First-Line LV5FU2 with or without Aflibercept in Patients with Non-Resectable Metastatic Colorectal Cancer: A Randomized Phase II Trial (PRODIGE 25-FFCD-FOLFA).

Fluropyrimidine monotherapy is an option for some patients with inoperable metastatic colorectal cancer. Unlike bevacizumab, the addition of aflibercept, an antibody acting as an anti-angiogenic agent, has never been evaluated in this context. The aim of the study was to determine whether aflibercept could increase the efficacy of fluoropyrimidine monotherapy without increasing toxicity. This multicenter phase II non-comparative trial evaluated the addition of aflibercept to infusional 5-fluorouracil/folinic acid (LV5FU2 regimen) as first-line treatment in patients unfit to receive doublet cytotoxic chemotherapy. The primary endpoint was 6-month progression-free survival (PFS). The clinical hypotheses expected a PFS rate at 6 months of over 40% (60% expected). A total of 117 patients, with a median age of 81 years, were included: 59 in arm A (LV5FU2-aflibercept) and 58 in arm B (LV5FU2 alone). Six-month PFS was 54.7% in both arms (90% CI 42.5-66.5 in both). Median overall survival was 21.8 months (arm A) and 25.1 months (arm B). Overall toxicity was more common in arm A: grade ≥ 3 toxicity in 82% versus 58.2%. Given the 6-month PFS, the study can be considered positive. However, the toxicity of aflibercept in this population was high, and continuation of the trial into phase III is not envisaged.

Optimization of G-CSF dosing schedule in patients treated with eribulin: a modeling approach.

BACKGROUND: Granulocyte colony-stimulating factors (G-CSF) are commonly given to limit chemotherapy-induced neutropenia, but, in case of weekly chemotherapy such as eribulin, their administration schedules remain empirical. OBJECTIVES: This pharmacokinetic/pharmacodynamic (PK/PD) study was conducted to establish the effect of different G-CSF regimens on neutropenia's incidence for patients treated by eribulin, to propose an optimal G-CSF dosing schedule. METHODS: A population PK/PD model was developed to describe absolute neutrophil counts' (ANC) time course in 87 cancer patients receiving eribulin. The structural model considered ANC dynamics, neutropenic effect of eribulin and stimulating effect of G-CSF. Final model estimates were used to calculate neutropenia's incidence following different G-CSF dosing schedules for 1000 virtual subjects. RESULTS: The final model successfully described most of the ANC time course for all patients. Simulations showed that a single G-CSF administration 48 h after each eribulin injection reduced the risk of severe neutropenia from 29.7 to 5.2%. Five days of G-CSF only after the second eribulin injection or no G-CSF administration induces similar incidence of neutropenia. CONCLUSION: Simulations showed a single G-CSF administration 48 h after the end of each eribulin injection seems to be the optimal schedule to reduce eribulin-induced neutropenia. However, the new administration scheme should be tested in real life to evaluate its pertinence. TRIAL REGISTRATION: Eudract 2015-001753-32, 2015/01/26.

Trabectedin for recurrent WHO grade 2 or 3 meningioma: A randomized phase II study of the EORTC Brain Tumor Group (EORTC-1320-BTG).

