Predictive Factors For Toxicity Research Articles

Predictive factors of toxicity of immune checkpoint inhibitors (ICI) in older patients with lung cancer: The ToxImmune study.

12048 Background: Immunotherapy (Im) improved the survival of patients with lung cancer. It may be responsible for adverse events impacting these patients' quality of life. We have few data on the tolerance of older cancer patients (OP) to immunotherapy. The Toximmune study aims to describe the safety of older lung cancer patients to Im and identify clinical, biological and radiological markers that can help to predict immune-related adverse events for OP. Methods: All patients aged 60 years and older who had received at least one dose of ICI between June 2015 and December 2020 and diagnosed with lung cancer were included. We collected patients' baseline demographic characteristics, biological blood markers and imaging by PET-scanner. All adverse events (AEs) and immune-related AEs (irAEs) were recorded (CTCAE V.5.0). Results: 49 patients were included, median age was 71 (range 61-97). The incidence of grade 2 and grade 3-4 was 34% and 6% respectively. The main irAEs reported were: asthenia in 51% patients after 13.5 months median delay (grade ≥2 in 22%),musculoskeletal disorders in 45% after 21 months median delay (grade ≥2 in 10%), pneumonitis in 37% after 21 months median delay (grade ≥2 in 10%), and colitis in 35% after 21 months median delay (grade ≥2 in 6%). Female sex, primitive tumor SUV max < 5, number of metastases ≥ 3, prior systemic therapy > 1, PLR < 250 were significantly associated with a risk of toxicity in univariate analysis (p < 0.05) We developed the ToxImmune score (0, 1, or ≥2) to predict the risk of having a grade ≥2 adverse event by adding the following risk factors: Primitive Tumor SUV < 5 = 1, Number of metastases ≥3 = 1, And L1 = 0 vs > L1 = 1. The incidence of grade ≥2 adverse events was 31%, 35% and 86% with ToxImmune scores 0, 1 and 2 respectively (p = 0.032). Median overall survival times (OS) & progression-free survival (PFS) were 21.8 & 21 months, 15.1 & 6.6 months, and 9.8 & 2.1 months for ToxImmune scores 0, 1 and ≥ 2 respectively (p = 0.06 & p = 0.001). There was significant association between the ToxImmune score and the risk of "progressive disease" at the first assessment of the disease: 16% for score = 0, 48% for score = 1, and 71% for score = 2, (p = 0.01). Conclusions: The quality of life is our goal for OP care. The ToxImmune score, which is based on objective clinical parameters, identifies OP with a significant higher risk of severe adverse events. Also, this score was significantly associated with patients’ PFS risk of developing rapid tumor progression. It could be used in clinical practice to personalize toxicity surveillance in OP treated for lung cancer with immunotherapy. This score will be validated in larger prospective cohorts.

Evaluating predictive factors for toxicities experienced by head & neck cancer patients undergoing radiotherapy

PurposeThe purpose of this study was to evaluate if HPV status serves as an independent predictor of early and late dysphagia outcomes when considered alongside standard patient characteristics and dose metrics for head and neck cancer patients treated with radiotherapy.Methods and materialsThe age, sex, smoking history, cancer type (oropharyngeal vs non-oropharyngeal), HPV status, and early and late dysphagia outcomes were obtained for 99 retrospective head and neck cancer patients treated at our clinic with radiotherapy. Additionally for each patient, the mean radiation dose to the pharynx, superior/middle/inferior pharyngeal constrictor muscles, and cricopharyngeus was calculated. The predictive power of these clinical characteristics and radiation metrics was evaluated using chi-square tests for categorical variables and t-tests for continuous variables. Then multi-variate logistic models were built for each outcome using a single dose metric at a time, and either HPV status, cancer type, or both. Multi-variate models were built using both top-down and bottom-up technique to establish the most predictive independent covariates.ResultsIn the univariate analysis for early dysphagia, cancer type (p = 0.04) and four dose metrics (p ≤ 0.02) were significantly associated with outcome, while for late dysphagia, only cancer type (p = 0.04) was associated with outcome. In the multivariate analysis for early dysphagia, cancer type, smoking history, and mean dose to the five structures were consistently selected as covariates. For late dysphagia, either HPV status or cancer type was selected in each model and the mean dose to the cricopharyngeus was selected in one model.ConclusionWhile HPV is a known contributing factor for tumor prognosis in oropharyngeal cancers, its role in normal tissue toxicities for head and neck cancers has not previously been evaluated. Our results indicate having an oropharyngeal cancer may increase a patient’s risk of high-grade early and late dysphagia while HPV status was seldom selected.

