K Tkaczuk

P1-12-20: The Safety and Tolerability of Vorinostat in Combination with Lapatinib in Advanced Solid Tumors.

Background: Lapatinib has been previously shown to markedly decrease cancer stem cells (CSC) in HER2−positive breast cancer. In preclinical models, we have demonstrated that histone deacetylase inhibitors (HDACi) such as vorinostat can induce differentiation and decrease CSC. The combination of vorinostat and lapatinib is synergistic with a combination index of 0.32 (synergism if CI Method: Patients were eligible if they were: age ≥ 18 years with incurable solid tumors, ECOG PS 0–2, adequate organ function, and no prior exposure to HDACi. The first 3 patients received lapatinib at the dose of 1,250 mg continuous daily and vorinostat 300 mg 4 days on 3 days off. The second dose level with lapatinib 1,250 mg continuous daily and vorinostat 400 mg 4 days on 3 days off were administered in 6 patients. Cycles were repeated every 21 days until disease progression. Echocardiogram and radiologic evaluation were performed every 12 weeks. During the first cycle, pharmacokinetic (PK) evaluation was performed on days 18 and 21. Results: Nine consented patients (7 with metastatic breast cancer, 1 with non-small cell lung cancer, and 1 with thyroid cancer) have been enrolled with the median age of 52 (range 25–66). Patients received an average of 6 prior treatments (range 2–10). No dose limiting toxicity or drug related death have been observed. Grade 1–2 toxicities including diarrhea, fatigue, muscle cramps and stomatitis were observed. No grade 3 or 4 hepatic, renal or cardiac toxicity were observed (including no QTc prolongation and no significant reduction in the left ventricular ejection fraction). Patients have received the maximum of 7 cycles (median 3 cycles, range 2–7). Response: as of June 2011, 2 patients are still on treatment. Two patients achieved stable disease (triple negative metastatic breast cancer and HER2−positive breast cancer), 6 patients with progressive disease, and 1 patient is too early to evaluate for response. PK analysis will be presented at the time of the meeting. Conclusions: The combination of vorinostat and lapatinib is tolerable and has some antitumor activity in heavily pretreated advanced solid tumors. A phase II study in HER2−positive metastatic breast cancer is underway with lapatinib 1,250 mg continuous daily and vorinostat 400 mg 4 days on 3 days off. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-12-20.

Elevated serum levels of the growth factor GP88 are found in breast cancer patients when compared to healthy individuals.

CTRC-AACR San Antonio Breast Cancer Symposium: 2008 Abstracts Abstract #2006 Background: GP88 is an autocrine growth factor that plays a critical role in breast tumorigenesis. GP88 is expressed in human BC tumors in a positive correlation with their tumorigenicity. Increased GP88 expression is associated with resistance to anti-estrogen therapy in ER + cells and with herceptin resistance in Her-2 overexpressing breast tumors. Inhibition of GP88 expression in human breast adenocarcinoma inhibited tumor incidence and growth in nude mice. Immunohistochemical studies have shown that GP88 was expressed in invasive ductal carcinomas in correlation with the expression of poor prognosis markers whereas normal tissues and benign lesions were negative. High GP88 expression in tumor biopsies was accompanied by decreased disease-free survival. Since GP88 can be secreted, we have hypothesized that GP88 could be secreted in the circulation and found in serum. We examined whether GP88 could be found in the circulation and whether GP88 could be elevated in the sera of breast cancer patients when compared to healthy individuals. Methods: An IRB approved blood sampling study was conducted at the University of Maryland Breast Clinic to determine the serum level of GP88 in healthy volunteers (HV) and breast cancer patients (BC pts). Serum GP88 concentration was determined in triplicate by quantitative enzyme immunoassay. 189 BC pts were accrued. In addition, sera from 18 HV were obtained to establish a GP88 baseline in healthy volunteers. BC patient characteristics: Race: Caucasian- 91, African American-92, Asian-6; median age, 51 (range 29-86), stage I – 48, II - 52, III – 26, IV - 63. Results: Circulating GP88 was measurable in the serum. Median level of GP88 was 28.7 ng/ml (range 16.6-38.2) in HV; 40.7 ng/ml (range 6.4-100) in early stage (stage 1 –3) BC pts (p- value = 0.007) and 45.3 ng/ml (range 9.8 to 158.4) in stage 4 metastatic BC patients (p-value= 0.0007). Statistically significant increase in circulating GP88 level was found in early stages as well as in metastatic disease. Correlation studies with BC prognostic factors such as stage, tumor size, lymph node involvement, tumor grade and presence of ER and HER-2 will be presented. Conclusion: GP88 can be detected in the sera of HV and BC pts. Comparison between the two groups of subjects indicates that GP88 level is significantly higher in the sera of BC pts. These studies are important as they identify as a measurable circulating biomarker GP88 that is also a therapeutic target of malignant transformation or malignant progression of breast carcinoma (BC). Future studies will examine whether there is any correlation between the serum level of GP88 and therapeutic response to systemic therapy in breast cancer patients. This study was supported by grant from MIPS, the Avon Foundation and 1R43 CA 124179-01A1 from the National Institutes of Health. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2006.