BACKGROUND: No systemic treatment has been established for meningioma progressing after local therapies. METHODS: This randomized, multicenter, open-label, phase II study included adult patients with recurrent WHO grade 2 or 3 meningioma. Patients were 2:1 randomly assigned to intravenous trabectedin (1.5 mg/m2 every 3 weeks) or local standard of care (LOC). The primary endpoint was progression-free survival (PFS). Secondary endpoints comprised overall survival (OS), objective radiological response, safety, quality of life (QoL) assessment using the QLQ-C30 and QLQ-BN20 questionnaires, and we performed tissue-based exploratory molecular analyses. RESULTS: Ninety patients were randomized (n = 29 in LOC, n = 61 in trabectedin arm). With 71 events, median PFS was 4.17 months in the LOC and 2.43 months in the trabectedin arm (hazard ratio [HR] = 1.42; 80% CI, 1.00-2.03; P = .294) with a PFS-6 rate of 29.1% (95% CI, 11.9%-48.8%) and 21.1% (95% CI, 11.3%-32.9%), respectively. Median OS was 10.61 months in the LOC and 11.37 months in the trabectedin arm (HR = 0.98; 95% CI, 0.54-1.76; P = .94). Grade ≥3 adverse events occurred in 44.4% of patients in the LOC and 59% of patients in the trabectedin arm. Enrolled patients had impeded global QoL and overall functionality and high fatigue before initiation of systemic therapy. DNA methylation class, performance status, presence of a relevant co-morbidity, steroid use, and right hemisphere involvement at baseline were independently associated with OS. CONCLUSIONS: Trabectedin did not improve PFS and OS and was associated with higher toxicity than LOC treatment in patients with non-benign meningioma. Tumor DNA methylation class is an independent prognostic factor for OS.

Treatment and outcomes of older versus younger women with HER2-positive metastatic breast cancer in the real-world national ESME database.

BACKGROUND: Treatment and outcomes of patients with HER2-positive (HER2+) metastatic breast cancer (MBC) have dramatically improved over the past 20 years. This work evaluated treatment patterns and outcomes according to age. METHODS: Women who initiated a treatment for HER2+ MBC between 2008 and 2016 in one of the 18 French comprehensive centers part of the ESME program were included. Objectives were the description of first-line treatment patterns, overall survival (OS), first-line progression-free survival (PFS), and prognostic factors among patients aged 70 years or more (70+), or less than 70 (<70). RESULTS: Of 4045 women diagnosed with an HER2+ MBC, 814 (20%) were 70+. Standard first-line treatment (chemotherapy combined with an anti-HER2 therapy) was prescribed in 65% of 70+ versus 89% of <70 patients (p < 0.01). Median OS was 49.2 (95% CI, 47.1-52.4), 35.3 (95% CI, 31.5-37.0) and 54.2 months (95% CI, 50.8-55.7) in the whole population, in patients 70+ and <70, respectively. Corresponding median PFS1 were 12.8 (95% CI, 12.3-13.3), 11.1 (95% CI, 10.0-12.3) and 13.2 months (95% CI, 12.7-13.9), respectively. In 70+ women, initiation of non-standard first-line treatment had an independent detrimental time-varying effect on both OS and PFS (HR on OS at 1 year: chemotherapy without anti-HER2 2.79 [95% CI: 2.05-3.79]; endocrine therapy and/or anti-HER2 1.96 [95% CI: 1.43-2.69]). CONCLUSIONS: In this large retrospective real-life database, older women with HER2+ MBC received standard first-line treatment less frequently than younger ones. This was independently associated with a worse outcome, but confounding factors and usual selection biases cannot be ruled out.

FOLFIRINEC: a randomized phase II trial of mFOLFIRINOX vs platinum-etoposide for metastatic neuroendocrine carcinoma of gastroenteropancreatic or unknown origin.

BACKGROUND: Poorly differentiated neuroendocrine carcinomas (NEC) are rare diseases with a poor prognosis. Platinum-etoposide (PE) has been the recommended first-line treatment for decades. FOLFIRINEC (NCT04325425) is a national multicenter randomized phase II study which aims to challenge this standard regimen. METHODS: The primary objective is to compare the median progression-free survival (PFS) under mFOLFIRINOX versus PE. The secondary objectives are to evaluate the objective response rates (ORR), median overall survival (OS), safety and quality of life. The associated real-time translational study will establish a molecular profile for each patient enrolled. MAIN INCLUSION CRITERIA ARE: NEC of gastroenteropancreatic (GEP) or unknown origin, metastatic and RECIST 1.1 evaluable disease, tumor sample available and no contraindication to chemotherapy. Patients will be randomized 1:1 between PE every 21 days for 6-8 cycles and mFOLFIRINOX every 14 days for up to 12 cycles and stratified according to center, performance status, Ki67 and pathological subtype. This trial will randomize 218 patients (24 months of follow-up) to have 80% power to detect an improvement of the median PFS from 5 months under PE to 7.5 months under mFOLFIRINOX (HR of 0.67, α =5%, two-sided). An intermediate analysis is planned at 50% of events. Recruitment started on October 20, 2020.

