Search

Background: The approved dosing schedule of capecitabine monotherapy in metastatic breast cancer (MBC) is 1250 mg/m2/dose administered days 1 through 14 of a 21-day cycle, but many patients (pts) have difficulty with this schedule due to side effects. Use of a lower starting dose such as 1000 mg/m2/dose or use of an alternative 28-day administration schedule (7 day on, 7 day off, repeat) allows for greater tolerability. Given limited data regarding efficacy of the alternative 28-day schedule, the primary objective of this study was to compare the efficacy of different schedules of capecitabine in patients with MBC. Methods: A retrospective chart review of pts with metastatic breast cancer who received capecitabine as monotherapy between 2002 and 2014 at the Ohio State University James Cancer Hospital was performed. We excluded any HER2-positive patients who had received concurrent HER2-targeted therapy. Pts who initiated therapy at a dose of 1000 mg/m2/dose were classified by these dosing schedules: Arm A (21 day), B (28 day), and C (changeover from 21 day to 28 day). Time to treatment failure (TTF) and overall survival (OS) were compared between dosing schedules using Kaplan Meier curves and log-rank tests. Results: A total of 181 MBC patients (Arm A: n = 113, Arm B: n = 25, Arm C: n = 43) with the following patient characteristics met eligibility criteria; 86.2% Caucasians, 13.8% non-Caucasians, 64.64% estrogen receptor (ER)-positive, 3.31% ER positive/HER2-positive, 2.22% ER negative/HER2-positive, and 29.83% triple-negative. The HER2-positive patients were excluded as they received concurrent therapy. A significant difference was seen in TTF (Arm A: 2.7 mo, Arm B: 2.8 mo, Arm C: 7.1 mo, p = 0.001) when comparing all dosing schedules as well as in OS (Arm A: 5.7 yrs, Arm B: 9.6 yrs, Arm C: 7.8 yrs, p = 0.006). After an initial dose reduction, patients on Arm B tolerated capecitabine for a longer period of time than patients on Arm A before needing a second dose reduction (Table 1). The median time on capecitabine for Arm A was 11.9 weeks and 12.6 weeks for Arm B, and the mean time of both Arm A and Arm B on capecitabine was 22.2 weeks. Patients with ER-positive breast cancer had improved TTF (4.45 months vs 2.32 months, p < 0.001) and OS (7.26 years vs 3.99 years, p < 0.001) compared to ER-negative breast cancer. Caucasians had improved TTF compared to African Americans (AA) and other races (3.90 mo vs 2.87 mo, p = 0.004); however, there was no significant difference in OS. Median starting dose (mg/m2): Arm A - 1000; Arm B - 1043; Arm C - 1000 Time to 1st dose reduction (weeks): Arm A - 6; Arm B - 6; Arm C - 6.5 Dose after 1st reduction (mg/m2): Arm A - 808; Arm B - 848.5; Arm C - 802 Time to 2nd dose reduction (weeks): Arm A - 6; Arm B - 20; Arm C - 8 Dose after 2nd reduction (mg/m2): Arm A - 599.5; Arm B - 690; Arm C - 697 Time to 3rd dose reduction (weeks): Arm A - 6; Arm B - 0; Arm C - 24 Dose after 3rd reduction (mg/m2): Arm A - 575; Arm B - 0; Arm C - 557 Table 1: Median dose (mg/m2) and median time to reductions (in weeks) Conclusions: Our study shows that patients who received the 28-day cycle initially or who were switched to the 28-day cycle appeared to have improved TTF and OS compared to patients on the 21-day cycle. It also shows that AA women had worse TTF on capecitabine when compared to Caucasians. One hypothesis for the improved TTF and OS is that this could be due to a higher total dose of capecitabine received in Arm B and C as shown in Table 1. We acknowledge that the limitations of our study include the sample size and the retrospective nature, and that further work needs to be done. However, the 28-day dosing schedule for capecitabine could be an alternative for elderly patients or patients with poor performance status who are at higher risk for drug toxicities. Citation Format: Nicole Olivia Williams, Anupama Suresh, Julie Stephens, Marilly Palettas, Michael J. Berger, Akaansha Ganju, Raquel Reinbolt, Robert Wesolowski, Anne M. Noonan, Jeffrey Bryan VanDeusen, Sagar Sardesai, Maryam Lustberg, Maryam B. Lustberg, Bhuvaneswari Ramaswamy. Efficacy of alternative 28-day capecitabine dosing schedule in metastatic breast cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr A69.

Introduction: The effect of chemotherapy on the presence of tumor-infiltrating lymphocytes (TILs) and expression of PD1 and PD-L1 is unclear. We sought to describe the differences in the percentage (%) of TILs, cytotoxic T lymphocytes (CTL), and expression of PD1/PD-L1 in tumors of patients (pts) with operable breast cancer (BC) treated with neoadjuvant chemotherapy (NAC) who were enrolled in a biomarker study at our institution (IRB protocol# 2010C0036). Methods: A multicolor immune-histochemical multiplex assay simultaneously detecting PD1, PD-L1, and CD8 expressing cells was performed on formalin-fixed, paraffin-embedded diagnostic pretreatment biopsy or resected tumor specimen following NAC in 18 of 26 pts participating in the study. A cut-off of ≥1% was considered positive for PD1 and PD-L1 expression. We evaluated stromal and intratumoral CTLs by estimating % of stroma and tumor that contained CD8+ cells. In addition, stromal TILs (sTILs) were identified on full-face hematoxylin and eosin stained sections and defined as the % of tumor stroma containing infiltrating lymphocytes. Pathologic complete or near-complete response (pCR) was analyzed based on residual cancer burden (RCB) score and defined as RCB class 0 or I. Analysis of all slides was performed by an expert breast pathologist. Since the number of pts was limited, we only provide descriptive statistics (mean, range). In addition, because most pts had only a biopsy or only residual tumor available for the analysis, we divided pts into 2 separate cohorts based on what tissue was available. Results: Of 18 pts, biopsy was analyzed in 7 (Bx cohort) and residual tumor was analyzed in 11 pts (RT cohort). The median age of study pts was 48 (range 32-70); 11 (61%), 6 (33%), and 1 (6%) of pts were Caucasian, African American, and Hispanic, respectively. Ten pts (5 in Bx and RT cohorts each) had triple-negative BC (TNBC), 4 had HER2+ BC (1 and 3 in Bx and RT cohorts, respectively), and 4 had hormone receptor-positive, HER2- BC (1 and 3 in Bx and RT cohorts, respectively). Eight pts (44%) had pCR. In the bx cohort, 85% of pts had pCR while 18% of pts in the RT cohort had minimal residual disease (RCB class I). In the Bx cohort, average % of sTILs was 30% (range 2-70%), including 1 pt (14%) with lymphocyte predominant tumor (≥50% of sTILs). The % of sTILs was similar in the 11 residual tumors (mean 22, range 2-60) with 2 pts having lymphocyte predominant tumors. Average % of CTLs was 19 (range 1-50) in the Bx cohort and 14 (range 1-50) in the RT cohort. An average % of intratumoral CTLs was 8 (range 1-30) and 7.5 (range 0-40) while the average % of stromal CTLs was 25 (range 1-60) and 19 (range 1-60) in the Bx and RT cohorts, respectively. Similar % and trends were seen in 10 TNBC pts. PD-L1 expression was seen in 86% and 36% of tumors in the Bx and RT cohorts, respectively, with majority of expression present in the stroma. All cases of intratumoral PD-L1 expression were also positive for stromal PD-L1 expression. This difference was also seen in the TNBC pts (80% vs. 40% of tumors were PD-L1+ in Bx and RT cohorts, respectively). An average PD-L1 intensity was approximately 3% in both cohorts (range 1-20%). Expression of PD1 was very low (1% intensity in 3 pts in Bx cohort and in 1 pt in RT cohort) and it was seen on CD8+ CTLs. Conclusion: Our study preliminarily shows that percent of sTILs and stromal and intratumoral CTLs does not differ between pretreatment biopsy and residual tumors following NAC. Lower proportion of residual tumors were PD-L1+ compared to pretreatment biopsy specimen. The study limitations include small number of subjects and lack of comparison in the same pts. Future studies are needed to confirm these findings. Citation Format: Robert Wesolowski, Zaibo Li, Christopher McQuinn, Maryam Lustberg, Bhuvaneswari Ramaswamy, Anne Noonan, Raquel Reinbolt, Sagar Sardesai, Jeffrey B. VanDeusen, Nicole Williams, William E. Carson, III. Analysis of tumor infiltrating lymphocytes and expression of PD1 and PD-L1 in breast tumors prior to and after neoadjuvant chemotherapy [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr A20.

