Alexander Petrovsky

Oligomerization of Paramagnetic Substrates Result in Signal Amplification and can be Used for MR Imaging of Molecular Targets

Magnetic resonance imaging (MRI) has evolved into a sophisticated, noninvasive imaging modality capable of high-resolution anatomical and functional characterization of transgenic animals. To expan...

Optical Imaging of Apoptosis as a Biomarker of Tumor Response to Chemotherapy

A rapid and accurate assessment of the antitumor efficacy of new therapeutic drugs could speed up drug discovery and improve clinical decision making. Based on the hypothesis that most effective antitumor agents induce apoptosis, we developed a near-infrared fluorescent (NIRF) annexin V to be used for optical sensing of tumor environments. To demonstrate probe specificity, we developed both an active (i.e., apoptosis-recognizing) and an inactive form of annexin V with very similar properties (to account for nonspecific tumor accumulation), and tested the agents in nude mice each bearing a cyclophosphamide (CPA) chemosensitive (LLC) and a chemoresistant LLC (CR-LLC). After injection with active annexin V, the tumor-annexin V ratio (TAR; tumor NIRF/background NIRF) for untreated mice was 1.22+/-0.34 for LLC and 1.43+/-0.53 for CR-LLC (n=4). The LLC of CPA-treated mice had significant elevations of TAR (2.56+/-0.29, P=.001, n=4), but only a moderate increase was obtained for the CR-LLC (TAR=1.89+/-0.19, P=.183). The in vivo measurements correlated well with terminal deoxyribosyl transferase-mediated dUTP nick end labeling indexes. When inactive Cy-annexin V was used, with or without CPA treatment and in both CCL and CR-CCL tumors, tumor NIRF values ranged from 0.91 to 1.17 (i.e., tumor were equal to background). We conclude that active Cy-annexin V and surface reflectance fluorescence imaging provide a nonradioactive, semiquantitative method of determining chemosensitivity in LLC xenografts. The method maybe used to image pharmacologic responses in other animal models and, potentially, may permit the clinical imaging of apoptosis with noninvasive or minimally invasive instrumentation.

Detection of Early Antiangiogenic Effects in Human Colon Adenocarcinoma Xenografts: In vivo Changes of Tumor Blood Volume in Response to Experimental VEGFR Tyrosine Kinase Inhibitor

Antiangiogenesis is emerging as efficient strategy for targeting and potentially eliminating neoplastic tumor vessels. The main goal of this study was to establish whether absolute tumor blood volume (V(b)) change could be used as an early predictor of antiangiogenesis in ectopic and orthotopic colon carcinomas. To assess therapy-induced changes of V(b), we did comparative analysis of signal intensities in tumors and muscle using steady-state magnetic resonance imaging (MRI) assisted with an intravascular paramagnetic contrast agent [gadolinium-labeled protected graft copolymer (PGC-Gd)]. Athymic mice with implanted human MV522 tumors were treated with vascular endothelial growth factor type 2 receptor tyrosine kinase inhibitor (VEGFR2-TKI) that has been shown to inhibit VEGFR2 phosphorylation and tumor growth in vivo. Animals were imaged either after a single day or after a 1-week course of treatments. The measured V(b) in ectopic tumors was 2.5 +/- 1.5% of total tissue volume 1 week after the implantation (n = 8). Two doses of VEGFR2-TKI (25 mg/kg, p.o., b.i.d.) resulted in a decrease of V(b) to 1.3 +/- 0.3%. In orthotopic tumors, the measured V(b) was initially higher (11.9 +/- 2.0%); however, VEGFR2-TKI treatment also resulted in a statistically significant decrease of V(b). The absolute V(b) was not affected in the muscle as a result of treatments. MRI measurements were corroborated by using isotope and correlative histology experiments. Our results show that steady-state MRI is highly sensitive to early antiangiogenic effects caused by small molecule drugs.