Abstract OT3-01-07: Phase II study of trastuzumab and pertuzumab alone and in combination with hormonal therapy or chemotherapy with eribulin in women aged ≥60 with HER2/neu overexpressed locally advanced and/or metastatic breast cancer

Her2 overexpression is both a predictive and prognostic marker with tumors overexpressing Her2 having an aggressive natural history, but also responding to targeted therapy. The standard of care for Her2 positive metastatic cancer is docetaxel paired with combined antibody therapy of pertuzumab (P) and trastuzumab (T). Older patients are known to have more difficulty tolerating traditional cytotoxic chemotherapy. Neoadjuvant studies have shown a proportion of patients have pathologic complete responses (pCR) with dual Her2 targeted therapy without chemotherapy. The NEOSPHERE trial demonstrated at 17% pCR after 3 cycles of T+P. The Translational Breast Cancer Research Consortium has shown 12-28% pCR with the combination of estrogen deprivation, trastuzumab, and lapatinib (TBCRC 006 and 023). We have designed a phase II study of T+P alone and then in combination with hormonal or chemotherapy after progression in women age ≥ 60 with Her2 overexpressed locally advanced or metastatic breast cancer (BC). As a primary endpoint, this study seeks to evaluate the overall response rate (ORR) of dual Her2 targeted therapy with T+P without chemotherapy in older patients with locally advanced or metastatic Her2 positive BC (cohort 1). At progression,depending on tumor characteristics and disease status, chemotherapy with eribulin or hormone therapy with anastrozole plus fulvestrant will be added (cohort 2 – A and B). ORR for cohorts 1, 2A and 2B will be determined. Secondary end points will evaluate clinical benefit, progression free survival, overall survival, tolerability, safety, and quality of life. Translational studies involving circulating tumor cells identified through OncoCEE – Biocept system and glycoprotein 88 expression will be performed. Eligibility includes patients9 age ≥60 with locally advanced or metastatic Her2 positive BC treated with 0-3 lines of chemotherapy. Patients must have an ejection fraction >50% and meet set hematologic and metabolic lab criteria. Her2 status is per ASCO/ACP guidelines. Excluded patients include patients with active brain metastasis, second malignancies, anticancer treatment Citation Format: Rosenblatt PY, Kesmodel SD, Bellavance E, Nichols EM, Feigenberg SJ, Tait N, Lewis J, Sivisailam SS, Couzi R, Goloubeva O, Tkaczuk KHR. Phase II study of trastuzumab and pertuzumab alone and in combination with hormonal therapy or chemotherapy with eribulin in women aged ≥60 with HER2/neu overexpressed locally advanced and/or metastatic breast cancer. [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 OT3-01-07.

Abstract P6-17-04: A phase II, open-label, multi-center study of ANG1005, a novel brain-penetrant taxane derivative, in breast cancer patients with recurrent CNS metastases