Background: Adults over age 65 are the fastes- growing segment of the US population. However, clinicians have less evidence of how to treat older adults, because they are underrepresented in clinical trials, and studies designed specifically for older adults are rare. Therefore, clinicians have to extrapolate from trials conducted in younger, healthier populations when developing treatment plans for older adults. Over 40% of new breast cancer diagnoses in the US occur in women aged over 65 years. In general, breast cancer in the older woman has distinct biologic features, including less aggressive characteristics and greater expression of estrogen receptor and progesterone receptor. Increasing age is associated with higher rates of comorbidity and frailty, which has been shown to potentially reduce the survival advantage of more aggressive breast cancer therapies. We are conducting a prospective cohort study of adults > or = 65 years with a new diagnosis of breast cancer (OSU-16153) in order to better understand the complex health issues faced by this population, and to collect data with which to support future studies designed to improve the management of these patients. Specific Aims: 1) To assess overall and progression-free survival of breast cancer patients ages 65 and older seen in the Breast Medical Oncology clinics at the Stefanie Spielman Comprehensive Breast Center at The Ohio State University; 2) to examine the association of demographic, diagnostic, and treatment data with patient outcomes, such as progression-free and overall survival, within this patient population; 3) to evaluate the unique needs of breast cancer patients ages 65 and older by implementing a Comprehensive Geriatric Assessment (CGA) within the Breast Medical Oncology clinics at The Ohio State University. Methods: The study will enroll patients > or = 65 years with a new diagnosis of breast cancer. Participants will complete a brief baseline questionnaire, including items addressing demographics, lifestyle, and health history. Patients will then be asked to complete a Comprehensive Geriatric Assessment (CGA) at the time of enrollment, and approximately every six months while on follow-up. The CGA contains both performance-based assessments of patients’ function, completed by study staff, as well as the patients’ self-reports of symptoms and quality of life. The CGA contains a multifaceted battery of clinical instruments including the PROMIS Global Short Form, Functional Assessment of Cancer Therapy-Breast (FACT-B), Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale, The Pittsburgh Sleep Quality Index, Geriatric Depression Scale, The James Supportive Care Screening Tool, Timed Up & Go Test, Grip Strength, Blessed Orientation-Memory-Concentration Test, Mini-Cog Test, Charlson Comorbidity Index, Mini Nutritional Assessment, Katz Index of Independence in Activities of Daily Living, and Instrumental Activities of Daily Living. Participant medical records will be reviewed every three months to assess survival, disease progression, and treatment changes. All questionnaire data will be completed using iPads, and will be directly recorded into the REDCap database. Electronic medical records will be reviewed by research staff, and relevant data will be manually entered into the REDCap database. The aim is to enroll 1,000 participants, and the recruitment period will be five years from study initiation. Participants will be followed for five years from the time of enrollment, resulting in a total study length of ten years. The study opened to accrual on 18 April 2017. To date 3 patients have been enrolled and have completed baseline assessments. Citation Format: Anne M. Noonan, Janine A. Overcash, Anupama Suresh, Laura K. Flora, Julie Stephens, Geetika Bhatt, Raquel Reinbolt, Nicole O. Williams, Robert Wesolowski, Jeffrey B. VanDeusen, Sagar D. Sardesai, Maryam B. Lustberg, Bhuvaneswari Ramaswamy. A prospective geriatric breast cancer cohort study to define unique features and outcomes in older breast cancer patients [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr A55.

A 40-YEAR-OLD premenopausal woman presents with a palpable lump in her left breast. She first noted it 2 months ago on self-examination, and it has steadily grown in size regardless of the phase of her menstrual cycle. The patient has never undergone mammography. Her menarche was at age 12. At age 35, she had one child (whom she breast-fed) after a normal first full-term pregnancy. She took oral contraceptives for 10 years before her pregnancy. She has no other medical problems. She has no family history of breast or ovarian cancer. On examination, her breasts are slightly asymmetric, without skin discoloration, tenderness, swelling, nipple retraction, or discharge. A 1.5- to 2-cm, rubbery, mobile lump can be felt in the left breast at about the 2 o'clock position. No axillary lymph nodes can be palpated. The rest of her examination is normal.

e14537Background: Interspecies allometric scaling is used to extrapolate pharmacokinetics (PK) from preclinical data to human PK and dosing. Efficacy of BXQ-350, a novel Saposin C phosphatidylserin...

TPS1118Background: Triple negative breast cancer (TNBC) has an aggressive clinical course with higher relapse rates and shorter overall survival compared to patients with hormone receptor-positive ...

e14533Background: Saposin C is a lysosomal activator protein that can be combined with a phosphatidylserine lipid to create a nanovesicle that targets cancer cells. Similar lipid nanovesicle prepar...

2517Background: BXQ-350 is a novel agent composed of the multifunctional, lysosomal activator protein Saposin C and phosphatidylserine. BXQ-350 demonstrated antitumor effects in vitro and in vivo, ...

1040Background: The majority of women with ER+ MBC develop resistance to ET. ET plus a CDK4/6 inhibitor (CDKi 4/6) demonstrate improved progression-free survival (PFS) in first/later line MBC. Prec...

e21048Background: Ataxia telangiectasia and Rad3-related protein (ATR) is an essential regulator of the DNA damage response and is required for the survival of proliferating cells. DNA-damaging age...

e14640 Background: Poly(ADP-ribose) polymerase (PARP) enzymes are involved in DNA repair and activated by DNA strand breaks. DNA damage from carboplatin is associated with activation of PARP. Preclinical data indicate that PARP inhibition and trapping potentiates the anti-tumor effect of platinum chemotherapy. Talazoparib (T) is an oral, selective PARP inhibitor. This phase I study combines T with carboplatin (C) and paclitaxel (P). Methods: Two dosing schedules are being investigated. C is administered on day 1 and P on days 1, 8, and 15 of a 21-day cycle. T (100-1000mcg) is dosed once daily for days 1-7 (schedule A) or days 1-3 (schedule B). Dose escalation is by 3+3 design. Patients (pts) must have tumor type that is expected to respond to C + P or have BRCA germline or somatic mutation and adequate organ function. After 4-6 cycles of combination therapy, pts may continue the combination, change to C and intermittent T without P or change to T alone. Each schedule will have a 6 pt dose expansion at the MTD. The dose level (DL) 1 for schedule B is the previously reported MTD from schedule A (T 250mcg with C AUC 6 + P 80mg/m2). Results: Schedule B results are reported: 15 pts (median age 56 yrs [range 43-76]) have been enrolled. Primary malignancies include colorectal (4), pancreas (4), prostate (2), urothelial (2), and other (3). Dose was initiated at Schedule A MTD. DL2 (T 350mcg with C AUC 6 + P 80mg/m2) exceeded the MTD with 2 of 6 pts experiencing hematologic dose limiting toxicities (DLTs). DL1 is the confirmed schedule B MTD. Dose expansion to 6 pts is ongoing. Of the 11 pts with measurable disease, 3 (27%) had PR and 5 (45%) had SD. Pts were on study a median of 10 weeks (range 5-36+). Most common grade 3/4 AEs include leukopenia (53%), neutropenia (47%), and anemia (47%). One grade 5 AE of intracranial hemorrhage occurred, possibly related to therapy in the setting of grade 3 thrombocytopenia and concern for CNS disease. Conclusions: The schedule B MTD and RP2D is T 250 mcg with C AUC 6 and P 80mg/m2. Data from the full dose expansion will be presented. This combination was tolerated with prolonged responses seen at lower dose T in combination with C+P. Clinical trial information: NCT02317874.

2550Background: PLX51107 is an orally active small molecule inhibitor that exhibits low nanomolar potency in blocking interactions mediated by the four BET family proteins and a unique pharmacokine...

A previously healthy 31-year-old man was seen at our institution for evaluation of severe fatigue, night sweats, and supraclavicular lymphadenopathy. About 9 months earlier, he experienced symptoms...

Summary Gastric cancer remains one of the most common forms of cancer worldwide. Unfortunately, most patients will present with advanced-stage disease, and will therefore need palliative chemotherapy. Some chemotherapy regimens have been well established as first-line therapy, and have been shown to increase survival; however, almost all patients with metastatic gastric cancer will develop progressive disease after first-line therapy. With the availability of several active chemotherapy drugs, many patients who retain a good performance status after the initial treatment remain good candidates for additional therapy; however, no standard approach for second-line therapy exists. Many small, phase 2 trials have been done and the findings are variable. No data from randomised-controlled trials suggest a benefit of second-line chemotherapy compared with supportive care alone. We review the published data concerning the use of chemotherapy in the second-line setting for the treatment of advanced gastric cancer.

Purpose: This was a phase I study evaluating the dose limiting toxicity (DLT) and the maximum tolerated dose (MTD) of weekly docetaxel, doxorubicin and daily oral cyclophosphamide with G-CSF support (ConTAC regimen). Patients and Methods: Cohorts of 3–6 patients with advanced breast or other solid malignancies were entered at subsequently higher dose levels until dose-limiting toxicities (DLT) were noted in 2 or more patients per dose level during the first 6 weeks of therapy. This study escalated dosages of docetaxel and doxorubicin simultaneously, while the dose of oral cyclophosphamide was fixed at 60 mg/m2 daily. Results: Sixteen patients were enrolled. Grade 3–4 adverse events during the first 6 weeks of treatment were neutropenia (n = 1 at dose level #1 and n = 3 at dose level #4), anemia (n = 2 at dose levels 1 and 4), and nausea/vomiting (n = 1 at dose level #4). After 6 weeks of therapy, grade 3–4 toxicities included anemia (n = 3), neutropenia (n = 7), Hand-Foot syndrome (n = 2) and grade 3 cystitis and pneumonia (n = 1 at dose level #4). Five patients with advanced breast cancer and 1 patient with metastatic lung cancer responded to the chemotherapy. Conclusions: Grade 4 neutropenia was the DLT. The MTD, was established at dose level #3 (doxorubicin at 25 mg/m2 and docetaxel at 25 mg/m2 weekly with oral cyclophosphamide dose of 60 mg/m2 daily). Myelosuppression at that dose level was moderate with G-CSF given concurrently.