A multicenter prospective phase II study of postoperative hypofractionated stereotactic body radiotherapy (SBRT) in the treatment of early-stage oropharyngeal and oral cavity cancers with high risk margins: the STEREO POSTOP GORTEC 2017-03 trial

BackgroundPrimary surgery is usually the mainstay treatment in early-stage oropharyngeal and oral cavity cancer. Typically, neck surgery is performed. Negative tumor margins are recommended (> 5 mm). If feasible, re-resection of any positive margin is preferred. Otherwise, postoperative radiotherapy is required. Adjuvant postoperative radiotherapy can be limited to the primary site for patients with pT1-T2 tumors and negative neck exploration. Currently, both fractionated external beam radiotherapy and brachytherapy can have a role in the postoperative management of early-stage oropharyngeal and oral cavity cancer with high risk margins. Another possible alternative could be postoperative stereotactic body radiotherapy (SBRT). The aim of this study is to evaluate postoperative SBRT in the treatment of early-stage oropharyngeal and oral cavity cancer with high risk margins.MethodsThe STEREO POSTOP study is a national, open-label, non-randomized phase II trial within the GORTEC network. Patients with early-stage oropharyngeal and oral cavity cancers with high risk margins indicating the need for postoperative radiation are eligible for enrollment. SBRT consists of a total dose of 36 Gy in 6 fractions over 2 weeks. The primary endpoint is severe late toxicity defined as 2-year toxicity of grade ≥ 3 according to CTCAE V4.03 classification. The secondary endpoints include acute toxicity (≤ 3 months), local and locoregional control, disease-free and overall survival, quality of life of patients, nutritional impact and predictive factors of toxicity. The experimental design chosen is a one-step Fleming plan design without interim analysis as the primary endpoint will be evaluated at a 2-year follow-up. Ninety patients will be recruited. The study was started in January 2018 with a 4-year enrollment period and an estimated completion in January 2024.DiscussionThis study is the first prospective trial to evaluate head and neck cancer postoperative SBRT in the setting of early-stage oropharyngeal and oral cavity cancers with high risk margins. SBRT is an attractive option because it delivers a highly conformal dose of radiation in a limited number of fractions (like brachytherapy but with less contraindication), with steep dose gradients resulting in reduced normal tissue irradiation and with a short overall treatment time.Trial registrationClinicaltrials.gov: NCT03401840, registered on 17-1-2018. Identifier in French National Agency for the Safety of Medicines and Health Products (ANSM): N°ID - RCB 2017-A02058–45, registered on July 2017.Protocol version: Version 3 dated from 25th November 2019.

Frailty score of older patients with haematological malignancies: unsuspected role of mild cognitive impairment

Frailty assessment in older patients with haematological malignancies is extremely beneficial in order to optimize treatment decisions and supportive interventions. A comprehensive geriatric assessment can provide a better understanding of the functional age than clinical judgement by evaluating several skills domains such as physical function, autonomy, comorbidities, nutrition, cognition, psychological status and social support. However, the use of a multidisciplinary geriatric assessment may fail to detect unsuspected vulnerability such as mild cognitive impairment among so-called "clinically fit" patients. The objective of this paper is to update the current knowledge about predictive factors for toxicity and "frailty scoring" in older patients with haematological malignancies. The unsuspected major role of cognitive impairment and how to detect it will be emphasized.