Background: Treatment options for brain metastases are limited to local therapies due to the inability of most anti-cancer agents to cross the blood brain barrier (BBB). ANG1005 is a novel taxane derivative, being developed for targeted treatment of brain metastases. It consists of 3 paclitaxel molecules covalently linked to Angiopep-2 designed to cross the BBB and to penetrate malignant cells, regardless of location, via the low density lipoprotein (LDL) receptor related protein-1 (LRP-1) transport system. Methods: Adult patients with measurable recurrent brain metastases from breast cancer with, or without, leptomeningeal disease are currently being enrolled in this multi-center, open-label study (planned n=56). ANG1005 is administered IV at 600 mg/m 2 every three weeks (one cycle) until disease progression, unacceptable toxicity or consent withdrawal. HER2+ patients are allowed to continue HER2 targeted therapies. The primary endpoint is intracranial objective response rate, as assessed by MRI using CNS RECIST 1.1. Secondary endpoints include duration of intracranial response, median progression-free survival, 3/6/12-month progression-free survival rate, overall survival at 6 months, extracranial objective response rate, safety and tolerability. Extracranial response is also assessed by CT using RECIST 1.1. An imaging sub-study, evaluating the use of 18F-FLT-PET in comparison to MRI, is also ongoing in 10 patients with measurable brain metastases from breast cancer, receiving ANG1005 IV at 550 mg/m 2 . Results: Accrual is ongoing and to date, 48 patients have been treated with a range of 1-18 cycles of ANG1005. Median age is 47 years (range: 26-65). Safety profile is similar to that of paclitaxel with myelosuppression as the predominating toxicity. Based on data from patients evaluated to date for intracranial response, 6/30 (20%) patients had a partial response (PR) and 17/30 (57%) had a stable disease (SD), as best response. A sub-analysis, based on breast cancer sub-type is presented below: The longest duration on treatment is for 18 cycles, seen in a patient with an intracranial PR that sustained for 10 cycles; the treatment is still ongoing. Extracranial tumor evaluations were completed in 14 patients, all showing disease control including in those previously treated with paclitaxel. One (7%) patient had a PR and 13 (93%) patients had an SD. Conclusions: CNS activity was observed in all subsets of breast cancer, suggesting that ANG1005 is a promising therapy for treatment of brain and leptomeningeal metastases from breast cancer. ANG1005 treatment also resulted in disease control in extracranial lesions, including patients previously treated with paclitaxel. The dose and treatment regimen were well tolerated with a safety profile similar to paclitaxel. Updated efficacy and safety data will be presented at the meeting. Citation Format: Tang S-C, Bates S, Kesari S, Brenner AJ, Anders CK, Garcia A, Ibrahim NK, Tkaczuk KHR, Kumthekar P. A phase II, open-label, multi-center study of ANG1005, a novel brain-penetrant taxane derivative, in breast cancer patients with recurrent CNS metastases. [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 P6-17-04.

Abstract OT3-03-03: A prospective study of glycoprotein 88 (GP-88) blood test in healthy women undergoing screening for breast cancer (BC) with mammography (MM)

Background: Population based BC screening with XRAY mammography (MM) has been widely accepted as standard of care for women aged 40+ with average risk of developing BC. Sensitivity and specificity of MM is dependent on breast tissue density and up to ∼20% of BC are undetected by MM. The development of a dependable, low cost blood-based BC screening test to increase the sensitivity and specificity of currently existing BC screening methods is needed. Rationale: GP88 is expressed & secreted by BC cells & is not expressed by normal mammary epithelial cells, 2 retrospective randomized multi-site trials (a training study & a validation study of 300 cases each) demonstrated that elevated GP88 expression in estrogen positive (ER+) invasive BC was statistically correlated with a 4-fold increase in the risk of 5-yr BC recurrence. GP88 was an independent predictor of BC recurrence in multivariate analysis of other factors such as PR expression, tumor size, grade, lymph node status & stage. The quantitative GP88 EIA was developed to determine the amount of GP88 in biological fluids. The blood based EIA assay is highly specific for GP88 & both sensitive & linear over a wide dynamic range, i.e. detection of GP88 concentrations from 0.1 to 20ng/ml. A baseline GP-88 level of28.4 ± 5 ng/ml was established by us for healthy volunteers (HV). In BC pts a statistically significant increase of serum GP88 was observed in early stage pts (40.7 ± 16 ng/ml; p=0.007). Stratification of BC pts according to their clinical outcomes shows that pts having no evidence of disease (NED) have serum GP88 levels within the range of HV. These data suggest that pts with breast tumors express & secrete high levels of GP88. Objectives: 1. To determine prospectively GP-88 blood levels in HV at average risk of developing BC screened by MM & in women with recently biopsy-confirmed BC. 2. To establish the statistical distribution of GP88 serum levels in subjects by baseline BIRAD classification (1-6). 3. To determine if the initial GP88 level is predictive of change in BIRADS classification from baseline to 12-mos follow-up. 4. To determine if baseline GP88 level is predictive of the appearance of BC at 12 mos follow-up in HV who were cancer-free at study entry. Inclusion Criteria: Female, aged >=40 yrs old, presenting for screening or diagnostic MM or diagnostic workup and/or biopsy due to abnormal MM Study procedures: Serum levels of GP88 in subjects with average BC risk factors will be measured prospectively at baseline; 3-6 mos & 6-12 mos & correlated with BIRADS reading of the screening MM, BIRADS 1-6; GP88 serum level will be correlated with pathologic results of breast biopsies performed on subjects with suspicious BIRADS (4 & 5) MM & final pathologically confirmed diagnosis of breast cancer as BIRADS 6. Study Progress: The study is ongoing; currently we have 308 subjects enrolled, the total number of subjects will be up to 725 & screened up to 1400. Study is UM IRB approved & is conducted at the University od Maryland Medical Center (UMMC) and UM Baltimore Washington Medical Center (BWMC). Funding is provided by Maryland Industry Partnership Grant (MIPS)& Avon Grant No. 02-2013-018. Citation Format: Tkaczuk KHR, Campassi C, Kesmodel S, Bellavance E, Rosenblatt P, Nichols E, Feigenberg SJ, Coughlin P, Drogula C, Urban B, Galandak J, Dromi S, Kuo L, Yue B, Hicks D, Serrero G. A prospective study of glycoprotein 88 (GP-88) blood test in healthy women undergoing screening for breast cancer (BC) with mammography (MM). [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 OT3-03-03.