There is no clear consensus regarding the most effective management of poor responders to neoadjuvant chemotherapy. Intensifying or changing primary systemic treatment has not been shown to offer any benefit. There is a paucity of trials testing the utility of adjuvant chemotherapy in this setting. Adjuvant hormonal treatment significantly decreases relapse rates in patients with estrogen receptor-positive breast cancer, regardless of initial response to chemotherapy. Neoadjuvant hormonal therapy is usually reserved for patients who are not candidates for chemotherapy or surgery. In patients with HER-2-overexpressing tumors who are candidates for chemotherapy, trastuzumab improves outcomes when administered in the preoperative or postoperative setting. This article examines issues related to the assessment of response to preoperative therapy and the clinical use of these assessments. It reviews important clinical evidence related to the utility of further treatment in patients with breast cancer that has responded poorly to neoadjuvant treatment.

Objective: To review palbociclib, a novel small-molecule inhibitor of cyclin-dependent kinases 4 and 6, and its current place in therapy for the treatment of hormone receptor (HMR)-positive, human epidermal growth factor receptor 2 (Her2)-negative advanced breast cancer. Study Selection and Data Abstraction: Four phase I trials, 2 phase II trials, and 1 phase III trial were identified from May 2004 to May 2015 using PubMed, American Society of Clinical Oncology (ASCO) abstracts, and European Society of Medical Oncology (ESMO) abstracts. Data Synthesis: In the first-line setting, the phase II PALbociclib: Ongoing trials in the Management of breast cAncer (PALOMA)-1 trial randomized patients to receive letrozole alone or letrozole plus palbociclib 125 mg daily for 3 weeks, followed by 1 week off, as initial therapy for advanced breast cancer. The investigator-assessed median progression-free survival (PFS) was 20. 2 months for the combination versus 10.2 months for letrozole alone (hazard ratio [HR] = 0.488; 95% CI = 0.319-0.748; 1-sided P = 0.0004). The ensuing Food and Drug Administration approval of palbociclib was given a “breakthrough therapy” designation, where preliminary evidence suggests substantial improvement over existing therapies for a serious or life-threatening disease. A confirmatory phase III trial, PALOMA-2, is under way. In patients who were previously treated with endocrine therapy for advanced breast cancer, the phase III PALOMA-3 trial randomized patients to fulvestrant plus palbociclib versus fulvestrant plus placebo. The investigator-assessed median PFS at the time of a preplanned analysis was 9.2 months with palbociclib-fulvestrant compared with 3.8 months with placebo-fulvestrant (HR = 0.42; 95% CI = 0.32-0.56; P < 0.001). Conclusions: Palbociclib, the first-in-class CDK4/6 inhibitor, significantly extended PFS in combination with endocrine therapy in the first and subsequent lines of treatment for HMR-positive, Her2-negative advanced breast cancer.

Myeloid-derived suppressor cells (MDSC) are a heterogeneous group of immature myeloid cells that expand in tumor-bearing hosts in response to soluble factors produced by tumor and stromal cells. MDSC expansion has been linked to loss of immune effector cell function and reduced efficacy of immune-based cancer therapies, highlighting the MDSC population as an attractive therapeutic target. Ibrutinib, an irreversible inhibitor of Bruton's tyrosine kinase (BTK) and IL2-inducible T-cell kinase (ITK), is in clinical use for the treatment of B-cell malignancies. Here, we report that BTK is expressed by murine and human MDSCs, and that ibrutinib is able to inhibit BTK phosphorylation in these cells. Treatment of MDSCs with ibrutinib significantly impaired nitric oxide production and cell migration. In addition, ibrutinib inhibited in vitro generation of human MDSCs and reduced mRNA expression of indolamine 2,3-dioxygenase, an immunosuppressive factor. Treatment of mice bearing EMT6 mammary tumors with ibrutinib resulted in reduced frequency of MDSCs in both the spleen and tumor. Ibrutinib treatment also resulted in a significant reduction of MDSCs in wild-type mice bearing B16F10 melanoma tumors, but not in X-linked immunodeficiency mice (XID) harboring a BTK mutation, suggesting that BTK inhibition plays an important role in the observed reduction of MDSCs in vivo. Finally, ibrutinib significantly enhanced the efficacy of anti-PD-L1 (CD274) therapy in a murine breast cancer model. Together, these results demonstrate that ibrutinib modulates MDSC function and generation, revealing a potential strategy for enhancing immune-based therapies in solid malignancies. Cancer Res; 76(8); 2125–36. ©2016 AACR.

Phenoxodiol, a synthetic analog of the plant isoflavone genistein, represents a new generation of oncology drugs acting as multiple signal transduction regulators. Phenoxodiol exerts its effect mainly by the induction of apoptosis through multiple mechanisms resulting in degradation of antiapoptotic proteins, with increased levels being linked to chemoresistance in tumor cells. Preclinical studies with this agent showed promising anticancer activity leading to a potential role in the treatment of a wide range of solid and hematologic cancers. Early clinical studies, especially in chemotherapy-resistant ovarian cancer, showed minimal toxicity with minor antitumor activity. Hormone-refractory prostate cancer is another promising area in which phenoxodiol is being actively tested. Studies are ongoing to define the optimal use of this novel anticancer agent.

3075 Background: AGEN1884 is a fully human IgG1 monoclonal antibody targeting the co-inhibitory protein cytotoxic T lymphocyte-associated protein 4 (CTLA-4). CTLA-4 blockade has been shown to augment T cell activation and proliferation, resulting in immune infiltration of the tumor and subsequent regression. Objectives: Assess the safety, maximum tolerated dose (MTD), and pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of AGEN1884 in patients (pts) with advanced and refractory malignancies using a “3+3” trial design. Methods: Eleven pts have been enrolled and treated to date. AGEN1884 was administered intravenously q3w for 4 doses and then q12w. Three (0.1, 0.3 and 1 mg/kg) of six (3, 6 and 10 mg/kg) planned dose levels have been completed. Results: Five pts were accrued at 0.1 mg/kg dose level (2 were not DLT evaluable) and three pts each at doses of 0.3 mg/kg and 1 mg/kg. Median age was 56 years (range 26–70), ECOG 0–2, with a median of 4 (range 1–8) prior therapies. No DLT events have been observed thus far. Data from 5 pts were available for PK evaluation. Half-life of AGEN1884 post first dose was 8.8 and 9.6 days for 0.3 mg/kg and 0.1 mg/kg dose levels, respectively, as measured by ELISA. As of Jan 31, 2017, pts across cohorts were followed for a median of 6 weeks (range 0-28). Six pts (54.5%) have come off study due to disease progression, while 5 (45.5 %) remain on study. One confirmed partial response (80% reduction) by RECIST criteria was seen at 0.1 mg/kg in a patient with angiosarcoma. Conclusions: AGEN1884 is safe at 0.1 and 0.3 mg/kg dose levels. Dose escalation is ongoing and updated safety and PK data will be presented. Clinical trial information: NCT02694822.

TPS1113 Background: Hormone receptor positive (HR+) disease is the most common subset of both early and late stage breast cancer (BC). The majority of women with HR+ metastatic BC (MBC) ultimately develop resistance to endocrine therapy, with a median survival of ~2-3 years. A new standard-of-care strategy to treat HR+ metastatic disease involves the combination of hormone therapy and cyclin-dependent kinase (CDK) 4/6 inhibition, which has demonstrated improved progression-free survival (PFS) in both the first- and later-line metastatic setting. More recently, preclinical data with the dual phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor gedatolisib (PF-05212384) suggest synergy with the combination of hormone therapy, CDK 4/6 inhibition, and inhibition of the PI3K/mTOR pathway. Methods: This phase Ib study includes a dose escalation portion to evaluate dose-limiting toxicities (primary endpoint) and determine the recommended phase II dose for triplet therapy with gedatolisib combined with palbociclib/letrozole or palbociclib/fulvestrant in women with HR+ HER2-negative MBC or locally advanced/recurrent BC, in the first- and later-line setting. Thereafter, a 3-arm expansion for early signals of efficacy will investigate objective response rates (primary endpoint) with gedatolisib combined with palbociclib/letrozole (n = 26), palbociclib/fulvestrant in patients without prior CDK 4/6 inhibition (n = 28), and palbociclib/fulvestrant in patients who have previously received palbociclib (n = 27). The rates of objective response will be compared to historical controls. Secondary endpoints include safety, tumor response, PFS (expansion portion only), pharmacokinetics, and biomarker correlations associated with the PI3K/mTOR pathway. This trial is now recruiting. Clinical trial information: NCT02684032.