Predictive factors for toxicity and survival of second-line sunitinib in advanced gastrointestinal stromal tumours (GIST)

Introduction: Sunitinib is a standard second-line treatment in advanced gastrointestinal stromal tumours (GIST). We aimed to search for predictive factors for grade 3 and 4 toxicity, progression-free survival (PFS) and overall survival (OS) in a GIST reference center patient population, outside clinical trials.Methods: A retrospective analysis was performed of patients treated in two European Comprehensive Cancer Centers between January 2005 and December 2015. Demographic and clinical features, tumour characteristics and biological parameters were investigated. Logistic regression models were used to find factors associated with grade 3 and 4 toxicity. To identify predictive factors for PFS and OS, variables that were statistically significant in univariate analysis were used in the multivariate Cox proportional hazards model.Results: Ninety-one patients were included in this analysis. Age >60 years (HR 5.0, p = .006) and body weight ≤70 kg (HR 4.7, p = .009) were predictive factors for grade 3 and 4 toxicity. When divided into two categories, non-haematological grade 3 and 4 toxicity was predicted by age >60 years (HR 3.8, p = .012) and body weight ≤70 kg (HR 3.3, p = .025) whereas haematological toxicity had no significantly associated predictive factors. The median PFS and OS with sunitinib were 8.8 months and 27.5 months, respectively. The use of imatinib less than six months compared to 6–12 months (HR 0.2, p = .013) and to >12 months (HR 0.3, p = .016) and liver and/or peritoneal metastases (HR 0.1, p < .001, HR 0.2, p = .003 and HR 0.2, p = .004) compared to locally advanced disease only were predictive for longer PFS. High neutrophil (HR 3.1, p = 0.04) and platelet count (HR 2.4, p = .046) predicted a shorter OS. Flexible sunitinib dosing was associated with superior OS (p = .021).Conclusion: In advanced GIST patients treated with sunitinib, older and low-weight patients are at risk for grade 3 and 4 toxicity. Clinical (prior imatinib use and metastases), biological (neutrophil and platelet count) and treatment characteristics independently predict PFS and OS.

Identifying risk factors for high-dose methotrexate-induced toxicities in children with acute lymphoblastic leukemia.

BackgroundWhether monitoring of the methotrexate (MTX) concentrations after high-dose MTX (HD-MTX) infusion can predict toxicities is still controversial, especially when HD-MTX therapy is used in the treatment of children with acute lymphoblastic leukemia (ALL), which is different than the previous schedules. The relationship between patient characteristics and severe adverse events (AEs) has yet to be determined.ObjectiveTo analyze the relationship between the MTX concentration and toxicities and to identify the risk predictors from patient characteristics for severe AEs during HD-MTX therapy in children with ALL.MethodsWe conducted a retrospective study on children with ALL who were treated with 388 HD-MTX infusions. The chi-square test and univariate and logistic regression analyses were used to analyze the relationship between the MTX concentrations and toxicities and to identify predictors for severe AEs.ResultsFebrile neutropenia (P=0.000) and vomiting (P=0.034) were more likely to occur if the infusion had an MTX level ≥1 μmol/L at 44 h, but other toxicities had no correlations with MTX concentration. Predictive factors for toxicities were as follows: higher risk stratification and higher values of albumin (ALB) for leucopenia, higher values of white blood cell count (WBC) for anemia, higher values of ALB and creatinine (Cr) for neutropenia, higher risk stratification and higher 44-h MTX concentration for febrile neutropenia, higher values of alanine transferase (ALT) for elevated ALT, higher values of ALT for elevated aspartate transferase (AST), and higher values of total bilirubin (TBil) for vomiting.ConclusionRoutine monitoring of 44-h MTX concentrations is essential to identify patients at high risk of developing febrile neutropenia and vomiting. This study may provide a reference for clinicians to distinguish patients with a relatively high risk of severe AEs based on certain characteristics before HD-MTX infusion.

Body composition and sarcopenia: The next-generation of personalized oncology and pharmacology?

