Pollak, Michaël

3035 Background: Energy balance-associated biomarkers such as insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) have been associated with risk and prognosis of various malignancies. Their relationship to disease progression and mortality in metastatic colorectal cancer (mCRC) requires further study. Methods: In a prospective cohort study, baseline plasma IGFBP-3, IGFBP-7, C-peptide, IGF-I, and adiponectin were measured at trial registration among 1,086 patients participating in a National Cancer Institute-sponsored clinical trial of first-line therapy for mCRC. We used Cox proportional hazards regression to adjust for confounders and examine associations of biomarkers with overall (OS) and progression-free survival (PFS). Results: Higher plasma IGFBP-3 was associated with longer OS (adjusted Ptrend < .001) and PFS (adjusted Ptrend = .003). Compared to patients in the lowest IGFBP-3 quintile, patients in the highest quintile experienced an adjusted HR for all-cause mortality of 0.58 (95% CI 0.42 to 0.78) and for disease progression or mortality of 0.60 (95% CI 0.45 to 0.82). Higher plasma IGFBP-7 was associated with shorter OS (adjusted Ptrend < .001) and PFS (adjusted Ptrend = .02). Compared to patients in the lowest IGFBP-7 quintile, patients in the highest quintile experienced an adjusted HR for all-cause mortality of 1.52 (95% CI 1.24 to 1.88) and for disease progression or mortality of 1.28 (95% CI 1.05 to 1.57). C-peptide and IGF-I were not significantly associated with patient outcomes (adjusted Ptrend = .73 and .30 for OS). Adiponectin was not associated with OS; there was a U shaped association between adiponectin and PFS, wherein low and high values were associated with shorter PFS ( Pnon-linear trend = .03). Conclusions: In patients with mCRC, high plasma IGFBP-3 and low IGFBP-7 were associated with reduced risk of disease progression and mortality. These data suggest that energy-balance associated biomarkers may offer prognostic and biologic insights into mCRC. Support: U10CA180821, U10CA180882, BMS, Genentech, Pfizer, Sanofi; https://acknowledgments.alliancefound.org .

Abstract Background: Insulin-like growth factor (IGF)-I and IGF binding protein (IGFBP)-3 play important roles in carcinogenesis, particularly for breast cancer. However, little is known about whether the IGF system influences histologic characteristics of normal glandular tissue and whether relationships vary by race. Lesser degrees of age-related terminal duct lobular unit (TDLU) involution, as reflected by higher numbers of TDLUs and acini per TDLU, have been associated with higher breast cancer risk. We examined the associations of IGF measures with TDLU involution of normal breast using standardized TDLU measures. Methods: Among 715 Caucasian and 283 African American (AA) women with normal breast tissue samples from the Komen Tissue Bank, serum concentrations of IGF-I and IGFBP-3 were quantified using enzyme-linked immunosorbent assay (ELISA). Hematoxilyn and eosin-stained tissue sections were assessed for numbers of TDLUs (“TDLU count”) and acini/TDLU. Zero-inflated Poisson regression models with a robust variance estimator were used to estimate associations of IGF-I, IGFBP-3, and IGF-I:IGFBP-3 molar ratio (tertiles) with TDLU count by race and menopausal status, adjusting for potential confounders. We also tested for interactions by race using likelihood ratio tests. Results: AA (vs. Caucasian) women had higher age-adjusted mean levels of serum IGF-I (137 vs. 131 ng/mL, p=0.07) and lower levels of IGFBP-3 (4165 vs. 4684 ng/mL, p&lt;0.0001); the differences persisted after adjustment for additional covariates including BMI and parity/age at first birth. Postmenopausal IGFBP-3 was inversely associated with TDLU count among both AA (RR T3vs.T1=0.49, 95% CI=0.28-0.84, p-trend=0.04) and Caucasian (RR T3vs.T1=0.63, 95% CI=0.41-0.99, p-trend=0.04) women. In premenopausal women, higher IGF-I:IGFBP-3 ratios were associated with higher TDLU count in Caucasians (OR T3vs.T1=1.33, 95% CI=1.01-1.31, p-trend=0.04) but not in AA (OR T3vs.T1=0.65, 95% CI=0.42-1.00, p-trend=0.05) women. There was no statistically significant interaction by race (p-interaction≥0.10). Conclusions: Our data suggest the potential role of the IGF system, particularly IGFBP-3, in TDLU involution of the normal breast among both Caucasian and AA women. Citation Format: Hannah OH, Ruth M. Pfeiffer, Roni T. Falk, Hisani N. Horne, Jackie Xiang, Michael Pollak, Louise A. Brinton, Anna Maria V. Storniolo, Mark E. Sherman, Gretchen L. Gierach, Jonine D. Figueroa. Serum insulin-like growth factor (IGF)-I and IGF binding protein-3 in relation to terminal duct lobular unit involution in Caucasian and African American women: The Susan G. Komen Tissue Bank [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr A36.