2523 Background: Binding of CSF-1 to the CSF-1 receptor (CSF-1R) results in proliferation, differentiation, and migration of monocytes/macrophages. Intratumoral infiltration with macrophages correlates with increased invasiveness, growth, and immunosuppression. LY3022855 (LY) is a human IgG1 antibody (mAb) targeting CSF-1R. Methods: Eligible pts (ECOG 0-2) with advanced solid tumors were enrolled. Mandatory pre and post-treatment biopsies were obtained. LY was given on a 6-week cycle. Two escalation regimens (Part A: weight-based dosing; Part B: flat dosing) were investigated in a 3+3 design. Primary objective was to establish the safety and characterize the pharmacokinetics (PK) of LY. Secondary objectives were to establish recommended phase 2 dose (RP2D) and to characterize pharmacodynamics (PD). Results: As of Sept 6, 2016, 35 cancer pts (colorectal 14; lung 4; pancreas 3; others 14) were treated (29 in Part A; 6 in Part B) with median treatment duration 4 weeks (range 1-21). Common treatment-emergent adverse events (TEAEs) were fatigue (54%), hypoalbuminemia (40%), nausea (37%), AST increase (37%), anemia (34%), anorexia (34%), creatine kinase elevation (29%), and constipation (23%). Most common grade (G) 3/4 TEAEs were anemia (11%), fatigue (11%), ascites (9%), and lymphocyte count decrease (9%). 3/28 evaluable pts had DLTs: G3 left ventricular systolic dysfunction (1), G4 rhabdomyolysis and G4 acute renal failure (1), and G3 pancreatitis (1). Eight treatment unrelated deaths were reported. One pt (adenoid cystic carcinoma) had stable disease (~3 mo as of last visit), 19 pts had progressive disease, and 15 pts were non-evaluable for response assessment. PK profile of LY was consistent with IgG1 mAbs. An interim analysis following completion of Part A demonstrated a lack of relationship between weight and clearance, prompting evaluation of non-weight based dosing. PD analyses revealed dose-dependent increases in serum CSF-1 levels as well as suppression of circulating non-classical monocytes (CD14dim CD16bright), indicating biologic activity at studied doses. Conclusions: RP2D for LY monotherapy has been determined. Detailed PK and PD data will be presented. Clinical trial information: NCT01346358.

TPS1127 Background: Heat shock protein 90 (HSP90) is a molecular chaperone which is necessary for proper folding and stabilization of proteins. Client proteins of HSP90 include many oncogenic proteins known to be over-activated in triple negative breast cancer such as AKT, EGFR, members of RAS/MAPK signaling pathway and androgen receptor. High expression of HSP90 in breast cancer has been associated with poor outcome. In addition, over-expression of HSP90 client proteins such as AKT and c-RAF has been implicated in paclitaxel resistance. Onalespib (AT13387) is a synthetic non-ansamycin small molecule that acts as an inhibitor of HSP90 by binding to the amino terminal of the protein and has dissociation constant (Kd) of 0.71 nM. Methods: Patients with inoperable or metastatic, triple negative or < 10% hormone receptor positive breast cancer are treated with onalespib and paclitaxel on days 1, 8, 15 every 28 days. Paclitaxel is given at a standard dose of 80 mg/m2 while the dose of onalespib is gradually increased using standard 3+3 design (see table). In order to assess the effect of each drug on pharmacokinetics of the other drug, onalespib is given on day -7 prior to cycle 1 and skipped on day 1 of cycle 1 during which paclitaxel is administered alone. The primary objective of the study is to determine recommended phase II dose and assess the toxicity profile of the combination. The secondary objectives include pharmacokinetic of each agent. Overall response rate, response duration and progression-free survival will also be assessed. The study is currently enrolling patients to dose level 2. Clinical trial information: NCT02474173. [Table: see text]

e12126 Background: Even with neo-adjuvant chemotherapy (NAC) many breast cancer (BC) patients (pts) relapse, especially triple negative pts. The incorporation of checkpoint inhibitors into NAC for BC is being tested in clinical trials. How NAC affects checkpoint receptor expression is not known. Such information could aid in the rational selection of checkpoints to target during NAC. We sought to characterize changes in the frequency of circulating CD4 and CD8 T cells expressing PD1, CTLA4, LAG3, TIM3, and OX40 over the course of NAC. Methods: In this prospective trial, expression of PD-1, CTLA-4, Lag3, Tim3 and Ox40 on circulating CD4 and CD8 T cells were measured by FACS analysis in pts with operable breast cancer (BC) prior and at the end of NAC. The primary objective was to explore the association between NAC and expression levels of the immune checkpoints. Results: 1, 20 and 3 pts had clinical stage I, II, IIIA, respectively. Median age was 48. 11, 6 and 7 pts were triple negative (TN), HER2+ and hormone receptor (HR)+, respectively. Complete pathologic response rate was 45.8%. Globally CD4 T cells expressing CTLA4, Lag3, Ox40 and PD1 decreased following NAC (all p < 0.01). Conversely, CD8 T cells expressing CTLA4, Lag3 and Ox40 significantly increased (all p < 0.01). More CD8 T cells from HER2+ pts expressed Lag3 prior to therapy compared to HR+ pts (p < 0.05) with a similar trend compared to TN pts. Prior to therapy more CD8 T cells from HER2+ and TN pts expressed Tim3 compared to HR+ pts (p < 0.05 for each). Post therapy more CD4 T cells from HER2+ pts expressed PD1 compared to HR+ and TN pts (p = 0.027 and 0.018 respectively). Clinical response did not predict change in checkpoint expression. An interaction analysis revealed that HER2+ disease predicted a drop in CTLA4 CD4 T cells and a drop in Lag3 CD4 and CD8 T cells over NAC (p < 0.05). Conclusions: This analysis identified changes in checkpoint receptor expression by CD4 and CD8 T cells in BC pts after NAC. Differences in checkpoint receptor expression were found between BC subgroups. This data provides a starting point for understanding checkpoint receptor expression changes with NAC, and could help guide the selection and timing of incorporating checkpoint inhibitors in BC.

10102 Background: Many BC patients treated with aromatase inhibitors (AIs) develop AIA; 20% have symptoms severe enough to effect treatment compliance. Results of candidate gene studies to identify AIA risk are limited in scope. In this case-controlled study, we evaluated the potential of a NAA to predict AIA using germline single nucleotide polymorphism (SNP) data obtained prior to treatment initiation. Methods: Systematic chart review of 700 AI-treated patients with stage I-III BC between 2003-2012 identified asymptomatic patients (n = 39) and those with clinically significant AIA resulting in AI termination or therapy switch (n = 123). Germline DNA was obtained from peripheral blood cells and SNP genotyping performed using the Affymetrix UK BioBank Axiom Array to yield 695,277 SNPs. The identity of the cluster of SNPs that most closely defined AIA risk was discovered using an NAA that sequentially combined statistical filtering and a machine learning algorithm. NCBI PhenGenI and Ensemble databases were used to define gene attribution of the 200 most discriminating SNPs. Phenotype, pathway, and ontologic analyses assessed functional and mechanistic validity. Results: Cases and controls were similar in demographic characteristics. A cluster of 70 SNPs, correlated to 57 genes (accounting for linkage disequilibrium), was identified. This SNP group predicted AIA occurrence with a maximum accuracy of 75.93%. Strong associations with arthralgia, breast cancer, and estrogen phenotypes were seen in 19/57 genes (33%) and were functionally and ontologically consistent. Conclusions: Using a NAA, we identified a 70 SNP cluster that predicted AIA risk with fair accuracy. Phenotype, functional, and pathway analysis of attributed genes was consistent with clinical phenotypes. This study is the first to link a specific SNP/gene cluster to AIA risk independent of candidate gene bias. An ongoing prospective companion study will be used to validate and to expand upon results.

Natural killer (NK) cells are innate immune effector cells that play a crucial role in immune surveillance and the destruction of cancer cells. NK cells express a low-affinity receptor for the Fc or constant region of immunoglobulin G (FcγRIIIa) and multiple cytokine receptors that respond to antibody-coated targets and cytokines in the tumor microenvironment. In the present work, microarray gene expression analysis revealed that the IL-21 receptor (IL-21R) was strongly upregulated following FcR stimulation. The IL-21R was found to be upregulated on FcR-stimulated NK cells at the transcript level as determined by reverse transcription polymerase chain reaction (RT-PCR). Immunoblot analysis revealed that protein expression of the IL-21R peaked at 8 h post-stimulation of the FcR. Inhibition of the mitogen-activated protein kinase (MAPK) pathway downstream of the FcR blocked the induction of IL-21R expression. Increased expression of the IL-21R sensitized NK cells to IL-21 stimulation, as treatment of FcR-stimulated NK cells led to significantly increased phosphorylation of STAT1 and STAT3, as measured by intracellular flow cytometry and immunoblot analysis. Following FcR-stimulation, IL-21-activated NK cells were better able to mediate the lysis of trastuzumab-coated human epidermal growth factor receptor 2 (HER2+) SK-BR-3 tumor cells as compared to control-treated cells. Likewise, IL-21-induced NK cell secretion of IFNγ following exposure to antibody-coated tumor cells was enhanced following FcR-stimulation. The analysis of NK cells from patients receiving trastuzumab therapy for HER2+ cancer exhibited increased levels of the IL-21R following the administration of antibody suggesting that the presence of monoclonal antibody-coated tumor cells in vivo can stimulate the increased expression of IL-21R on NK cells.