Body composition has gained increasing attention in oncology in recent years due to fact that sarcopenia has been revealed to be a strong prognostic indicator for survival across multiple stages and cancer types and a predictive factor for toxicity and surgery complications. Accumulating evidence over the last decade has unraveled the "pharmacology" of sarcopenia. Lean body mass may be more relevant to define drug dosing than the "classical" body surface area or flat-fixed dosing in patients with cancer. Since sarcopenia has a major impact on patient survival and quality of life, therapeutic interventions aiming at reducing muscle loss have been developed and are being prospectively evaluated in randomized controlled trials. It is now acknowledged that this supportive care dimension of oncological management is essential to ensure the success of any anticancer treatment. The field of sarcopenia and body composition in cancer is developing quickly, with (i) the newly identified concept of sarcopenic obesity defined as a specific pathophysiological entity, (ii) unsolved issues regarding the best evaluation modalities and cut-off for definition of sarcopenia on imaging, (iii) first results from clinical trials evaluating physical activity, and (iv) emerging body-composition-tailored drug administration schemes. In this context, we propose a comprehensive review providing a panoramic approach of the clinical, pharmacological and therapeutic implications of sarcopenia and body composition in oncology.

Is there any predictor for hypersensitivity reactions in gynecologic cancer patients treated with paclitaxel-based therapy?

Recently, generic drugs of paclitaxel have been commonly used mainly by economic reasons; however, predictive factors for toxicities are not fully determined. Hypersensitivity reaction (HSR) is one of the most important adverse events in the paclitaxel-based therapy, and sometimes leads to lethal condition. The aim of the study was to identify predictors for HSR in patients treated with paclitaxel-based regimens. All the patients treated with chemotherapy including paclitaxel at our hospital between 1998 and 2013 were retrospectively evaluated. Clinicopathological factors of the patients that developed HSR and those without HSR were compared, and predictive factors for HSR were identified. Among 414 patients enrolled in the study, 26 patients (6.3%) developed HSR. Multivariate analyses showed that younger age (odds ratio 6.31), a history of allergy (odds ratio 3.79), and short-course premedication (odds ratio 14.1) were identified as predictive factors for HSR. There was no significant difference in the incidence of HSR between original paclitaxel and generic drug. The incidence of HSR was higher as the number of these predictors was accumulated. Three factors were identified as predictive factors for HSR: younger age, a history of allergy, and short-course premedication. Accumulation of these factors increased the incidence of HSR; however, the use of generic drug was not associated HSR in gynecologic cancer patients.

The role of pharmacogenetics in the new ESMO colorectal cancer guidelines.

The role of pharmacogenetics in the new ESMO colorectal cancer guidelines.

1416P - Predictive factors for toxicity and survival of second line sunitinib in advanced gastrointestinal stromal tumours (GIST)

1416P - Predictive factors for toxicity and survival of second line sunitinib in advanced gastrointestinal stromal tumours (GIST)

Acute and Late Genitourinary Toxicity after 72 Gy of Conventionally Fractionated Conformal Radiotherapy for Localised Prostate Cancer: Impact of Individual and Clinical Parameters

AimOur aim was to estimate the incidence of acute and late genitourinary toxicity in patients treated with three-dimensional conformal radiotherapy (3DCRT) for localised prostate cancer and to estimate the possible influence of individual and clinical characteristics. Materials and methodsBetween September 2009 and September 2013, 225 patients with localised prostate cancer were treated with 3DCRT. Ninety-four patients with an estimated risk of lymph node involvement ≤15%, according to the Roach formula, were evaluated in this study. All patients received a total dose of 72 Gy in 36 fractions. Acute and late genitourinary toxicity were graded according to the European Organization for Research and Treatment of Cancer radiation morbidity scoring scale. Characteristics such as age, smoking status, previous abdominal or pelvic surgery (PAPS), diabetes mellitus and the use of diuretics were analysed as possible predictive factors of toxicity. The median follow-up was 27 months. ResultsGrade ≥2 acute toxicity during 3DCRT developed in 25 of 94 patients (26.5%). Predictive factors of acute genitourinary toxicity grade ≥2 in the multivariate logistic regression analysis (MVA) were current smoking status (P = 0.003), PAPS (P = 0.012) and the use of diuretics (P = 0.017). The 2 and 3 year cumulative risk of late genitourinary toxicity grade ≥1 was 25.3% and 30.2%, respectively. In the MVA, acute genitourinary toxicity was significantly associated with late genitourinary toxicity (P = 0.024). ConclusionCurrent smoking status, PAPS and the use of diuretics have a significant effect on the occurrence of acute genitourinary toxicity grade ≥2. The occurrence of any grade of acute genitourinary toxicity has a significant influence on the development of any grade of late genitourinary toxicity.