Contemporary outcomes of metastatic breast cancer among 22,000 women from the multicentre ESME cohort 2008-2016.

AIM: Real-world data inform the outcome comparisons and help the development of new therapeutic strategies. To this end, we aimed to describe the full characteristics and outcomes in the Epidemiological Strategy and Medical Economics (ESME) cohort, a large national contemporary observational database of patients with metastatic breast cancer (MBC). METHODS: Women aged ≥18 years with newly diagnosed MBC and who initiated MBC treatment between January 2008 and December 2016 in one of the 18 French Comprehensive Cancer Centers (N = 22,109) were included. We assessed the full patients' characteristics, first-line treatments, overall survival (OS) and first-line progression-free survival, as well as updated prognostic factors in the whole cohort and among the 3 major subtypes: hormone receptor positive and HER2-negative (HR+/HER2-, n = 13,656), HER2-positive (HER2+, n = 4017) and triple-negative (n = 2963) tumours. RESULTS: The median OS of the whole cohort was 39.5 months (95% confidence interval [CI], 38.7-40.3). Five-year OS was 33.8%. OS differed significantly between the 3 subtypes (p < 0.0001) with a median OS of 43.3 (95% CI, 42.5-44.5) in HR+/HER2-; 50.1 (95% CI, 47.6-53.1) in HER2+; and 14.8 months (95% CI, 14.1-15.5) in triple-negative subgroups, respectively. Beyond performance status, the following variables had a constant significant negative prognostic impact on OS in the whole cohort and among subtypes: older age at diagnosis of metastases (except for the triple-negative subtype), metastasis-free interval between 6 and 24 months, presence of visceral metastases and number of metastatic sites ≥ 3. CONCLUSIONS: The ESME program represents a unique large-scale real-life cohort on MBC. This study highlights important situations of high medical need within MBC patients. DATABASE REGISTRATION: clinicaltrials.gov Identifier NCT032753.

Intrathecal liposomal cytarabine plus systemic therapy versus systemic chemotherapy alone for newly diagnosed leptomeningeal metastasis from breast cancer.

BACKGROUND: DEPOSEIN (NCT01645839) was a randomized open-label phase III study to explore the role of intrathecal chemotherapy in patients with newly diagnosed leptomeningeal metastasis (LM), a common manifestation of breast cancer. METHODS: Patients with newly diagnosed LM defined by tumor cells in the cerebrospinal fluid or combination of clinical and neuroimaging signs of LM were randomized to receive systemic therapy alone (control group) or systemic therapy plus intrathecal liposomal cytarabine (experimental group). Progression-free survival related to LM (LM-PFS) was the primary endpoint. RESULTS: Thirty-seven and 36 patients were assigned to the control and the experimental groups. Median number of liposomal cytarabine injections in the experimental group was 5 (range 1-20). Focal radiotherapy was performed in 6 (16%) and 3 (8%) patients in the control and experimental groups. In the intent-to-treat population, median LM-PFS was 2.2 months (95% CI: 1.3-3.1) in the control versus 3.8 months (95% CI: 2.3-6.8) in the experimental group (hazard ratio 0.61, 95% CI: 0.38-0.98) (P = 0.04). Seventy-one patients have died. Median overall survival was 4.0 months (95% CI: 2.2-6.3) in the control versus 7.3 months (95% CI: 3.9-9.6) in the experimental group (hazard ratio 0.85, 95% CI: 0.53-1.36) (P = 0.51). Serious adverse events were reported in 22 and 30 patients, respectively. Quality of life until progression did not differ between groups. CONCLUSION: The addition of intrathecal liposomal cytarabine to systemic treatment improves LM-related PFS. Confirmatory trials with optimized patient selection criteria and more active drugs may be required to demonstrate a survival benefit from intrathecal pharmacotherapy.

Prognostic value of CEC count in HER2-negative metastatic breast cancer patients treated with bevacizumab and chemotherapy: a prospective validation study (UCBG COMET).