Background Preclinical and early clinical data support the use of Vascular Epithelial Growth Factor (VEGF)-targeted therapy with trastuzumab in Human Epidermal Receptor 2 (HER2) positive breast cancer. Adding bevacizumab to a taxane (docetaxel or paclitaxel) improves progression free survival (PFS) of metastatic breast cancer (MBC) patients. Objectives We evaluated the efficacy and feasibility of combining bevacizumab with trastuzumab and docetaxel in patients with HER2- positive MBC who received 0–1 prior chemotherapy regimens for metastatic disease. The primary end point was PFS. Materials and Methods Eligible patients received bevacizumab (15 mg/kg), trastuzumab (8 mg/kg loading dose followed by 6 mg/kg), and docetaxel (100 mg/m2 initially, later amended to 75 mg/m2) every three weeks for six cycles and then were allowed to receive bevacizumab and trastuzumab alone. Results Thirteen (50 %) of 26 patients enrolled completed all 6 cycles of bevacizumab, trastuzumab and docetaxel and went on to receive bevacizumab and trastuzumab alone (median: 11 cycles). The most common grade 3 or 4 toxicities include: neutropenia (8 %), septic death (4 %), infection not associated with neutropenia (15 %), fatigue (27 %), mylagia and/or arthraligia (20 %), and hand-foot syndrome (8 %). One patient (4 %) and six patients (23 %) developed grade 3 and grade 2 hypertension, respectively. Two (8 %) patients had transient grade 2 drop in Left Ventricular Ejection Fraction (LVEF) with full recovery later. The median progression free survival (PFS) was 14.3 months (95 % CI: 9.3–35 months), the objective response rate (ORR), defined as the best response of complete response (CR) or partial response (PR) was (12/26) 46 %. The clinical benefit rate (CBR), defined as the best response of CR or PR or stable disease (SD) for at least 24 weeks, was (18/26) 69 % (95 % CI: 48–86 %). Conclusion The combination of bevacizumab, trastuzumab and docetaxel is well tolerated and is clinically active in patients with HER2-positive MBC, with response rate and PFS comparable to previous reports utilizing higher dose of docetaxel (100 mg/m2). Recent randomized trials did not demonstrate additional overall survival (OS) benefit of adding bevacizumab to trastuzumab and docetaxel despite an improvement in PFS. Identification of predictive biomarkers and careful patient selection should be incorporated in further investigation of anti-VEGF in breast cancer.

Michele Arcopinto ⁎, Chiara A. Cella , Robert Wesolowski , Andrea Salzano , Eduardo Bossone , Antonio Cittadini , Ragavendra R. Baliga e a Department of Translational Medical Sciences, Federico II University, Naples, Italy b Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy c Division of Medical Oncology, College of Medicine, The Ohio State University, Columbus, OH, USA d Department of Cardiology and Cardiac Surgery, University Hospital “Scuola Medica Salernitana”, Salerno, Italy e Cardio-Oncology Program Division of Cardiovascular Medicine, The Ohio State University, Columbus, OH, USA

Tumor infiltrating lymphocytes are studied for their potential as new clinically useful prognostic and predictive biomarkers in patients with triple negative and HER-2/neu amplified breast cancer. This area of research could also help guide the development of novel therapeutic approaches for these diseases.

PURPOSE To describe a case of uveal metastasis secondary to hepatocellular carcinoma. METHODS The authors present a 57-year-old man with known diagnosis of hepatocellular carcinoma, with progressive visual problems in his right eye. Work-up including indirect ophthalmoscopic examination, ocular ultrasonography, and brain magnetic resonance imaging revealed a dome-shaped choroidal mass abutting the optic disk with surrounding shallow exudative retinal detachment. RESULTS A fine-needle biopsy of the lesion confirmed the presence of malignant cells suggestive of metastatic disease from hepatocellular carcinoma. The patient was subsequently treated with brachytherapy. The patient died 3 weeks after the treatment due to pneumonia, which was felt to be unrelated to his ocular disease. CONCLUSION This is a report of a very unusual case of hepatocellular carcinoma with metastasis to uveal tract.

Introduction: Foundation Medicine Incorporated (FMI) uses next generation sequencing (NGS) to simultaneously identify oncogenic molecular events and match targeted therapies to these alterations. We conducted a prospective study of the FMI test to describe the incidence of actionable genomic alterations found in advanced breast cancer patients. Methods: This is a prospective, single center, single-arm trial in advanced breast cancer patients designed to assess FMI testing’s feasibility and impact. Adult metastatic breast cancer patients with an estimated survival of ≥ 3 months were included, had tumor sample available for testing, and were within 10 weeks of starting their current therapy line. A massively-parallel sequencing platform (FoundationOne™) used the patient’s tumor (FFPE tissue) to sequence for 236 cancer-related genes plus 47 introns of 19 genes often rearranged in cancer to high depth (>500x). Genomic alterations were categorized as actionable if linked to an approved therapy in the solid tumor of study or another malignancy, a known or suspected contraindication to a given therapy, or a clinical trial linked to the alteration. The number of genomic alterations was quantified; genes with > 1 alteration were counted once. Results: Forty-nine patients were consented to FMI testing. Forty patients (82%) successfully completed testing; analysis was insufficient in 6 tissue samples, 2 failed DNA extraction, and 1 patient’s tissue was not received. Of the 8 unsuccessful tests, sampling from the bone (50%) and liver (38%) were the most common sites of failure. Thirty-seven reports have been received; 27 (73%) samples were taken from metastatic tissues, 10 (27%) from the primary breast tumor. A total of 192 actionable alterations were detected in tumors tested, with a median of 5 (range 1-11) alterations found per patient. Amplifications comprised 87 alterations, 105 were a base substitution, insertion/deletion or other copy number alteration. Of the 192 alterations, the TP53 gene was the most often altered [n=22 (11%)] and most frequent in ER/PR/HER2-neu negative breast tumors. Alterations in PIK3CA [n=16 (8%)] and ZNF217 [n=8 (4%)] were the 2nd and 3rd most commonly altered genes. The NGS report provided 24 of the 37 patients (65%) with a recommended FDA approved breast therapy; an additional 24 patients (65%) were suggested a non-breast FDA approved therapy. At least 1 potential treatment or clinical trial was proposed to 36 patients (97%) with everolimus (n=30) and temsirolimus (n=30) the most commonly recommended FDA approved interventions, and trametinib (n=6), regorafenib (n=6), and pazopanib (n=6) the next most commonly suggested interventions. Patients had a median of 3 (range 0-7) genomic alterations paired with a recommended clinical trial. Conclusions: This prospective study shows NGS testing in advanced breast cancer patients is successful in over 80% of patients screened. Two-thirds of patients were recommended a FDA approved therapy and nearly all patients were suggested at least one potential clinical trial. Further studies to assess barriers to patients’ access to these recommended targeted therapies are currently underway. Citation Format: Raquel E Reinbolt, Katlyn Tolliver, Mahmoud Abdel-Rasoul, Cynthia Timmers, Bhuvaneswari Ramaswamy, Rachel M Layman, Robert Wesolowski, Maryam B Lustberg, Ewa Mrozek, Susan Ottman, James Chen, Charles Shapiro, Michael C Ostrowski, Gustavo W Leone, Erin Macrae. Incidence of actionable genomic alterations in metastatic breast cancer: A prospective study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-03-03.

Fosaprepitant is known to cause infusion-site reactions. However, there is limited data regarding these reactions including the effect of peripheral intravenous administration or other potential factors on their incidence. This single-institution retrospective study was undertaken to investigate the incidence of infusion-site reactions with single-dose intravenous (IV) fosaprepitant when given through a peripheral line prior to administration of chemotherapy. Risk factors for the development of infusion-site reactions with fosaprepitant were also explored.Medical records of patients with cancer receiving IV fosaprepitant through a peripheral line were reviewed. The primary objective of this study was to estimate the incidence of infusion-site reactions at our institution. Data collection included demographics, fosaprepitant infusion information, and grading of reactions.We found a 15 % incidence of infusion-site reactions among all peripherally administered doses of fosaprepitant. The 50 reactions occurred in 43 unique patients representing an incidence per patient of 28.7 % (43/150; 95 % confidence interval (CI) 21.6-36.6). Factors found to be associated with infusion-site reactions included age [odds ratio (OR) 0.97 (95 % CI 0.94-0.99)], location of IV line [OR forearm vs. hand 0.41 (95 % CI 0.20-0.85); OR antecubital fossa vs. hand 0.31 (95 % CI 0.11-0.87)], and simultaneous maintenance IV fluid rate ≥100 mL/h during fosaprepitant infusion [OR 0.19 (95 % CI 0.08-0.44)].The incidence of infusion-site reactions with peripherally administered fosaprepitant as seen in this study is higher than that reported in the package insert. Risk factors for developing infusion-site reactions in our patient population include age, location of IV line, and simultaneous maintenance IV fluid rate of100 mL/h.