Plasma and intracellular exposure to ganciclovir in adult renal transplant recipients: is there an association with haematological toxicity?

Ganciclovir is the most widely used treatment for cytomegalovirus infections. However, neutropenia is a frequent associated adverse effect leading to a decrease in the ganciclovir dose or discontinuation of the therapy, thereby favouring viral resistance. In the present study, the objectives were: (i) to describe the pharmacokinetics of blood and intracellular ganciclovir and its metabolites; and (ii) to explore the relationship between exposure to ganciclovir and/or its metabolites and evolution of the neutrophil count under treatment. Pharmacokinetic profiles (pre-dose and 1, 2, 3 and 5 h after dosing) of ganciclovir and its metabolites were measured in 22 adult renal transplant patients and further modelled by a non-parametric approach (PMetrics(®)). The relationship between exposure indices to ganciclovir and the slope of the neutrophil count was investigated using multiple linear regression. A four-compartment open model was able to accurately describe ganciclovir and its intracellular forms. A significant association was found between intracellular ganciclovir triphosphate concentrations (AUC0-5) and the decrease in neutrophil count over the first 3 months of treatment (β= -0.0019 ± 5 × 10(-4); P < 0.01). In this population of renal transplant patients, the decrease in neutrophil count, used as a surrogate marker of haematological toxicity, was associated with ganciclovir triphosphate accumulation in blood cells. Further studies are needed to test this biomarker as a predictive factor for toxicity.

External Beam Radiation Therapy Versus Image Guided High-Dose-Rate Endorectal Brachytherapy in the Management of Rectal Cancer: A Retrospective Study

brachytherapy is an effective treatment for anal cancer and is often used in Europe as exclusive or boost treatment. The purpose of this study was to retrospectively assess the clinical outcome of patients undergoing brachytherapy as sole treatment or in combination with external beam radiation therapy and to search clinical predictive factors of toxicity and efficacy. Materials/Methods: From June 2000 to June 2010, 89 patients with anal canal carcinoma were treated in the 3 institutions of the GOCO (Occitan Catalan Oncologic Group) (39 patients in Montpellier, 31 in Toulouse and 19 in Barcelona). Data was retrospectively collected. Survival analyses were performed with the Kaplan-Meier method. The log rank test was used to find predictive factors of efficacy ant toxicity. Results: Brachytherapy was given as a boost in 94% of the patients. Tumor staging reported was T1 Z 19 patients (21%), T2 Z 63 patients (71%), T3 Z 5 patients (6%), and T4 Z 2 patients (2%). Tumor size was less than 3 cm in 52% of the patients. Lymph node status was N0 in 74 patients (83%), N1 in 10 patients (11%) and N2 in 5 patients (6%). Concomitant chemotherapy was associated with external beam radiation therapy in 51% of the cases. Pulsed dose rate brachytherapy was used in 73% of the cases (low dose rate in 27%). The median brachytherapy dose was 20 Gy. The median total radiation therapy dose was 64.6 Gy. 95.5% of patients had a complete clinical response at 3 months. Acute grade 3 or 4 toxicity occurred in 25% of the patients and was significantly correlated with the use of concomitant chemotherapy (p Z 0.003). The median follow-up was 4.6 years. Late grade 3 or 4 toxicity was observed in 9% of the patients but no clinical factor was correlated. The overall survival was 96, 91and 78%, respectively, at 3, 5 and 7 years. Local relapse free survival (LRFS) was 90, 84 and 80%, respectively, at 3, 5 and 7 years. LRFS was significantly correlated with the use of concomitant chemotherapy (p Z 0.016), especially in tumors less than 3 cm in size (1 local relapse with concomitant chemotherapy Vs 7 local relapse without, p Z 0.043). Conclusions: Interstitial brachytherapy is an effective and safe treatment which permits to deliver high dose to the tumor while limiting the risk of induced toxicity. Concomitant chemotherapy during the first part of external radiation therapy induces more acute toxicity but is an important factor for local control, even in tumors less than 3 cm, and despite the high dose of radiation delivered. Author Disclosure: O. Riou: None. F. Castan: None. F. Picaud: None. C. Llacer Moscardo: None. C. Gutierrez: None. J. Dubois: None. M. Cambray: None. D. Azria: None. F. Ferrer: None. M. Delannes: None.