3516 Background: Epidemiological data suggest a protective effect of vitamin D on CC risk. However, association of serum vitamin D level with clinical outcome in pts with surgically resected CC remains unknown. We analyzed total circulating 25-hydroxyvitamin D [25(OH)D)] with clinical outcome in pts with resected stage III CC treated with FOLFOX +/- cetuximab in a phase III trial. Methods: Association of pre-treatment level of plasma 25(OH)D with disease-free survival (DFS) and time-to-recurrence (TTR) was analyzed with 25(OH)D as a continuous variable by a relative risk model with splines and as a binary variable (vitamin D deficient [<30 ng/mL]) using multivariable Cox regression. Results: Overall, 49% (291/600) of pts were vitamin D deficient. Prevalence of vitamin D deficiency was significantly higher in women vs men (52% vs. 48%, p=0.030) and in blacks vs whites (74% vs. 45%, p=0.0003). The continuous 25(OH)D level and pt sex were associated by the interaction test (pinteraction=0.044). There were no statistically significant associations with DFS/TTR for either continuous 25(OH)D level (DFS, p=0.22; TTR, p=0.26) nor for vitamin D deficiency (DFS, adjusted hazard ratio [HRadj]=1.01, 95% CI, 0.74-1.38; padj=0.94; TTR, HRadj=1.00; CI, 0.72-1.38; padj=0.99. A comparison of the highest vs lowest tertile showed a significant association between the highest 25(OH)D level and better outcomes in men (DFS, HRadj.=0.18, CI, 0.04-0.76, padj=0.020; TTR, HRadj.=0.12, CI, 0.02-0.64, padj=0.014), but not in women (DFS, pinteraction=0.039; TTR, pinteraction=0.033). Conclusions: Nearly one-half of pts in the clinical trial cohort were vitamin D deficient with lowest 25(OH)D levels found in women and blacks. While vitamin D deficiency was not associated with adverse outcome, high levels of vitamin D in men, but not women, were associated with longer survival. Support: U10CA180821, U10CA180882, U10CA180820, U10CA180863, U10CA180888, U10CA077202, CCSRI 021039. ClinicalTrials.gov Identifier: NCT00079274.