As the result of a recent national shortage in paclitaxel, some patients who were receiving or scheduled to receive weekly paclitaxel were converted to every 3-week (q3w) docetaxel with granulocyte colony-stimulating factor support. Our institution noted higher than expected incidence of severe skin toxicity events attributable to docetaxel during the shortage period among our breast cancer patients. In this report, we summarize the clinical course of the first five cases, review the literature surrounding docetaxel-induced skin toxicity, and offer possible prevention and treatment strategies to improve docetaxel tolerability.The observation period for this case series was August 1 through October 21, 2011. All patients treated with docetaxel were identified from our electronic medical record. Operable stage I-III breast cancer patients who received ≥ 1 dose of docetaxel monotherapy at 75-100 mg/m(2) q3w were included in this study. The cases of grade 3-4 docetaxel-induced skin toxicities identified by the treating oncologists were then contacted and signed an informed consent through an Institutional Review Board-approved protocol.Thirty-four patients met the inclusion criteria. Five patients (14.7 %) experienced grade 3 skin toxicity events attributable to docetaxel, a significantly higher rate than previously reported for docetaxel dosed at 75-100 mg/m(2).Docetaxel-induced dermatologic toxicity is well characterized; nonetheless, its etiology is largely unknown and evidence-based prevention and management strategies are lacking. This report shows that the use of docetaxel 75-100 mg/m(2) q3w subsequent to dose-dense doxorubicin and cyclophosphamide regimen can lead to unacceptable rate of severe skin toxicity.

Myeloid Derived Suppressor Cells (MDSC) are a heterogeneous population of immature myeloid cells that are increased in states of cancer, inflammation and infection. In malignant states, MDSC are induced by tumor secreted growth factors. MDSC play an important part in suppression of host immune responses through several mechanisms such as production of arginase 1, release of reactive oxygen species and nitric oxide and secretion of immune-suppressive cytokines. This leads to a permissive immune environment necessary for the growth of malignant cells. MDSC may also contribute to angiogenesis and tumor invasion. This review focuses on currently available strategies to inhibit MDSC in the treatment of cancer.

Background: Preclinical data demonstrates that activation of RAS/MEK/ERK pathway in basal-like breast cancer (BLBC) leads to resistance to chemotherapy. Inhibiting MEK pathway was highly effective in BLBC models with intact PTEN. Conversely activated PI3K/AKT pathway (loss of PTEN which occurs in ∼ 30% of TNBC) led to resistance to MEK inhibition. We proposed to test the hypothesis that single agent trametinib (T) will demonstrate efficacy in a subset of TNBC and that addition of AKTi, GSK2141795 (G) will overcome resistance to T. Methods: This is a single arm, multicenter study through the ETCTN. Eligible patients (pts) with advanced TNBC, measurable disease with 1-3 prior chemotherapies received mandatory research biopsy and entered Part I of the study with T alone (2 mg Q day-28 days). At the point of progression pts received a mandatory second biopsy and moved to PART II of study with 1.5 mg of T + 50 mg of G. Optional research biopsy was performed at the point of progression on the combination. Restaging scans were done every 2 cycles. Blood samples were collected at baseline, cycle 2 and at progression. Results: 33 pts with median age 55 (35-71) from six cancer centers were enrolled to Part I (T alone) and 17 pts entered part II (T +G). Most common toxicities for pts on T alone included Gr1: diarrhea, rash, transaminitis, Gr 2: fatigue; Gr 3: thromboembolism. Of 31 evaluable pts on T alone, two pts (1 still on study after 8 cycles) had a partial response (PR) and one pt has stable disease after 8 cycles and remains on study. Of the sixteen evaluable patients on part II (T+G) one patient has an unconfirmed PR (34% reduction on RECIST). Common toxicities for the combination include: Gr1: diarrhea, nausea, vomiting, myelosuppression, rash, hypertension, transaminitis, Gr2: Rash, fatigue, mucositis, diarrhea, Gr 3: diarrhea. Eleven patients died on study (10-progression, 1-adverse event). Blood and tissue samples are being analyzed for whole genome sequencing, IHC for PTEN, Quantitative targeted absolute proteomics (QTAP) for kinome assay and RPPA for PTEN, PI3KCA, AKT, ERK and MEK. This study is currently closed to accrual for interim analysis for efficacy on part II. Conclusion: Trametinib alone and in combination with AKTi, GSK2141795 has limited efficacy in TNBC. Proposed correlatives in serial biopsies may identify biomarkers in the few responders and help identify other novel targets. Citation Format: Bhuvaneswari Ramaswamy, Ewa Mrozek, Maryam Lustberg, Robert Wesolowski, Rachel Layman, Mahmoud Abdel-Rasoul, Cynthia Timmers, Robyn Patrick, Jennifer Sexton, Erin Macrae, Charles Shapiro, Thomas Budd, Lyndsay Harris, Claudine Isaacs, Roohi Ismail-Khan, Claire Dees, Andrew Poklepovic, Micheal Grever, Helen Chen, Miguel Villalona, William Carson. NCI 9455: Phase II study of trametinib followed by trametinib plus AKT inhibitor,GSK2141795 in patients with advanced triple negative breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-216.

Myeloid derived suppressor cells (MDSC) interfere with anti tumor immune responses. MDSC have also been shown to antagonize the effectiveness of immune based therapies including immune checkpoint blockade. As a result, MDSC have received attention as potential targets for immune based combination therapies. There has been limited success in the identification of clinically active agents with the ability to inhibit the function or generation of MDSC. Ibrutinib is an orally available irreversible inhibitor of Bruton's tyrosine kinase (BTK) that is FDA approved for the treatment of B cell malignancies. In addition to B cells, cells of the myeloid lineage including monocytes and macrophages express BTK, and treatment with ibrutinib has been shown to alter their function and differentiation. As a result, it was hypothesized that ibrutinib would interfere with the function or generation of MDSC in the setting of cancer. MDSC isolated from the spleens of multiple murine tumor models (EMT6, 4T1, and C26) as well as MDSC from patients with metastatic melanoma expressed BTK. Treatment with ibrutinib at doses ranging from 0.1-5 μM inhibited the phosphorylation of BTK in both murine and human MDSC. Ibrutinib treatment of murine and human MDSC resulted in a significant reduction in nitric oxide (NO) production (p< 0.05), but had only modest effects on MDSC levels of IDO and arginase. Ibrutinib was also able to inhibit murine MDSC migration in response to EMT6 cell line conditioned media and the chemokine CXCL12 (p< 0.05). In addition, ibrutinib inhibited human MDSC migration in response to GM CSF (p< 0.05). Ibrutinib reduced the expression of the myeloid adhesion molecules CD11a (p< 0.05) and CD49D (p< 0.01) by MDSC, which could explain the reduction in migration. Importantly, ibrutinib significantly reduced the ability of MDSC to suppress CD8+ T cell proliferation compared to DMSO (21.98% vs. 12.49% proliferation, p< 0.05). Daily treatment with ibrutinib effectively inhibited the in vitro generation of human MDSC from monocytes by promoting HLA DR expression (p< 0.05). Using the EMT6 mammary carcinoma model in vivo, ibrutinib treatment resulted in a significant reduction of MDSC in both the spleen and tumor (p< 0.05). Ibrutinib also reduced the frequency of splenic MDSC in wild type B16F10 tumor bearing mice, but not in BTK mutant XID mice. In addition, both murine and human MDSC did not express significant levels of alternative ibrutinib targets including ITK, Bmx, and Blk. These results suggest that inhibition of BTK is the primary driver behind the observed effects of ibrutinib on MDSC function and generation. Finally, the combination of ibrutinib and anti PDL1 therapy was significantly more effective than either agent alone (p< 0.01 and p< 0.05) producing complete tumor regression in 50% of EMT6 tumor being mice. The results support further investigation of ibrutinib in combination with immune based therapies for solid tumors. Citation Format: Andrew R. Stiff, Prashant Trikha, Robert Wesolowski, Kari Kendra, Sarvani Uppati, David Abood, Elizabeth McMichael, Megan Duggan, Amanda Campbell, Natarajan Muthusamy, Susheela Tridandapani, Michael Caliguiri, John C. Byrd, William E. Carson. Ibrutinib, a BTK inhibitor, impairs the generation and function of myeloid derived suppressor cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 553.

Background: Heat shock protein 90 (HSP90) is a molecular chaperone that is required for proper folding and stabilization of proteins. Client proteins of HSP90 include many mediators of signal transduction known to be over-activated in triple negative breast cancer such as AKT, EGFR, members of RAS/MAPK signaling pathways and androgen receptor. Expression of HSP90 has been found to be upregulated in multiple triple negative breast cancer cell lines and associated with poor outcome of breast cancer patients. In addition, over-expression of HSP90 client proteins such as AKT and c-RAF has been implicated in paclitaxel resistance. Onalespib (AT13387) is a synthetic non-ansamycin small molecule that acts as an inhibitor of HSP90 by binding to the amino terminal of the protein and has dissociation constant (Kd) of 0.71 nM. Materials and Methods: Patients with inoperable or metastatic triple negative or weakly hormone receptor positive breast cancer are treated with onalespib and paclitaxel on days 1, 8, 15 every 28 days. Paclitaxel is given at a standard dose of 80 mg/m2 while the dose of onalespib is gradually increased using standard 3+3 design (see table). In order to assess the effect of each drug on pharmacokinetics of the other drug, onalespib is given on day -7 prior to cycle 1 and skipped on day 1 of cycle 1 during which paclitaxel in administered alone. The primary objective of the study is to determine recommended phase 2 dose and assess the toxicity profile of the combination. The secondary objectives include effect of onalespib on pharmacokinetics of paclitaxel and effect of paclitaxel on pharmacokinetics of onalespib. Overall response rate, response duration and progression-free survival will also be assessed. Dose Escalation ScheduleDose LevelDoseOnalespib (mg/m2 IV on days 1, 8, 15)Paclitaxel (mg/m2 IV on days 1, 8, 15)Level -110080Level 112080Level 215080Level 320080Level 426080 Conclusion: The study opened to accrual on January 15, 2016 and is currently enrolling the first 3 patients to dose level 1. Citation Format: Robert Wesolowski, Maryam B. Lustberg, Ewa Mrozek, Rachel Layman, Raquel Reinbolt, Ming Poi, Nadia Osman, Andrea Lively, Julie Stephens, Michael Grever, Bhuvaneswari Ramaswamy. Phase 1b study of heat shock protein 90 inhibitor onalespib in combination with paclitaxel in patients with advanced, triple-negative breast cancer (NCT02474173). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT033.