Abstract P5-09-05: Progranulin (GP88) expression and letrozole resistance in breast cancer

The 88 kDa glycoprotein GP88 (Progranulin, PCDGF, acrogranin) is the largest member of the granulin/epithelin family of growth modulators. GP88 was originally characterized in our laboratory through a biological screen to identify drivers of tumorigenesis. Published studies have established that GP88 represents an ideal therapeutic and diagnostic target in breast cancer (BC) leading to the development of validated tools to measure GP88 in tumor biopsies and biological fluids as well as blocking its action. It was shown that: 1) GP88 expression increases with tumorigenesis; 2) in ER+ breast cancer cells, GP88 stimulates proliferation and its overexpression confers estrogen independence and resistance to several anti-estrogens and aromatase inhibitor; 3) inhibition of GP88 expression by antisense transfection inhibited proliferation in vitro and in vivo; 4) In Her-2 overexpressing breast tumors, GP88 stimulated Her-2 phosphorylation and conferred trastuzumab resistance; 5) GP88 is expressed in 80% invasive ductal carcinoma (IDC) and 60% of ductal carcinoma whereas it is negative in lobular carcinoma, benign lesions and normal mammary tissues; 6) GP88 is secreted and can be detected in the serum of BC patients at an increased level when compared to healthy subjects; 7) Pathological studies with 530 cases of ER+ IDC with clinical outcomes showed that GP88 tumor expression was an independent prognostic indicator of recurrence in early stage BC patients. Training study followed by an independent validation study demonstrated that high GP88 tissue expression (GP88 3+) was associated with a 4-fold increase in risk of recurrence at 5 years. Since GP88 displays not only diagnostic but also therapeutic potentials, we developed a neutralizing anti-GP88 antibody AG1 that inhibited GP88 biological effect (proliferation and migration) in a dose-dependent fashion in vitro. AG1 was expressed in a high yield CHO cell line and formulated. We have shown that in tamoxifen resistant cells, treatment with AG1 would inhibit tumor growth and restore tamoxifen sensitivity. The present study examined the effect of AG1 in letrozole resistant cells. We have developed from a letrozole sensitive cell ER+ BC cell line, a letrozole-resistant cell line by long term selection in letrozole-supplemented medium. This cell line (LetR) shows also decreased letrozole responsiveness in vivo and therefore constitutes an excellent model for investigating letrozole resistance in vivo as well as in vivo. Here we investigated the effect of various doses of AG1 on LetR tumor development alone or in combination with letrozole. Treatment with AG1 (10 mg/kg i.p.) in combination with letrozole was efficient to maintain long term responsiveness to letrozole and inhibited tumor growth. In addition to the mouse xenografts study, an IRB approved clinical study examines changes in GP88 circulating levels in patients with resistance to aromatase inhibitors. Preliminary data will be presented. In conclusion, inhibiting GP88 could provide a novel and alternative therapeutic strategy for patients with resistance to anti-estrogen therapy, being tamoxifen or letrozole. This work is supported by 2R44CA124179 and HHSN 261201200060C from NCI and 02- 2013-018 from the Avon Foundation for Women. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-09-05.