BACKGROUND: Proof of concept studies has reported that circulating endothelial cell (CEC) count may be associated with the outcome of HER2-negative metastatic breast cancer (mBC) patients treated by chemotherapy and the anti-VEGF antibody bevacizumab. We report the results obtained in an independent prospective validation cohort (COMET study, NCT01745757). METHODS: The main baseline criteria were HER2-negative mBC, performance status 0-2 and no prior chemotherapy for metastatic disease. CECs were detected by CellSearch® from 4 ml of blood at baseline and after 4 weeks of weekly paclitaxel and bevacizumab therapy. CEC counts (considered both as a continuous variable and using the previously described 20 CEC/4 ml cutoff) were associated with clinical characteristics and progression-free survival (PFS). RESULTS: CEC count was obtained in 251 patients at baseline and in 207 patients at 4 weeks. Median baseline CEC count was 22 CEC/4 ml (range 0-2231). Baseline CEC counts were associated with performance status (p = 0.02). No statistically significant change in CEC counts was observed between baseline and 4 weeks of therapy. High baseline CEC count was associated with shorter PFS in univariate and multivariate analyses (continuous: p < 0.001; dichotomized: HR 1.52, 95% CI [1.15-2.02], p = 0.004). CEC counts at 4 weeks had no prognostic impact. CONCLUSION: This study confirms that CEC count may be associated with the outcome of mBC patients treated with chemotherapy and bevacizumab. However, discrepancies with previous reports in terms of both the timing of CEC count and the direction of the prognostic impact warrant further clinical investigation.

Complementary and alternative medicine use in glioma patients in France.

PURPOSE: Complementary and alternative medicine (CAM) use increases in cancer patients, including adult patients with diffuse gliomas. METHODS: Questionnaires addressing CAM use were distributed to adult patients with gliomas of WHO grades II-IV and ECOG performance score of 0-2 during hospital visits and filled in anonymously. The study was conducted in nine centers in France from May 2017 to May 2018. Descriptive cohort analyses and comparative analyses according to gender, age, WHO grade, and recurrent versus newly diagnosed disease were conducted. RESULTS: Two hundred twenty-seven questionnaires were collected; 135 patients (59%) were male. Median age was 48 years, 105 patients (46%) declared having glioblastoma, 99 patients (43%) declared having recurrent disease. Hundred-three patients (45%) had modified their alimentary habits after the glioma diagnosis. At the time of the questionnaire, 100 patients (44%) were on complementary treatment, mainly vitamins and food supplements, and 73 patients (32%) used alternative medicine approaches, mainly magnetism and acupuncture. In total, 154 patients (68%) declared using at least one of these approaches. Expenditures exceeding 100 € per month were reported by users in 14% for modification of alimentary habits, in 25% for complementary treatment, and in 18% for alternative medicines. All approaches were commonly considered as improving quality of life and experienced as efficient, notably those associated with more expenditures. CONCLUSIONS: CAM are frequently used by glioma patients in France. Underlying needs and expectations, as well as potential interactions with tumor-specific treatments, and financial and quality of life burden, should be discussed with patients and caregivers.

Assessment of the efficacy of successive endocrine therapies in hormone receptor-positive and HER2-negative metastatic breast cancer: a real-life multicentre national study.