Lesser degrees of terminal duct lobular unit (TDLU) involution, as reflected by higher numbers of TDLUs and acini/TDLU, are associated with elevated breast cancer risk. In rodent models, the insulin‐like growth factor (IGF) system regulates involution of the mammary gland. We examined associations of circulating IGF measures with TDLU involution in normal breast tissues among women without precancerous lesions. Among 715 Caucasian and 283 African American (AA) women who donated normal breast tissue samples to the Komen Tissue Bank between 2009 and 2012 (75% premenopausal), serum concentrations of IGF‐I and binding protein (IGFBP)‐3 were quantified using enzyme‐linked immunosorbent assay. Hematoxilyn and eosin‐stained tissue sections were assessed for numbers of TDLUs (“TDLU count”). Zero‐inflated Poisson regression models with a robust variance estimator were used to estimate relative risks (RRs) for association of IGF measures (tertiles) with TDLU count by race and menopausal status, adjusting for potential confounders. AA (vs. Caucasian) women had higher age‐adjusted mean levels of serum IGF‐I (137 vs. 131 ng/mL, p = 0.07) and lower levels of IGFBP‐3 (4165 vs. 4684 ng/mL, p < 0.0001). Postmenopausal IGFBP‐3 was inversely associated with TDLU count among AA (RRT3vs.T1 = 0.49, 95% CI = 0.28–0.84, p‐trend = 0.04) and Caucasian (RRT3vs.T1=0.64, 95% CI = 0.42–0.98, p‐trend = 0.04) women. In premenopausal women, higher IGF‐I:IGFBP‐3 ratios were associated with higher TDLU count in Caucasian (RRT3vs.T1=1.33, 95% CI = 1.02–1.75, p‐trend = 0.04), but not in AA (RRT3vs.T1=0.65, 95% CI = 0.42–1.00, p‐trend = 0.05), women. Our data suggest a role of the IGF system, particularly IGFBP‐3, in TDLU involution of the normal breast, a breast cancer risk factor, among Caucasian and AA women.

Purpose Previous studies have suggested that higher plasma 25-hydroxyvitamin D3 [25(OH)D] levels are associated with decreased colorectal cancer risk and improved survival, but the prevalence of vitamin D deficiency in advanced colorectal cancer and its influence on outcomes are unknown. Patients and Methods We prospectively measured plasma 25(OH)D levels in 515 patients with stage IV colorectal cancer participating in a randomized trial of chemotherapy. Vitamin D deficiency was defined as 25(OH)D lower than 20 ng/mL, insufficiency as 20 to 29 ng/mL, and sufficiency as ≥ 30 ng/mL. We examined the association between baseline 25(OH)D level and selected patient characteristics. Cox proportional hazards models were used to calculate hazard ratios (HR) for death, disease progression, and tumor response, adjusted for prognostic factors. Results Among 515 eligible patients, 50% of the study population was vitamin D deficient, and 82% were vitamin D insufficient. Plasma 25(OH)D levels were lower in black patients compared to white patients and patients of other race (median, 10.7 v 21.1 v 19.3 ng/mL, respectively; P < .001), and females compared to males (median, 18.3 v 21.7 ng/mL, respectively; P = .0005). Baseline plasma 25(OH)D levels were not associated with patient outcome, although given the distribution of plasma levels in this cohort, statistical power for survival analyses were limited. Conclusion Vitamin D deficiency is highly prevalent among patients with stage IV colorectal cancer receiving first-line chemotherapy, particularly in black and female patients.

Abstract Purpose: Insulin-like growth factor (IGF)-I and IGF-II stimulate neoplastic cell growth and inhibit apoptosis, whereas IGF-binding protein-3 (IGFBP-3) inhibits the bioavailability of IGF-I and has independent proapoptotic activity. We examined the influence of baseline plasma levels of IGF-I, IGF-II, IGFBP-3, and C-peptide on outcome among patients receiving first-line chemotherapy for metastatic colorectal cancer. Experimental Design: The plasma levels of IGF-I, IGF-II, IGFBP-3, and C-peptide as well as data on prognostic factors and body size were measured at baseline among 527 patients participating in a randomized trial of first-line chemotherapy for metastatic colorectal cancer. Results: Higher baseline plasma IGFBP-3 levels were associated with a significantly greater chemotherapy response rate (P = 0.03) after adjusting for other prognostic factors, whereas neither IGF-I nor IGF-II levels significantly predicted tumor response. Higher levels of IGF-I, IGF-II, and IGFBP-3 were all univariately associated with improved overall survival (P = 0.0001 for all). In a model that mutually adjusted for IGF-I and IGFBP-3, as well as other prognostic factors, increasing baseline-circulating IGFBP-3 was associated with a significantly longer time to tumor progression (P = 0.03), whereas circulating IGF-I was not associated with disease progression (P = 0.95). Levels of C-peptide were not associated with any measure of patient outcome. Conclusion: Among colorectal cancer patients receiving first-line chemotherapy, increasing levels of IGFBP-3, an endogenous antagonist to IGF-I, are associated with an improved objective treatment response and a prolonged time to cancer progression. The IGF pathway may represent an important target for future treatment strategies.