Background: ATR is a regulator of the cellular response to replication stress, where it signals DNA damage repair through the homologous recombination pathway. Many cancer cells depend on ATR to survive DNA damage. VX-970 is a potent, selective inhibitor of ATR with marked preclinical anticancer activity in combination with DNA-damaging chemotherapy in preclinical models. Methods: Pts received intravenous VX-970 in combination with Cis using a 3+3 dose escalation design. Cis was administered on day 1 and VX-970 on days 2 and 9 in 21-day cycles. Results: 28 pts were treated (12 M/16 F); median age 62.5 yrs (range 28-79 yrs) and ECOG PS 0-1. Primary tumors were colorectal (n = 5), breast (n = 4), ovarian (n = 3), pancreatic (n = 2), and other cancers (n = 14). CohortVX-970 dose (mg/m2)Cis dose (mg/m2)No. pts treated/No. pts evaluable for dose limiting toxicities (DLTs)DLTs190403/32140404/33210404/442106010/101 (grade 3 elevated ALT)5140757/61 (grade 3 drug hypersensitivity) Non-DLT grade 3-4 treatment-related adverse events occurred in 11 pts, including nausea, cytopenias, hypotension, hypoalbuminemia, hypokalemia, elevated LFTs, and drug hypersensitivity. Maximum tolerated combination dose was not reached; dose escalation was stopped because pharmacokinetic (PK) exposures of VX-970 at 140 mg/m2 exceeded levels previously shown in preclinical models to result in robust target engagement and tumor regression in combination with Cis. There was no effect of Cis on VX-970 PK. Terminal elimination half-life was ?16h and PK was proportional across the dose range. Among pts who received VX-970 at 140 mg/m2 with Cis, preliminary results showed RECIST partial responses in 4 pts: 3 platinum-resistant/refractory (mesothelioma, ovarian and TNBC) and 1 ongoing unconfirmed response in a pt in which platinum sensitivity is currently unknown (neuroendocrine prostate cancer). Conclusions: The recommended phase 2 dose is VX-970 140 mg/m2 and Cis 75 mg/m2 with RECIST antitumor responses observed including platinum-refractory/resistant pts. Combination studies involving pts with biomarker-defined NSCLC (gemcitabine) and TNBC (platinum) are ongoing. Citation Format: Geoffrey Shapiro, Robert Wesolowski, Mark Middleton, Craig Devoe, Anastasia Constantinidou, Dionysis Papadatos-Pastos, Marjorie Fricano, Yanqiong Zhang, Sharon Karan, John Pollard, Marina Penney, Mohammed Asmal, F. Gary Renshaw, Scott Z. Fields, Timothy A. Yap. Phase 1 trial of first-in-class ATR inhibitor VX-970 in combination with cisplatin (Cis) in patients (pts) with advanced solid tumors (NCT02157792). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT012.

11578Background: Foundation Medicine Incorporated (FMI) uses comprehensive genomic profiling (CGP) to identify oncogenic drivers that suggest benefit from molecularly targeted therapies. We conduct...

e12552Background: Metaplastic breast cancer (MBC) is a histologically diverse sub-type of invasive breast cancer accounting for less than 1% of all breast cancers. MBC are often triple negative (TN...

10098Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting toxicity of several commonly used chemotherapy drugs including taxanes, vinca alkaloids, and platinum compounds...

Epithelial breast malignancies are a group of several disease entities that vary in their biology and response to specific therapies. Historically, classification of different molecular types of breast cancer was done through the use of conventional methods such as tumor morphology, grade, and immunophenotyping for estrogen, progesterone, and HER-2/neu receptor expression. Such techniques, although helpful, are not sufficient to accurately predict biologic behavior of breast cancers. Over the last several years, much progress has been made in more precise identification of molecular breast cancer subtypes. Such advances hold a great promise in improving estimation of prognosis and assigning most appropriate therapies. Thanks to use of cDNA microarrays expression technology and quantitative reverse transcriptase polymerase chain reaction (RT-PCR), tumors with specific gene expression patterns can now be identified. This process is presently reshaping perceptions of how breast cancer should be classified and treated. Categorization of breast cancers by gene expression is only beginning to make its way into the daily clinical practice and likely will complement, but not replace, the conventional methods of classification.

94 Background: Weight gain concerns breast cancer patients, can impact quality of life, may lead to therapy non-adherence, and is associated with increased recurrence risk and mortality. Early placebo-controlled trials did not identify a clear correlation between Tamoxifen (TAM) and weight gain; gain due to aromatase inhibitors (AIs) is not well characterized. We hypothesized that weight gain occurs more frequently than previously reported in breast cancer patients receiving endocrine therapy. Methods: This is a retrospective chart review investigating body mass index (BMI) change in women after breast cancer therapy. Patients with early stage breast cancer and whom had BMI and treatment data (at least 90 days) from 2003-2012 were identified in The Columbus Breast Cancer Tissue Bank. Patients were separated by treatment received: chemotherapy with and without endocrine therapy vs. endocrine therapy alone (including both TAM and AIs) vs. no other treatment. Results: A total of 970 subjects were included in the analysis. At diagnosis and/or treatment initiation, patients’ mean BMI was 29.2 ± 7.0 kg/m2; mean age 53.7± 11.6 years; and average length of therapy/follow up per patient, 1833 days (range 90-3,990). Patients who received an AI alone had significantly decreased BMIs during therapy (-0.65± 0.29 kg/m2, p = 0.025), whereas patients receiving chemotherapy alone, chemotherapy with TAM, or TAM followed by AI therapy, had significantly increased BMIs (0.51 ± 0.25, 0.73 ± 0.26, 1.01 ± 0.51 kg/m2; p = 0.039, 0.005, 0.045, respectively). Both older age and a higher BMI at diagnosis were associated with a significantly greater decline in BMI over treatment time (p < 0.001 and p < 0.001, respectively). In a multivariate regression model, after adjusting for age and initial BMI effect, the BMI change noted among different treatment groups was no longer significantly different (p = 0.43). BMI change was not statistically associated with treatment length (p = 0.26). Conclusions: Our review of a large, early stage breast cancer patient cohort showed no association between weight gain and endocrine therapy after adjusting for the effect of initial BMI and age at diagnosis. Additional study is needed to identify other factors impacting weight in this population.

Background: Women with locally advanced breast cancer (LABC) are often treated with neo-adjuvant chemotherapy to reduce the size of the tumor prior to surgery, to enable breast conserving surgery and to observe the clinical effect of therapy in real time. Studies have shown that the 25–27% of individuals who have a pathologic complete response (pCR) to neoadjuvant therapy have a survival advantage of 80% in 5 years, which is double the expected survival of the remaining patients without pCR. If patients who are likely to show a pCR could be identified prior to initiation of therapy, it would enable more informed treatment decisions – patients likely to respond would be served well by current neoadjuvant chemotherapy protocols, while those unlikely to respond may be better suited to innovative new strategies for drug discovery [von Minckwitz et al. JCO 2006]. Genomic assays, which are widely used to provide prognostic and predictive information in early breast cancer, have the potential to provide information on the likelihood of a patient with LABC responding to neo-adjuvant therapy [Glück et al. BRCRT2013]. Trial design: MINT I is a prospective study designed to test the ability of molecular profiling, as well as traditional pathologic and clinical prognostic factors, to predict response to neo-adjuvant chemotherapy in patients with LABC. MammaPrint risk profile, BluePrint molecular subtyping profile, TargetPrint estrogen receptor (ER), progesterone receptor (PR) and HER2 single gene readout, and TheraPrint Research Gene Panel will be analyzed on a fresh tumor specimen using the whole genome array. Patients will receive neo-adjuvant chemotherapy pre-specified in the protocol. Response will be measured centrally. pCR is defined as the absence of invasive carcinoma in both the breast and axilla at microscopic examination of the resection specimen, regardless of the presence of carcinoma in situ. Eligibility: The study will include women ≥18 years with histologically-proven invasive breast cancer T2 (≥3.5cm)-T4, N0M0 or T2-T4N1M0, adequate bone marrow reserves and normal renal and hepatic function who signed an IRB approved informed consent. Objectives: The objectives of the study are to: 1. Determine the predictive power of MammaPrint and BluePrint for sensitivity to neo-adjuvant chemotherapy as measured by pCR. 2. Compare TargetPrint ER, PR and HER2 with local and centralized IHC and/or CISH/FISH assessment. 3. Identify correlations between TheraPrint and response to neo-adjuvant chemotherapy. 4. Identify and/or validate predictive gene expression profiles of clinical response or resistance to neo-adjuvant chemotherapy. 5. Compare BluePrint with IHC-based subtype classification. Statistical methods: Standard statistical tests such as the Pearson Chi-square test will be used to characterize and evaluate the relationship between chemoresponsiveness and gene expression patterns. Accrual: A total of 226 eligible patients will be enrolled from multiple institutions. To date (June 06, 2014), 103 patients have been enrolled. Citation Format: Charles E Cox, Peter Blumencranz, Ruben Saez, Robert Wesolowski, William Dooley, Lisette Stork-Sloots, Femke de Snoo, Sarah Untch, Eli Avisar. MINT I: Multi-Institutional Neo-adjuvant Therapy, MammaPrint Project I [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT3-2-02.