BACKGROUND: For luminal metastatic breast cancer (MBC), endocrine therapy (ET) is the recommended initial treatment before chemotherapy. Our objective was to evaluate the efficacy of multiple ET lines in a real-life study. METHODS: The Breast Cancer Epidemiological Strategy and Medical Economics (ESME) project analysed data from all patients with systemic treatment for MBC initiated between 2008 and 2014 in one of the 18 French Comprehensive Cancer Centres. The primary end-point was the successive progression-free survival (PFS) evaluation. RESULTS: The ESME research programme included 9921 patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2 (HER2) negative (HER2-) MBC. Before any chemotherapy, 4195 (43.4%), 1252 (29.8%) and 279 (6.6%) patients received one, two or three ET ± targeted therapy, respectively. The median PFS for first-, second- and third-line ET ± targeted therapy was 11.5 (95% confidence interval [CI], 10.8-12.1), 5.8 (95% CI, 5.3-6.1) and 5.5 (95% CI, 4.6-6.3) months, respectively. In a multivariate analysis, time from diagnosis to metastatic recurrence (P < 0.0001), presence of symptoms at metastatic relapse (P = 0.01), number of metastatic sites (P = 0.0003) and their localisation (P < 0.0001) were prognostic factors for PFS1. Duration of previous PFS was the only prognostic factor for subsequent PFS (10% threshold). Ten percent of the patients showed long-term response to ET, with a total treatment duration before chemotherapy ≥43.6 months. CONCLUSIONS: Median PFS in our HR+/HER2- real-life cohort is similar to median first-line PFS reported in clinical trials, regardless of ET used as second- and third-line treatment. Despite the international consensus on early initiation of ET, the latter is not prescribed in most of the cases. Patients with a low tumour burden may achieve prolonged response on ET.

Individualized Prediction of Menses Recovery After Chemotherapy for Early-stage Breast Cancer: A Nomogram Developed From UNICANCER PACS04 and PACS05 Trials.

BACKGROUND: The likelihood of menses recovery varies greatly in premenopausal patients receiving adjuvant chemotherapy for breast cancer. Quantifying this probability for each patient could better inform the chemotherapy discussion and individualize fertility counseling. We performed a pooled analysis of the PACS04 and PACS05 adjuvant randomized trials to develop a nomogram to estimate the probability of menses recovery at 3, 6, and 18 months after the end of adjuvant chemotherapy. PATIENTS AND METHODS: Women who were premenopausal and aged ≤ 50 years at randomization in the PACS04 and PACS05 trials were included in the present analysis. The primary endpoint was the probability of menses recovery within 18 months of chemotherapy completion. Multivariable Cox proportional hazards regression was used to estimate the association of each variable with the likelihood of menses resumption. A nomogram was developed to predict menses recovery at different intervals. RESULTS: The factors associated with menses recovery were assessed for 1210 patients. At a median follow-up of 90 months (range, 3-189 months), 342 of 1210 patients (28.2%) had recovered menses. The probability of menses recovery at 18 months was 25.5% (range, 23.0%-27.9%). After backward elimination, age, final body mass index, type of chemotherapy, and hormone therapy were selected to build the nomogram to predict the probability of menstrual resumption at 3, 6, and 18 months after chemotherapy. CONCLUSION: An accurate and individualized prediction of menses recovery is feasible for premenopausal patients eligible for adjuvant chemotherapy for early-stage breast cancer. Our nomogram will be externally validated in a large prospective cohort.

The molecular landscape of glioma in patients with Neurofibromatosis 1.

Neurofibromatosis type 1 (NF1) is a common tumor predisposition syndrome in which glioma is one of the prevalent tumors. Gliomagenesis in NF1 results in a heterogeneous spectrum of low- to high-grade neoplasms occurring during the entire lifespan of patients. The pattern of genetic and epigenetic alterations of glioma that develops in NF1 patients and the similarities with sporadic glioma remain unknown. Here, we present the molecular landscape of low- and high-grade gliomas in patients affected by NF1 (NF1-glioma). We found that the predisposing germline mutation of the NF1 gene was frequently converted to homozygosity and the somatic mutational load of NF1-glioma was influenced by age and grade. High-grade tumors harbored genetic alterations of TP53 and CDKN2A, frequent mutations of ATRX associated with Alternative Lengthening of Telomere, and were enriched in genetic alterations of transcription/chromatin regulation and PI3 kinase pathways. Low-grade tumors exhibited fewer mutations that were over-represented in genes of the MAP kinase pathway. Approximately 50% of low-grade NF1-gliomas displayed an immune signature, T lymphocyte infiltrates, and increased neo-antigen load. DNA methylation assigned NF1-glioma to LGm6, a poorly defined Isocitrate Dehydrogenase 1 wild-type subgroup enriched with ATRX mutations. Thus, the profiling of NF1-glioma defined a distinct landscape that recapitulates a subset of sporadic tumors.