Clinical Activity and Tolerability of a 14-Day Infusional Ifosfamide Schedule in Soft-Tissue Sarcoma

Background. Soft-tissue sarcomas (STS) are a heterogeneous group of diseases with lack of effective treatments in most cases. Previous data suggest that continuous infusional ifosfamide regimens might improve cytotoxicity and tolerability compared to standard schedules. Methods. We retrospectively report the outcome of 35 patients affected by STS treated with a 14-day infusional ifosfamide regimen (1000 mg/m2/day) in our institution. Predictive factors for toxicity were also explored. Results. Median age was 53 years. There were 16 males and 19 females. Classification by histology was dedifferentiated liposarcoma (DDLPS): 22 (62.8%), synovial sarcoma: 7 (20%), myxoid/round-cell liposarcoma: 3 (8.5%), and others: 3 (8.5%). Overall, 7 patients (20%) achieved partial response (PR) and 10 patients (29%) achieved stable disease (SD). DDLPS showed special sensitivity: 5 patients (22.7%) had PR, 7 patients (31.8%) had SD, and disease control rate was 54.5%. Median progression-free survival and overall survival were 4.2 and 11.2 months, respectively. The most common toxicities were fatigue, nausea, and vomiting (all grades: 85.7%, 83%, and 54.3%, resp.). Neither hypoalbuminaemia nor gender was found to predict toxicity, although encephalopathy predominantly affected females. Conclusion. Ifosfamide administered as a 14-day continuous infusion is a safe regimen in STS with notable activity in DDLPS.

P3.13 Immune Status Stratification of Metastatic Breast Cancer Patients: Lympho-Divpenia Predicts Overall Survival

ABSTRACT Background Lymphopenia ( 1 Giga/L) before initiation of chemotherapy is a predictive factor for toxicity and death in metastatic phase for cancer patients. Combinatorial diversity of T Cell Receptor -beta chain (TCR-β), as a measure of T cell repertoire diversity, was investigated and tested either alone or in combination with lymphopenia as a prognostic factor for overall survival (OS) in first line treatment of metastatic breast cancer (MBC) patients. Methods Using semi quantitative multiplex PCR, the V-D-J combinatorial diversity of the TCR was measured on cryo-preserved blood samples from 2 cohorts of MBC patients before the initiation of the first line chemotherapy: in an experimental cohort (cohort A, n = 66) and in a validation series (cohort B, n = 67). A prognostic score, defined NDL (Number & Diversity of Lymphocytes) combining lymphocyte count and TCR diversity was delineated. Univariate and multivariate analysis of prognostic factors for OS were performed in both cohorts. Results Lymphopenia ( 1 Giga/L) was associated with shorter OS for cohort B while TCR diversity ≤33% (called divpenia) was associated with a reduced OS in cohort A. The combination of lymphopenia with low TCR diversity (called lympho-divpenia) was associated with poor OS compared to patients with either lymphocyte count ≥1 Giga/L or diversity >33% or both, in cohort A (median OS: 7.6 vs 24.5 months, p.value =0.0006) and cohort B (median OS 10.6 vs 22.9 months, p.value =0.0035). In a multivariate analysis, including all significant clinical factors from the univariate analysis (PS, liver metastasis, hemoglobin) lympho-divpenia was found to be an independent prognostic factor in the pooled cohort (A + B) (p = 0.005) along with triple negative tumors (p = 0.011) and hemoglobin level (11.5 g/dL) (p = 0.009). Conclusion NDL score combining lymphopenia and reduced TCR diversity seems to be a strong prognostic factor for OS and could be use to improve care quality of MBC patients.

Lymphopenia combined with low TCR diversity to predict overall survival in metastatic breast cancer patients.