Abstract P6-06-01: Improved outcomes with occult versus known primary breast cancer: A SEER analysis

Purpose: Controversy exists regarding the optimal management of the breast in the setting of lymph node presentation of an occult primary breast cancer (OPBC). Treatment includes radiation, a mastectomy or no treatment. Recent data confirms the need for a mastectomy or radiation for optimal outcomes with no clear difference between the two. In an effort to further elucidate this finding, we report outcomes of OPBC and known primary breast cancer (KPBC) who require local surgery using a large, population-based database. Materials and Methods: Using the Surveillance, Epidemiology and end Results (SEER) registry, data was obtained for all adult females diagnosed with T0-1 N1-3 M0 breast cancer who underwent definitive local therapy between 1990 and 2009. Patient characteristics that were analyzed included age at diagnosis, race, number of examined lymph nodes, number of positive lymph nodes, estrogen- and progesterone- receptor (ER, PR) positivity, and tumor grade. Propensity score modeling and Cox regression analysis were performed to compare overall survival (OS) and cause-specific survival (CSS) of patients with T0 and T1 breast cancer. Multivariate analysis (MVA) was used to determine independent predictors for OS and CSS. Given the large dataset, the propensity score model analyzed a randomly selected sample of 8000 subjects from the KPBC group, which was matched to the OPBC group. Results: 87,566 patients were identified of which 384 had OPBC and 87,182 had KPBC. The majority of patients were white (73.3%) with a median age of 58 and 56 years in the OPBC and KPBC groups, respectively. At baseline, the OPBC population had a greater median number of lymph nodes examined (18 vs. 16; p<.0001) and involved (4 vs. 2; p<.0001) lymph nodes, less ER+ (46.9% vs. 68.4%; p<.0001) and PR+ (33.3% vs. 57.7%; p<.0001) compared to the KPBC group. Regarding grade, the OPBC group had fewer moderately to well differentiated tumors compared to the KPBC group (7.8% vs. 47.5%; p<.0001). With a median follow-up of 74 months T0 OPBC had superior 5-/10-year OS (84%/68% vs. 81%/63%, p = 0.07) and 5-/10-year CSS (88%/80% vs. 88%/75%, p = 0.01) in comparison to KPBC. On MVA, the hazard of death is higher in the KPBC group for both OS [HR = 1.63 (95% CI 1.16-2.30), p = .005] and CSS [HR = 2.25 (95% CI 1.40-3.62), p = .0008]. Older age and a greater number of positive lymph nodes were associated with worse OS: an increase of one year in age at diagnosis was associated with a 4% increase in the hazard of death [HR = 1.04 (95% CI 1.03-1.05), p<.0001]; an increase of a single positive lymph node was associated with an 8% increase in the hazard rate [HR = 1.08 (95% CI 1.06-1.10), p<.0001]. For CSS, a greater number of positive lymph nodes were significantly associated with worse CSS [HR = 1.11 (95% CI 1.08-1.14), p<.0001]. Conclusions: Using the SEER registry, results from this large dataset demonstrate a significant improvement in OS and CSS in OPBC compared to KPBC, though only the CSS reached true statistical significance. These results help to clarify the controversial results of previously reported data for superior outcomes in OPBC. Future research is needed to identify additional predictors of outcomes. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-06-01.