Time trends of overall survival among metastatic breast cancer patients in the real-life ESME cohort.

AIM: Real-life analysis of overall survival (OS) trends among metastatic breast cancer (MBC) patients may help define medical needs and evaluate the impact of public health investments. The present study aimed to evaluate the independent impact of the year of MBC diagnosis on OS in the Epidemio-Strategy-Medical-Economical (ESME)-MBC cohort. METHODS: ESME-MBC (NCT03275311) is a French, national, multicentre, observational cohort including 16,702 consecutive newly diagnosed MBC patients (01 January 2008-31 December 2014). Of 16,680 eligible patients, 15,085 had full immunohistochemistry data, allowing classification as hormone receptor-positive and HER2-negative (HR+/HER2-, N = 9907), HER2-positive (HER2+, N = 2861) or triple-negative (HR-/HER2-, N = 2317) subcohorts. Multivariate analyses of OS were conducted among the full ESME cohort and subcohorts. RESULTS: Median OS of the whole cohort was 37.22 months (95% confidence interval [CI], 36.3-38.04). Year of diagnosis was an independent predictor of OS (hazard ratio 0.98 [95% CI, 0.97-1.00], P = .01) together with age, subtype, disease-free interval, visceral metastases and number of organs involved. Median OS of HR+/HER2-, HER2+ and HR-/HER2- subcohorts was, respectively, 42.12 (95% CI, 40.90-43.10), 44.91 (95% CI, 42.51-47.90) and 14.52 (95% CI, 13.70-15.24) months. Year of diagnosis was a strong independent predictor of OS in HER2+ subcohort (hazard ratio 0.91 [95% CI, 0.88-0.94], P < .001), but not in HR+/HER2- nor HR-/HER2- subcohorts (hazard ratio 1.00 [95% CI, 0.98-1.01], P = .80 and 1.00 [95% CI, 0.97-1.02], P = .90, respectively). CONCLUSIONS: The OS of MBC patients has slightly improved over the past decade. However, this effect is confined to HER2+ cases, highlighting the need of new strategies in the other subtypes.

[The anti-tumor immune response in breast cancer: Update and therapeutic perspectives]. / La réponse immunitaire anti-tumorale dans le cancer du sein : état des lieux et perspectives thérapeutiques.

The role of the immune response in breast cancer is now well recognized and increasingly taken in account. The goal of this article is, in the first part, to underline its prognostic impact and to precise the immunosurvelliance, immunoselection and the immunosubversion concepts involved in the control and evasion of breast carcinoma. In the second part, therapeutic strategies for the restauration of anti-tumor immunity are developed. Vaccination strategies and checkpoints inhibitors blockade strategies are discussed as well as the immunogenic death linked to the conventional treatments of breast cancer.

[CEA and early detection of relapse in breast cancer subtypes: Comparison with CA 15-3]. / ACE et diagnostic précoce de récidive dans les différents sous-types moléculaires de cancer du sein : comparaison au CA 15-3.

This retrospective study evaluates the interest of CEA measurement for early detection of breast cancer recurrences. Among 804 patients with invasive breast cancer, we selected 97 patients without recurrence (WR) for 5 years or more, 32 with a local recurrence (LR) and 131 with at least one distant metastasis (DM). Elevated CEA and CA 15-3 levels (>3.1 µg/L and >26 kU/L respectively) were found in 6 % and 22 % of patients with RL respectively and in 49 % and 69 % of patients with DM. Both CEA and CA 15-3 retained a significant value in predicting DM by univariate and multivariate analysis. Higher sensitivity of CEA and CA 15-3 were found in tumors with positive hormonal receptor status. CEA and CA 15-3 levels at DM were raised respectively in 23 and 65 % of the triple negative group, 58 and 75 % of the luminal, 56 and 78 % of the luminal-HER2 and 50 and 30 % of HER2-enriched group (P=0.0094 and 0.0252 respectively). The combination of CEA and CA 15-3 increased CA 15-3 sensitivity in especially luminal and HER2-enriched groups. In conclusion, elevated CA 15-3 and CEA levels at initial diagnosis of recurrence were found to be associated with hormonal receptor status and breast cancer subtypes. The combination of CEA and CA 15-3 appeared useful especially luminal and HER2-enriched groups.