Abstract P6-08-06: The multidisciplinary application of genomics in clinical practice (MAGIC) survey: Identification of early stage hormone receptor-positive (HR+), HER2– breast cancer (BC) patients for whom multigene assays may be valuable

Background Treatment recommendations for early stage HR+, HER2– BC patients depend on many factors. The MAGIC survey evaluated which criteria clinicians use regarding the need for adjuvant chemotherapy (AdjCT) and showed that there was substantial heterogeneity across clinicians and countries in treatment decisions (Aapro et al, EBCC 2014, abstract 24). Multigene assays (MGA) help to make more-informed decisions by providing prognostic and predictive information beyond traditional parameters, but are not always needed. The data presented here show for which BC patient profiles there is a high heterogeneity in treatment recommendations. We suggest that MGAs may be useful to guide treatment recommendations in these cases. Methods From August 2013 until January 2014, physicians with ≥5 years’ experience in BC treatment and participating in multidisciplinary teams were invited for the online MAGIC survey. The survey evaluated respondent characteristics and registered treatment recommendations for randomly generated early BC patient profiles (n=672). A conjoint analysis was used to assess which patient attributes were considered for treatment decisions. Results The survey was completed by 911 physicians from 52 countries, of whom 72% had >10 years’ experience. Their treatment recommendations showed that for BC patient profiles with only high-risk or only low-risk characteristics, there was a high consensus to recommend AdjCT or no AdjCT (endocrine treatment alone); 42% of the profiles had >75% probability of being recommended AdjCT and 6% had >75% chance of being recommended no AdjCT. If interactions between patient characteristics were not considered, age was ranked as the most important patient characteristic for AdjCT decisions, followed by tumor grade, tumor size, nodal status, and expression of Ki67, estrogen receptor (ER), and progesterone receptor. The combination of patient attributes and their interactions were, as expected, of importance; some node-positive patients or patients with a Grade 3 tumor had >75% probability to be recommended no AdjCT (eg, older patients or patients with a small [ 75% probability to be recommended AdjCT (eg, young or node-positive patients). In total, 104 patient profiles (15%) were identified for which treatment recommendations were highly heterogeneous, with a probability of 50 years old, tumor size Conclusions There was substantial heterogeneity in treatment recommendations and an overall tendency to give chemo-endocrine rather than endocrine treatment alone. The highest uncertainty in treatment decisions was seen in patients with intermediate risk by clinical and pathological parameters. This opens questions concerning treatment decisions and in such cases MGAs may be most useful. Citation Format: Matti Aapro, Juan Enrique Bargallo Rocha, Michele De Laurentiis, Roberto Elizalde, Laszlo Landherr, Barbro Linderholm, Terry Mamounas, Christos Markopoulos, Miguel Martin, Patrick Neven, Alexander Petrovsky, Dan Rea, Roman Rouzier, Vincent Smit, Christer Svedman, Christoph Thomssen. The multidisciplinary application of genomics in clinical practice (MAGIC) survey: Identification of early stage hormone receptor-positive (HR+), HER2– breast cancer (BC) patients for whom multigene assays may be valuable [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 P6-08-06.

261PDTHE EFFECT OF PHYSICIAN'S CHARACTERISTICS ON ADJUVANT CHEMOTHERAPY (CT) DECISIONS FOR EARLY STAGE HR + , HER2– BREAST CANCER (BC) PATIENTS (PTS)