10562 Background: Lymphopenia (&lt;1 Giga/L) before initiation of chemotherapy is a predictive factor for toxicity and death in metastatic phase for cancer patients. Combinatorial diversity of T Cell Receptor beta chain (TCR-ß), as a measure of T cell repertoire diversity, was investigated and tested either alone or in combination with lymphopenia as a prognostic factor for overall survival (OS) in first line treatment of metastatic breast cancer (MBC) patients. Methods: Using semi quantitative multiplex PCR, the V-D-J combinatorial diversity of the TCR was measured on cryo-preserved blood samples from 2 cohorts of MBC patients before the initiation of the first line chemotherapy: in an experimental cohort (cohort A, n=66) and in a validation series (cohort B, n=67). A prognostic score, defined NDL (Number &amp; Diversity of Lymphocytes) combining lymphocyte count and TCR diversity was delineated. Univariate and multivariate analysis of prognostic factors for OS were performed in both cohorts. Results: Lymphopenia (&lt;1 Giga/L) was associated with shorter OS for cohort B while TCR diversity ≤33% (called divpenia) was associated with a reduced OS in cohort A. The combination of lymphopenia with low TCR diversity (called lympho-divpenia) was associated with poor OS compared to patients with either lymphocyte count ≥1 Giga/L or diversity &gt;33% or both, in cohort A (median OS: 7.6 vs 24.5 months, p.value =0.0006) and cohort B (median OS 10.6 vs 22.9 months, p.value =0.0035). In a multivariate analysis, including all significant clinical factors from the univariate analysis (PS, liver metastasis, hemoglobin) lympho-divpenia was found to be an independent prognostic factor in the pooled cohort (A+B) (p=0.005) along with triple negative tumors (p=0.011) and hemoglobin level (11.5 g/dL) (p=0.009). Conclusions: NDL score combining lymphopenia and reduced TCR diversity seems to be a strong prognostic factor for OS and could be use to improve care quality of MBC patients.

Abstract LB-165: Low TCR diversity (divpenia) is a new prognosis factor of overall survival in metastatic breast cancer

Abstract Rationale Lymphopenia (&amp;lt;1000 Lymphocytes/μl) or CD4+ T cell lymphopenia (&amp;lt;450/μl), detected before initiation of chemotherapy are predictive factors for toxicity and death in metastatic solid tumors (Borg et al 2004; Ray Coquard et al 2009). The goal of the present study was to further identify the characteristics of the T cells in these lymphopenic patients. TCR diversity was investigated and tested as predictive factor for overall survival (OS). Patients and methods The ImmunTraCkeR® assay (ImmunID, Grenoble France), which analyzes, through semi quantitative multiplex PCR, the V-D-J combinatorial diversity of TCR-beta chain (TRB), was used to investigate diversity of T cell repertoire on cryopreserved blood samples from a prospective cohort of untreated metastatic breast cancer patients (SEMTOF study)(n=66). Univariate and multivariate analysis of prognostic factors for OS were investigated in this series as well as in a validation series. Results A severe T cell Divpenia (T cell diversity below 33%) (average diversity for healthy people is 70%) was associated with median survival of 9 months vs 24 months for the remaining patients (logrank p.value=0.0047). In a multivariate analysis, including haemoglobin level, polynuclear neutrophil count and liver metastasis, divpenia (defined at 30% threshold defined by ROC curve analysis) was identified as an independent prognostic factor. The NDL® score (Numeration Diversity Lymphocytes representation) that combines lymphocytes numeration with TRB diversity, demonstrated that lympho-divpenia (T cell diversity below 33% and lymphopenia at 1Giga/L threshold) was associated with a poor prognosis in term of patients survival compared to patients with either a good numeration or good diversity or both good numeration and diversity (p.value=0.0202). Prognostic value of NDL® score was then evaluated on a prospective validation cohort of 33 patients (logrank p.value=0.002). Conclusion: Divpenia, and a combined parameter NDL are predictive factors for survival in metastatic breast cancer patients. An open clinical study (LYMPHOS1) will investigate divpenia and NDL® score in a larger prospective cohort of metastatic breast patients. Acknowledgments M.MANUEL is a CIFRE recipient. This work (Proof of Concept “LYMPHOS1”) was financially supported by CLARA (LYON, France) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-165. doi:10.1158/1538-7445.AM2011-LB-165