[Clinical value of CA 15-3 for early detection of relapse in locally advanced breast cancer]. / Intérêt clinique du CA 15-3 dans la détection précoce des récidives de cancer du sein localement avancé.

This retrospective study evaluates the interest of CA 15-3 measurement for early detection of breast cancer recurrences. Among 804 patients with invasive breast cancer we selected 117 patients without recurrence (WR) for 5 years or more, 33 with a local recurrence (LR) and 149 with at least one distant metastasis (DM). The sensitivity of CA 15-3 depends on the type of recurrence ([LR] or [DM]), the localization of unique DM, the presence and the number of metastatic sites, on hormonal receptor status and tumor subtypes. The number of metastatic sites and hormonal receptor status are independent predictive criteria of an elevation of CA 15-3. The analysis of ROC curve in order to separate patients with DM and patients WR shows an AUC of 0.87 (p<0.0001). The optimal discriminative threshold is 26 kU/L. In conclusion, these data confirm that CA 15-3 increase depends on the kind of evolution and on initial tumor's hormonal status.

Identification of Biomarkers Including 18FDG-PET/CT for Early Prediction of Response to Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer.

PURPOSE: To investigate the value of the metabolic tumor response assessed with (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET), compared with clinicobiologic markers to predict pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) in women with triple-negative breast cancer (TNBC). EXPERIMENTAL DESIGN: Fifty consecutive women with TNBC and an indication for NAC were prospectively included. Different pretreatment clinical, biologic, and pathologic biomarkers, including SBR grade, the Ki-67 proliferation index, androgen receptor expression, EGF receptor (EGFR), and cytokeratin 5/6 staining, were assessed. Tumor glucose metabolism at baseline and its change after the first cycle of NAC (ΔSUVmax) were assessed using FDG-PET. RESULTS: The pCR rate was 42%. High Ki-67 proliferation index (P = 0.016), negative EGFR status (P = 0.042), and high ΔSUVmax (P = 0.002) were significantly associated with pCR. In multivariate logistic regression, both negative EGFR status (OR, 6.4; P = 0.043) and high ΔSUVmax (OR, 7.1; P = 0.014) were independent predictors of pCR. Using a threshold at -50%, tumor ΔSUVmax predicted pCR with a negative, a positive predictive value, and an accuracy of 79%, 70%, and 75%, respectively. Combining a low ΔSUVmax and positive EGFR status could predict non-pCR with an accuracy of 92%. CONCLUSIONS: It is important to define the chemosensitivity of TNBC to NAC early. Combining EGFR status and the metabolic response assessed with FDG-PET can help the physician to early predict the probability of achieving pCR or not. Given these results, the interest of response-guided tailoring of the chemotherapy might be tested in multicenter trials. Clin Cancer Res; 21(24); 5460-8. ©2015 AACR.

FOLFIRI plus bevacizumab as a second-line therapy for metastatic intrahepatic cholangiocarcinoma.