ABSTRACT Aim: For early stage HR + , HER2– BC pts with intermediate risk by clinical/pathologic criteria, treatment decisions should be based on sensitivity to endocrine therapy, risk of recurrence, and predicted benefit from CT. The ESMO guidelines highlight that multigene assays (MGA) may be used in these cases (Ann Oncol. 2013;suppl6:vi7-23). The MAGIC survey evaluated criteria considered for CT decisions and simulated CT recommendations for pts with different characteristics. We present CT recommendations for intermediate-risk BC pts based on characteristics of respondents. Methods: The online survey was completed by physicians working in multidisciplinary BC teams, having ≥5 year experience. A conjoint analysis was used to model CT recommendations for simulated pts. Results: Overall recommendations (n = 911, 52 countries) showed that BC pt profiles associated with a request for more information tended to have an intermediate/high age (>50 yr), intermediate/small tumor size, grade 1/2, low ER/intermediate Ki67 expression, and node-negative status. The table summarizes CT recommendations for 4 selected intermediate-risk BC pts. On average, CT was recommended for the 4 pt profiles by 29%, 42%, 31%, and 44% of responders. CT recommendation varied greatly among different countries for each pt profile. Physicians who always use international guidelines tended to prescribe CT more often, while those who use MGA, as expected, recommended CT less frequently for each pt profile. More-experienced physicians (ie, those who prescribe CT personally or who treat >200 pts/year) showed a slight trend to fewer CT recommendations. Conclusions: There is high variation in CT recommendations for intermediate-risk BC pts, primarily according to country of residence. There is a need for more broadly available tools, such as MGA, to help make more-informed treatment decisions in this pt population. Table: 261PD . Selected MAGIC survey respondent groups recommending CT for selected patient profiles Patient profile 1 ( age 35–50 , tumor size 1–2 cm, tumor grade 2, high ER, high PR , 14%–20% Ki67, node negative) Patient profile 2 ( age 35–50 , tumor size 1–2 cm, tumor grade 2, high ER, low PR , 14%–20% Ki67, node negative) Patient profile 3 ( age 51–70 , tumor size 2.1–3 cm, tumor grade 2, high ER, high PR , 14%–20% Ki67, node negative) Patient profile 4 ( age 51–70 , tumor size 2.1–3 cm, tumor grade 2, high ER, low PR , 14%–20% Ki67, node negative) All physicians (excluding pathologists, n = 877) 29% 42% 31% 44% All physicians – range between countries with >30 respondents 15%–41% 33%–50% 14%–48% 28%–56% Physicians personally prescribing CT (n = 610)/not prescribing CT (n = 267) 27%/31% 42%/44% 30%/34% 43%/46% Physicians treating 1–50 pts per year (n = 310)/ > 200 pts per year (n = 86) 32%/26% 45%/38% 36%/26% 49%/38% Physicians always (n = 482)/often (n = 377) using international guidelines 31%/25% 45%/39% 34%/27% 47%/40% Physicians using (n = 487)/not using (n = 390) MGA 26%/31% 39%/46% 29%/34% 41%/48% Medical oncologist (n = 485)/surgeons or gynecologists (n = 324)/radiation oncologists (n = 38) 27%/30%/32% 42%/42%/46% 30%/32%/33% 45%/44%/46% Physicians working in an academic hospital (n = 540)/community-based or private hospital (n = 240)/office-based or private practice (n = 77) 29%/27%/34% 42%/43%/45% 31%/31%/36% 43%/47%/47% ER, estrogen receptor; PR, progesterone receptor Disclosure: M. De Laurentiis: Advisory board: Genomic Health; M. Aapro: Advisory board: Genomic Health Corporate-sponsored research: Genomic Health; C. Markopoulos: Other substantive relationships: Genomic Health – Speakers Honoraria; T. Mamounas: Advisory board: Genomic Health Inc. Other substantive relationships: Speakers Bureau: Genomic Health Inc.; R. Rouzier: Advisory board: consultant for Genomic Health; C. Thomssen: Advisory board: Genomic Health Other substantive relationships: Speaker for Genomic Health; D. Rea: Advisory board: Genomic Health; B. Linderholm: Board of directors: Steering Committee for the BIG/EORTC/NABCG Male breast cancer project; V. Smit: Advisory board: Genomic Health Inc.; C. Svedman: Other substantive relationships: I am an employee of Genomic Health working in the medical department.All other authors have declared no conflicts of interest.