Antiangiogenic Therapies in Early-Stage Breast Cancer

Angiogenesis, which is crucial for the growth and spread of cancer cells, has become an important target for antineoplastic therapies in a variety of malignant tumors. Vascular endothelial growth factor and its receptor promote formation of new blood vessels in tumors. Several drugs, most notably the monoclonal antibody bevacizumab, have been developed to inhibit this process. Clinical trials utilizing bevacizumab and other antiangiogenic drugs in metastatic breast cancer have demonstrated enhanced response rates and prolonged progression-free survival, though no overall survival benefit has been seen. Trials are now under way exploring the use of antiangiogenic agents in patients with early stage breast cancer. We performed a comprehensive review of the published literature (English language), US National Institutes of Health clinical trials registry ( ClinicalTrials.gov), and established cooperative groups that revealed approximately 75 clinical trials, completed or ongoing, utilizing antiangiogenic drugs in early-stage breast cancer. A number of phase II trials in the neoadjuvant setting have reported preliminary results suggesting response rates similar to those seen with traditional anthracycline-plus-taxane combination regimens. Most of these early trials have not yet met any survival endpoints. Studies are also ongoing in the adjuvant setting, and these have not yet been reported. The toxicities associated with these agents are similar to those that have been reported in the metastatic trials. Most of these side effects are grade 1 or 2 and are easily manageable; however, there remain a small percentage of patients who sustain life-threatening vascular events, bleeding, or wound-healing complications. This number is significantly higher in patients receiving antiangiogenic drugs when compared with controls. While we eagerly await completion and results of this impressive portfolio of studies in early breast cancer with antiangiogenic agents, there is an urgent need for a more rational patient/antiangiogenic therapy selection with greater insight into predictive factors for toxicities, therapy efficacy, and clinical benefit.

3006 Predictive factors for toxicity of non platinum chemotherapy

3006 Predictive factors for toxicity of non platinum chemotherapy

Use of genotype subset selections of multi-UGT1As polymorphisms to predict severe neutropenia and tumor responses of metastatic CRC patients received FOLFIRI regimen

e15038 Introduction: The pharmacogenetics of irinotecan indicate that a common polymorphism in the uridine diphosphate glucuronosyltransferase 1As (UGT1As) gene predict severe toxicity. However the tumor response to irinotecan is variable and unpredictable. Methods: Two multi-center phase II studies of FOLFIRI (FLIGHT-1 and FLIGHT-2 study) were conducted for patients with metastatic colorectal cancer (CRC) in Japan. FLIGHT-1 study was first-line chemotherapy, and FLIGHT-2 study was FOLFOX-refractory second-line chemotherapy. 103 patients have been enrolled in these studies (53 patients in FLIGHT-1 and 50 patients in FLIGHT-2) from 20 institutions by April 2007 from November 2005. Seventy one patients were analyzed UGT1As polymorphisms, UGT1A1*28 (TA6&gt;TA7), UGT1A1*6 (G&gt;A), UGT1A1*60 (T&gt;C), UGT1A7 (N129K; T&gt;G), UGT1A7 (-57 T&gt;G), UGT1A9*22 (T10&gt;T9). Results: Out of 71 patients, 34 had G3/4 neutropenia or leukopenia, and 23 had tumor responses (CR +PR). G3/4 neutropenia was more frequent in patients with *6, N129K(G), -57(G), *22 allele than patients without these allele (p&lt;0.05). Other polymorphism was not the predictive factor for toxicity and tumor response, independently. On the other hand, genotype subset selection of multi-UGT1As polymorphisms was useful to predict severe toxicities and tumor responses. Only 7 patients of 22 patients with TA6/TA6 and T10/T10, or TA6/TA7 and -57(T/T), or *6(G/G) and *60(T/T) had grade3/4 toxicity. Similarly, high risk group of toxicity or high and low tumor responses groups was also predicted by genotype subset selections. Conclusions: Genotype subset selections of multi-UGT1As polymorphisms were the excellent predictor for severe toxicities and tumor responses of metastatic CRC patients received FOLFIRI regimen. No significant financial relationships to disclose.