Background: Women with locally advanced breast cancer (LABC) are often treated with neo-adjuvant chemotherapy to reduce the size of the tumor prior to surgery, to enable breast conserving surgery and to observe the clinical effect of therapy in real time. Studies have shown that the 25–27% of individuals who have a pathologic complete response (pCR) to neoadjuvant therapy have a survival advantage of 80% in 5 years, which is double the expected survival of the remaining patients without pCR. If patients who are likely to show a pCR could be identified prior to initiation of therapy, it would enable more informed treatment decisions – patients likely to respond would be served well by current neoadjuvant chemotherapy protocols, while those unlikely to respond may be better suited to innovative new strategies for drug discovery [von Minckwitz et al. JCO 2006]. Genomic assays, which are widely used to provide prognostic and predictive information in early breast cancer, have the potential to provide information on the likelihood of a patient with LABC responding to neo-adjuvant therapy [Glück et al. ASCO 2012]. Trial design: MINT I is a prospective study designed to test the ability of molecular profiling, as well as traditional pathologic and clinical prognostic factors, to predict response to neo-adjuvant chemotherapy in patients with LABC. MammaPrint risk profile, BluePrint molecular subtyping profile, TargetPrint estrogen receptor (ER), progesterone receptor (PR) and HER2 single gene readout, and TheraPrint Research Gene Panel will be analyzed on a fresh tumor specimen using the whole genome array. Patients will receive neo-adjuvant chemotherapy pre-specified in the protocol. Response will be measured centrally. pCR is defined as the absence of invasive carcinoma in both the breast and axilla at microscopic examination of the resection specimen, regardless of the presence of carcinoma in situ. Eligibility: The study will include women ≥18 years with histologically-proven invasive breast cancer T2 (≥3.5cm)-T4, N0M0 or T2-T4N1M0, adequate bone marrow reserves and normal renal and hepatic function who signed an IRB approved informed consent. Objectives: The objectives of the study are to: 1. Determine the predictive power of MammaPrint and BluePrint for sensitivity to neo-adjuvant chemotherapy as measured by pCR. 2. Compare TargetPrint ER, PR and HER2 with local and centralized IHC and/or CISH/FISH assessment. 3. Identify correlations between TheraPrint and response to neo-adjuvant chemotherapy. 4. Identify and/or validate predictive gene expression profiles of clinical response or resistance to neo-adjuvant chemotherapy. 5. Compare BluePrint with IHC-based subtype classification. Statistical methods: Standard statistical tests such as the Pearson Chi-square test will be used to characterize and evaluate the relationship between chemoresponsiveness and gene expression patterns. Accrual: A total of 226 eligible patients will be enrolled from multiple institutions. To date (June 06, 2013), 57 patients have been enrolled. Clinical trial registry number: NCT01501487. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT1-2-01.

Aim: CSF1R kinase regulates the recruitment of macrophages to tumors and osteoclast differentiation leading to bone lysis. PLX3397 (PLX), a small molecule CSF1R inhibitor, blocked paclitaxel (TAX) -induced macrophage infiltration in mouse tumor models, resulting in slower tumor growth and reduction of metastases. We conducted a phase Ib study of PLX combined with TAX in patients (pts) with advanced solid tumors. Methods: This trial has 2 parts: to explore safety of escalating doses of PLX with weekly 80 mg/m2 TAX to find a recommended Phase 2 dose (RP2D) of PLX, and to determine efficacy and safety of PLX dosed orally twice daily at the RP2D combined with weekly TAX. PLX dose started at 600 mg/day, escalating in increments of ≤ 50% using a standard 3 + 3 design. Endpoints also include pharmacokinetics (PK) and correlation of PLX biomarkers with clinical activity. Results: 36 pts received study drugs and 35 pts reported treatment-emergent adverse events (AEs) including anemia, fatigue, decreased appetite, diarrhea, nausea, AST increase, and alopecia. Grade 3-4 AEs were recorded in 28 (anemia, lymphopenia, hypertension, neutropenia), none clearly related to PLX. Treatment was discontinued in 3 (8%) pts due to AEs. No dose limiting toxicity (DLT) emerged after allowing growth factors for neutropenia. 15 pts have enrolled at the PLX RP2D of 1600 mg/day. Of 23 efficacy evaluable pts (600 mg - 1600 mg), 4 had PR (2 breast,1 squamous cell, 1 bladder cancer), 10 had SD, 9 had PD. Neither PLX or TAX affected PK of the other drug. Two biomarkers were evaluated: in all pts plasma CSF-1 levels increased (range: 1.6 to 53-fold) and CD14dim/CD16+ monocyte levels decreased (57% to 100%), indicating blockade of CSF1R signaling. Conclusions: Combining PLX with TAX was generally well-tolerated. No DLT was observed and RP2D for PLX was 1600mg/day. Biomarkers suggest that PLX blocked CSF1R signaling, predicting a strong impact on the macrophage tumor microenvironment. Enrollment at the R2PD is ongoing, with plans to combine PLX and TAX in the I-SPY2 adaptive neoadjuvant trial to assess efficacy in biologic subsets of breast cancer. Disclosure: H.S. Rugo, N. Sharma and R. Wesolowski: I have research funding from Plexxikon Inc.; B.L. West, A. Marimuthu and D.A. Karlin: I am an employee of Plexxikon Inc.; L.M. Coussens: I have research funding from the Komen Foundation. All other authors have declared no conflicts of interest.

TPS1137 Background: Women with locally advanced breast cancer (LABC) are often treated with neo-adjuvant chemotherapy to reduce the size of the tumor prior to surgery, to enable breast conserving s...

1074 Background: Poly(ADP-ribose) polymerase (PARPi) inhibitors have shown activity in BRCA mutant and triple negative breast cancers (TNBC). The ideal dose and schedule of C and oral PARPi V is no...

Introduction Circulating tumor cells (CTCs) are commonly isolated from the blood by targeting the epithelial cell adhesion molecule (EpCAM) through positive selection. However, EpCAM can be downregulated during metastatic progression, or it can be initially not present. We designed the present prospective trial to characterize CTCs as well as other circulating cell populations in blood samples from women with metastatic breast cancer without EpCAM-dependent enrichment and/or isolation technology. Methods A total of 32 patients with metastatic breast cancer were enrolled, and blood samples were processed using a previously described negative depletion immunomagnetic methodology. Samples from healthy volunteers were run as controls (n = 5). Multistep sequential labeling was performed to label and fix cell-surface markers followed by permeabilization for cytokeratins (CK) 8, 18 and 19. Multiparametric flow cytometry (FCM) analysis was conducted using a BD LSR II flow cytometer or a BD FACSAria II or FACSAria III cell sorter. Immunocytochemical staining on postenrichment specimens for DAPI, EpCAM, CD45, CK, epidermal growth factor receptor and vimentin was performed. Expression of these markers was visualized using confocal microscopy (CM). Results CD45-negative/CK-positive (CD45− CK+) populations with EpCAM + and EpCAM − expression were identified with both FCM and CM from the negatively enriched patient samples. In addition, EpCAM + and EpCAM − populations that were CK + and coexpressing the pan-hematopoietic marker CD45 were also noted. There were more CK + EpCAM − events/ml than CK + EpCAM + events/ml in both the CD45− and CD45+ fractions (both statistically significant at P ≤ 0.0005). The number of CK + CD45− and CK + CD45+ events per milliliter in blood samples (regardless of EpCAM status) was higher in patient samples than in normal control samples (P ≤ 0.0005 and P ≤ 0.026, respectively). Further, a significant fraction of the CK + CD45+ events also expressed CD68, a marker associated with tumor-associated macrophages. Higher levels of CD45-CK + EpCAM − were associated with worse overall survival (P = 0.0292). Conclusions Metastatic breast cancer patients have atypical cells that are CK + EpCAM − circulating in their blood. Because a substantial number of these patients do not have EpCAM + CTCs, additional studies are needed to evaluate the role of EpCAM − circulating cells as a prognostic and predictive marker.

Meeting abstracts Patients (pts) with breast cancer (BC) who achieve complete pathologic response (pCR) to neo-adjuvant chemotherapy (NAC) have better survival than pts without pCR. It is hypothesized that circulating levels of MDSC may be a potential predictive biomarker for NAC. Pts with