AIM: To evaluate the efficacy and tolerance of FOLFIRI plus bevacizumab treatment outcome as second-line treatment for metastatic intrahepatic cholangiocarcinoma. METHODS: Thirteen consecutive patients with metastatic intrahepatic cholangiocarcinoma who were refractory to first-line therapy consisting of gemcitabine plus oxaliplatin-based first-line chemotherapy given intravenously via intra-arterial infusion were treated with FOLFIRI [irinotecan (180 mg/m² i.v. over 90 min) concurrently with folinic acid (400 mg/m² i.v. over 120 min) followed by fluorouracil (400 mg/m² i.v. bolus) then fluorouracil 2400 mg/m² intravenous infusion over 46 h] and bevacizumab (5 mg/kg) every 2 wk. Tumor response was evaluated by computed tomography scan every 4 cycles. RESULTS: The best tumor responses using response evaluation criteria in solid tumor criteria were: complete response for 1 patient, partial response for 4 patients, and stable disease for 6 patients after 6 mo of follow-up. The response rate was 38.4% (95%CI: 12.5-89) and the disease control rate was 84.5% (95%CI: 42-100). Seven deaths occurred at the time of analysis, progression free survival was 8 mo (95%CI: 7-16), and median overall survival was 20 mo (95%CI: 8-48). No grade 4 toxic events were observed. Four grade 3 hematological toxicities and one grade 3 digestive toxicity occurred. An adaptive reduction in chemotherapy dosage was required in 2 patients due to hematological toxicity, and a delay in chemotherapy cycles was required for 3 patients. CONCLUSION: FOLFIRI plus bevacizumab combination treatment showed promising efficacy and safety as second-line treatment for metastatic intrahepatic cholangiocarcinoma after failure of the first-line treatment of gemcitabine plus oxaliplatin chemotherapy.

FOLFIRINOX bevacizumab is a promising therapy for chemorefractory metastatic colorectal cancer.

PURPOSE: Fluoropyrimidines, oxaliplatin, irinotecan and targeted therapies represent the standard treatment of metastatic colorectal cancer. After failure of all these treatments, few options are available. In such chemorefractory patients the effect of triplet chemotherapy with bevacizumab (FOLFIRINOX bevacizumab) has never been investigated. PATIENTS AND METHODS: 49 consecutive patients bearing unresectable metastatic colorectal cancer and who experienced failure to oxaliplatin- and irinotecan-based chemotherapy were treated with oxaliplatin (85 mg/m(2)), irinotecan (180 mg/m(2)), leucovorin (400 mg/m(2)), and fluorouracil (400 mg/m(2) bolus then 2,400 mg/m(2)) repeated every 2 weeks. RESULTS: Median age was 63 (range 36-82) years. After a median follow-up of 12 months, the median progression-free survival was 5.8 months (95% CI 3.4-6.8) and the median overall survival was 11.9 months (95% CI 8-18). The response rate after the cycle was evaluable for 36 patients, whereby we observed 18% (95% CI 8-35) partial or complete response, 45% (95% CI 28-68) stable disease of more than 2 months, and 37% (95% CI 21-58) progression. CONCLUSION: This study suggests that bevacizumab + FOLFIRINOX may be active in mCRC patients after failure of classical lines of chemotherapy.

Prognostic value of chemotherapy-induced hematological toxicity in metastatic colorectal cancer patients.

AIM: To establish whether chemotherapy-induced neutropenia is predictive of better outcome in patients with metastatic colorectal cancer (mCRC). METHODS: Survival and patient characteristics from consecutive mCRC patients treated in the Centre Georges Francois Leclerc, Dijon, France between January 2001 and December 2011 were analyzed. Patient and tumor characteristics, hematological toxicity (neutropenia, anemia, and thrombocytopenia), and type of chemotherapy received were recorded. RESULTS: We retrospectively analyzed data from 399 consecutive patients with mCRC who received at least one line of chemotherapy. Median follow up was 6.3 years. Eighty-eight percent of the patients received more than two lines of chemotherapy. By univariate analysis, whatever their grade, neutropenia and thrombocytopenia occurring during the first two lines of chemotherapy were significantly associated with better overall survival (HR = 0.55, 95%CI: 0.43-0.70, P < 0.0001 and HR = 0.70, 95%CI: 0.56-0.88, P = 0.025 respectively). In contrast, anemia during chemotherapy was significantly associated with poorer overall survival (HR = 1.9, 95%CI: 1.22-2.97, P = 0.005). Multivariate analysis revealed that both neutropenia and thrombocytopenia were significantly associated with better overall survival: HR = 0.43, 95%CI: 0.29-0.64, P < 0.0001 and HR = 0.69, 95%CI: 0.49-0.98, P = 0.036, respectively. CONCLUSION: These data suggest that occurrence of neutropenia or thrombocytopenia during first- or second-line chemotherapy for mCRC is associated with better survival.