Abstract OT3-1-09: Acupuncture to prevent chemotherapy dose reduction due to chemotherapy-induced peripheral neuropathy in breast cancer patients

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common and dose-limiting side effect of neurotoxic chemotherapy for breast cancer patients. CIPN develops within weeks or months after chemotherapy is initiated and affects 30-40% of breast cancer patients. As a result of severe CIPN, about 8% of breast cancer patients require their chemotherapy dose to be reduced or discontinued, which could detrimentally impact breast cancer related outcomes. Acupuncture is a Traditional Chinese Medicine technique that involves inserting filiform stainless steel needles into pre-defined points on the skin. Previous clinical trials suggest that acupuncture may be an effective treatment to reduce CIPN symptoms with minimal interactions with chemotherapy. Methods: We are conducting a pilot, randomized, standard care and placebo controlled clinical trial (N = 60) assessing the effects of acupuncture to prevent chemotherapy dose reduction due to CIPN. Breast cancer patients receiving taxane based chemotherapy in the neoadjuvant or adjuvant setting will be screened for development of Grade 2 CIPN by completing a weekly Functional Assessment of Cancer Therapy-Neurotoxicity (FACT-Ntx) questionnaire. If patients develop Grade 2 CIPN during chemotherapy they will be randomized to one of three groups: real acupuncture (N = 20), sham acupuncture (N = 20) or standard of care (N = 20). Patients and investigators will be blinded to the treatment assignments. All patients will complete FACT-Ntx and Neuropathy Pain Scale questionnaires weekly. Patients in the real or sham acupuncture groups will receive weekly real or sham acupuncture treatments. Use of pain medications and acupuncture-related adverse events will be self recorded daily in patient diaries. We will explore changes in serum nerve growth factor and other neurotrophic factors such: as brain-derived neurotrophic factor, neurotrophin-3, insulin-like growth factors, and vascular endothelial growth factor. Blood (4 ml) will be drawn before each real or sham acupuncture treatment, at the end of chemotherapy, and at a 4 week follow up visit. Statistics: We expect that acupuncture will significantly decrease the number of patients who require dose reduction during a course of chemotherapy, and increase chemotherapy cumulative relative dose intensity. When a sample size in each cohort is 20, a three group Chi-square test with a 0.05 Type I error will have an adequate 85% power to distinguish between these groups of patients when the proportions are characterized by effect size, of 0.187. We expect the following proportions of patients who would require dose reduction in the acupuncture, sham acupuncture and standard care arms to be 0.05, 0.2, and 0.5, respectively. Statistical analysis will be conducted on-intent-to treat basis. Our specific aims are: to determine the effect of acupuncture on chemotherapy dose reduction, to determine the effect of acupuncture on CIPN during chemotherapy and to explore the mechanisms of acupuncture in treating CIPN. Nine subjects have been consented for screening and one has been randomized. Recruitment is ongoing. Please contact rkirk@umm.edu if interested in the trial. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT3-1-09.

Abstract OT3-2-11: A phase II study of letrozole and lapatinib followed by an addition of everolimus in postmenopausal women with advanced endocrine resistant breast cancer (BC)

Background : Several preclinical studies demonstrated that crosstalk between growth factor receptor pathways, particularly HER2, and ER signaling confers resistance to endocrine therapy (ET). There are emerging data showing the involvement of immune system and miRNA with endocrine resistance. EGF30008 trial showed a benefit of lapatinib in combination with letrozole, mainly in HER2-positive (HER+) metastatic BC (MBC) while a subset analysis of this trial showed that HER2-negative (HER2-) patients (pts) with acquired endocrine resistance may also benefit from this combination. Our preclinical study suggests that everolimus is synergistic with letrozole and lapatinib. Trial Design : This is a single arm phase II study for postmenopausal women with hormone receptor-positive MBC progressing after aromatase inhibitor, tamoxifen, or fulvestrant. The total target accrual is 76 pts (38 HER2+ pts and 38 HER- pts). In the first phase of the study, pts will be treated with letrozole and lapatinib (1,500 mg daily). Upon disease progression, pts will enter the second phase where everolimus (5 mg daily) will be added to letrozole and the dose of lapatinib will be reduced to 1,250 mg daily. For correlative studies, peripheral blood samples will be serially collected to evaluate for serum HER2 extracellular domain (ECD), circulating miRNAs, PC cell-derived growth factor (GP88), immune regulatory cells including myeloid-derived suppressor cells, NK cells, and Treg cells. These parameters will be correlated with tumor response. In pts with accessible tumors, optional serial biopsies will be performed at baseline and upon progression in each phase of the study. The tumor tissue will be tested for total HER1, HER2, and HER2 expressions as well as HER2:HER2 homodimers, HER2:HER3 heterodimers, HER1:HER2 heterodimers, p95, and HER3/PI3K (p85 subunit) using VeraTag assay. Statistical Method : The primary objective is to evaluate the clinical benefit rate (CBR: CR, PR, SD > 24 weeks) of the combination of letrozole and lapatinib as well as the combination of everolimus, letrozole, and lapatinib. This is a three-stage design which is an extension of the Simon9s two-stage design. The sample size is based on the assumption that a CBR below 10% (null hypothesis) would indicate ineffective therapy and the statistical power is set at a higher CBR of 30% which we consider is plausible. Therefore, if 0 of the first 10 pts in each cohort have clinical benefit, the study will be closed; otherwise additional 8 pts will be enrolled. If ≤ 1 of the total 18 pts has clinical benefit, the study will be closed; otherwise an additional 9 pts will be enrolled. If ≤ 5 pts have clinical benefit the therapy is considered not promising; and if ≥ 6 pts of the total of 27 have clinical benefit, the therapy is considered worth pursuing. This design has ∼90% probability to accept the therapy for further trials if the true CBR is indeed at least 30% and 10% probability to accept it if the true clinical benefit is indeed below 10%. To date, there are a total of 6 pts enrolled. Accrual is currently ongoing. Please contact ntait@umm.edu for further information. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT3-2-11.

