phase III superiority trial of 5 yrs of exemestane vs anastrozole, in ER+ postmenopausal breast cancer accrued between 2003 and 2008; event free survival was similar. We examined by intention-to-treat, the multivariate time-to-breast cancer-specific (BrCa), cardiovascular (Cardio), and other causes (OT) of death with log-normal survival analysis adjusted by treatment and stratification factors (lymph node status, adjuvant chemotherapy, celecoxib, aspirin, and trastuzumab). We tested whether factors were associated with 1) all cause mortality, and if so, 2) cause-specific mortality. We also fit step-wise forward cause-specific adjusted models. Results: 7,576 women (median age 64.1 years; 5417 (71.5%) <70 yrs and 2159 (28.5%) >70 yrs) were enrolled and followed for a median of 4.1 yrs. The 432 deaths comprised: 187 (43.3%) BrCa, 66 (15.3%) Cardiovascular, and 179 (41.4%) OT MA.27 therapy was not associated with mortality (p=0.84). Five baseline factors were differentially associated with cause of death. Older age was associated with greater BrCa (p=0.03), Cardio (p<0.001), and OT (p<0.001) mortality. Pre-existing cardiovascular history led to worse Cardio mortality (p<0.001). Worse ECOG performance status led to worse OT death (p<0.001). T1 tumors were associated with less BrCa mortality (p<0.001). PgR+ tumors were also associated with less BrCa mortality (p<0.001). There were fewer BrCa deaths with Node –ve disease (p<0.001), ER+ tumors (p=0.001) and without adjuvant chemotherapy (p=0.005); there was worse Cardio mortality (p=0.01) with receipt of trastuzumab; worse OT (p=0.03) for non-whites, and without adjuvant radiotherapy (p=0.003). Conclusions: 56.7% of deaths in MA.27 patients were non-breast cancer related. We showed baseline patient and tumor characteristics, and prior treatment differentially affected cause of death. Clinical trial information: NCT00066573.

9581 Background: AKT, a serine threonine protein kinase, is activated downstream of phosphatidylinositol 3-kinase (PI3K) which transmits signals from cytokines, growth factors and oncoproteins to multiple targets. Activated AKT regulates survival, proliferation, and growth. The PI3K/AKT pathway is downstream of most of the common growth factor tyrosine kinase receptors in cancer, e.g., EGFR, HER2, IGFR, etc., and is a driver of tumor progression in many cancers. AKT protein kinase is activated in many pediatric solid tumors, including glioblastoma, malignant rhabdoid tumors, neuroblastoma, synovial sarcoma, rhabdomyosarcoma and medulloblastoma. MK2206, an oral allosteric AKT1, 2,3 inhibitor, has demonstrated antitumor activity in in vitro and in vivo cancer models.A phase I trial evaluating MK2206 was conducted in children with refractory solid tumors. Methods: Using a rolling-6 design, MK2206 was administered either once every 7 days (schedule 1), or once every other day (schedule 2) in a 28-day cycle. Serial PK studies were obtained on day 1, cycle 1 and trough samples were obtained on days 7, 14, 21 and 28. Biological studies included analysis of PI3K/PTEN/AKT-cell signaling pathway in pre and post-therapy in PBMC and in tumors at diagnosis or recurrence. Results: Forty-five patients [23 males, median age 13.6 years (range 3.1-21.9)] with malignant glioma (14), ependymoma (4), hepatocellular carcinoma (3), gliomatosis cereberi (2) or other tumors (22) were enrolled; 34 were fully evaluable for toxicity (schedule 1 n=17; schedule 2 n=17). Schedule 1 DLTs included: grade 3 dehydration in 1/6 patients at 28 mg/m2; grade 4 hyperglycemia and neutropenia in 1/6 patients at 45 mg/m2. There were no DLTs at 35 mg/m2 and dose level 4 (58 mg/m2) is currently open for patient accrual with one enrollment. Schedule 2 DLTs included: grade 3 alkaline phosphatase in 1/6 patients at 90 mg/m2; grade 3 rash in 1/6 patients at 120 mg/m2), and grade 3 rash in 2/6 patients at 155 mg/m2. Conclusions: The recommended pediatric phase II dose of weekly MK2206 is 120 mg/m2 and the last cohort of patients to the every other day dosing schedule of MMK206 is enrolling. PK and PD data are currently being analyzed and will be presented.