PurposeA phase I first-in-human study was conducted to characterize the safety, tolerability, pharmacokinetic, and pharmacodynamic properties of the anti–insulinlike growth factor 1 receptor (IGF-IR) monoclonal antibody CP-751,871.Patients and MethodsAfter informed consent and screening, 47 patients with multiple myeloma in relapse or refractory phase were enrolled into 11 dose-escalation cohorts of CP-751,871 at doses from 0.025 to 20 mg/kg for 4 weeks. Patients with less than a partial response to CP-751,871 treatment were eligible to receive CP-751,871 in combination with oral dexamethasone at the discretion of the investigator. Treatment with CP-751,871 and rapamycin with or without dexamethasone was also offered to patients enrolled in the 10 and 20 mg/kg cohorts with less than a partial response to initial therapy with single-agent CP-751,871.ResultsNo CP-751,871-related dose-limiting toxicities were identified. Plasma CP-751,871 concentrations increased with dose and concentration-time profiles were consistent with those of antibodies with target-mediated disposition. Importantly, CP-751,871 administration led to a decrease in granulocyte IGF-IR expression and serum insulinlike growth factor 1 accumulation at high doses, suggesting systemic IGF-IR inhibition. Tumor response was assessed according to the European Group for Blood and Marrow Transplantation criteria. Nine responses were reported in 27 patients treated with CP-751,871 in combination with dexamethasone. Of interest, two of the patients with a partial response were progressing from dexamethasone treatment at study entry.ConclusionThese data indicate that CP-751,871 is well tolerated and may constitute a novel agent in the treatment of multiple myeloma.

Abstract Purpose: To detect insulin-like growth factor-IR (IGF-IR) on circulating tumor cells (CTC) as a biomarker in the clinical development of a monoclonal human antibody, CP-751,871, targeting IGF-IR. Experimental Design: An automated sample preparation and analysis system for enumerating CTCs (CellTracks) was adapted for detecting IGF-IR–positive CTCs with a diagnostic antibody targeting a different IGF-IR epitope to CP-751,871. This assay was used in three phase I trials of CP-751,871 as a single agent or with chemotherapy and was validated using cell lines and blood samples from healthy volunteers and patients with metastatic carcinoma. Results: There was no interference between the analytic and therapeutic antibodies. Eighty patients were enrolled on phase I studies of CP-751,871, with 47 (59%) patients having CTCs detected during the study. Before treatment, 26 patients (33%) had CTCs, with 23 having detectable IGF-IR–positive CTCs. CP-751,871 alone, and CP-751,871 with cytotoxic chemotherapy, decreased CTCs and IGF-IR–positive CTCs; these increased toward the end of the 21-day cycle in some patients, falling again with retreatment. CTCs were commonest in advanced hormone refractory prostate cancer (11 of 20). Detectable IGF-IR expression on CTCs before treatment with CP-751,871 and docetaxel was associated with a higher frequency of prostate-specific antigen decline by &gt;50% (6 of 10 versus 2 of 8 patients). A relationship was observed between sustained decreases in CTC counts and prostate-specific antigen declines by &gt;50%. Conclusions: IGF-IR expression is detectable by immunofluorescence on CTCs. These data support the further evaluation of CTCs in pharmacodynamic studies and patient selection, particularly in advanced prostate cancer.