Abstract P2-13-05: A pilot prospective study of adherence to aromatase inhibitor adjuvant therapy in patients with stage 1–3 breast carcinoma.

Introduction: The most practical approach to assessment of medication adherence in clinical practice is via patient self-reporting, which can be measured using the 8-item Morisky Medication Adherence Scale (MMAS). The 8-item MMAS was developed from a previously validated 4-item scale by supplementing additional items measuring specific medication-taking behaviors to better capture barriers surrounding adherence behavior and has been determined to have better reliability than 4-item scale. Validated medication adherence surveys such as an 8-item MMAS, are untested in oncology, but have been validated in HTN, HIV, DM and other disorders in the setting of multiple chronic medications. Thus this study will serve as a pilot study of the MMAS in the oncology population. Methods: This is a prospective study conducted at the University of Maryland Greenebaum Cancer Center (UMGCC). The primary objective was to identify the adherence level (high, medium, low) to adjuvant (AI) in early stage (1–3) breast cancer (BC) patients in order to identify predictors of adherence. Subjects were stratified according to duration of therapy with AI (≤ 2 yrs or >2 yrs) at the time of the survey. The secondary objective was to identify baseline predictors for adherence. Patients received a maximum 8 points for maximum adherence to medication treatment or high adherence, 6–7 points for medium adherence and Eligibility: Adult females, postmenopausal, signed consent, hormone receptor-positive BC (ER and/or PR >=1%), pathologically confirmed Stage 1–3 BC, completed surgery, adjuvant chemotherapy, and/or radiation therapy, and were recommended by their medical oncologist to take adjuvant AI for 5 years. Pts received a prescription for adjuvant AIs (anastrozole, letrozole or exemestane) after completion of adjuvant chemotherapy. Results: Patient characteristics: 73 BC pts were sequentially accrued so far at the UMGCC and filled out the self-reported questionnaire; Causcasian-62%, African American (AAF)-37%, Asian-1%, median age at diagnosis-54 (range33-84); stage 1–36%, stage 2–47%, stage 3–17%; mastectomy-61%; lumpectomy-39%; local radiation therapy 62%; ER+ 95%; PR+ 78%, HER2+ 17 %; tumor type ductal-75%; lobular-20%; mixed ductal/lobular-5%; tumor grade-1–46%, 2–41%,3–12%; adjuvant chemotherapy- 63%. Educational level- N/A- 3%, Conclusions: Overall adherence to AI treatment measured by MMAS was High in 50.7%, Medium in 35.6% and Low in 13.7% pts; there was no difference in adherence by duration of treatment with AI ≤ 2 vs. > 2 years. Univariable regression models for continuous predictors and rxc contingency tables for categorical ones revealed that the adherence to AI therapy is not affected by age, marital status, education, prior cancer therapy, tumor stage, and concurrent medication. However, there was a trend for better adherence to AI therapy in Caucasian women vs. AAF (p = 0.013). The study is ongoing. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-13-05.