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1.
ESMO Open ; 9(7): 103602, 2024 Jun 18.
Article in English | MEDLINE | ID: mdl-38897136

ABSTRACT

BACKGROUND: Nivolumab is the first immune checkpoint inhibitor approved in Europe for the treatment of advanced renal cell carcinoma (aRCC) in patients resistant to prior antiangiogenic therapy. WITNESS is an ongoing, prospective, observational study designed to evaluate the effectiveness and safety of nivolumab in patients with aRCC treated in real life (or routine practice) in France (ClinicalTrials.gov identifier: NCT03455452). PATIENTS AND METHODS: This study includes adult patients with a confirmed diagnosis of aRCC who have initiated nivolumab after 1-2 prior lines of antiangiogenic therapy. Endpoints include overall survival (OS), progression-free survival (PFS), duration of treatment (DOT), duration of response (DOR), overall response rate (ORR), subgroup analyses, and treatment-related adverse events (TRAEs). Results after a median follow-up of 12.3 months are presented here. RESULTS: A total of 325 patients with aRCC were included, of whom 38.2% had a Karnofsky score <80, 77.8% received nivolumab as second-line therapy, and 69.5% had undergone a previous nephrectomy. In the overall population, median OS was 20.5 [95% confidence interval (CI) 17.6-25.0] months and median PFS was 5.2 (95% CI 4.5-5.9) months. ORR was 34.5%, median DOT was 3.8 months, and median DOR was 16.5 months. Nivolumab was effective in different subgroups including patients with bone or glandular metastases and those receiving baseline corticosteroids. Moreover, effectiveness was observed irrespective of prior nephrectomy and line of treatment. No new safety signals were identified; TRAEs of any grade were reported in 32.0% of patients, grade ≥3 and serious TRAEs in 11.1% each, and TRAEs leading to discontinuation in 8.9%. CONCLUSIONS: Preliminary results of the ongoing WITNESS study confirm the real-world effectiveness and safety of nivolumab monotherapy in previously treated patients with aRCC. Treatment benefits were similar to those observed in the pivotal phase III CheckMate 025 randomized clinical trial, despite a broader, real-life study population.

2.
Br J Cancer ; 128(11): 2072-2080, 2023 06.
Article in English | MEDLINE | ID: mdl-37012318

ABSTRACT

BACKGROUND: Efficacy of endocrine therapy in HR+/HER2- metastatic breast cancer could differ depending on the presence of BRCA1/2 germline mutation. METHODS: The ESME metastatic breast cancer platform (NCT03275311) is a French real world database. Multivariable models including a time-varying approach and landmark analyses assessed the association between time-dependent gBRCA status (categorised as gBRCAm, gBRCAwt (wild type), and untested), overall survival (OS), and first-line progression-free survival (PFS1). RESULTS: A total of 170 patients were gBRCAm carriers, 676 gBRCAwt, and 12,930 were untested at baseline. In the multivariable analysis, gBRCAm carriers overall had a lower OS compared to gBRCAwt (adjusted HR [95% CI] 1.26 [1.03-1.55]). gBRCAm patients treated with front-line endocrine therapy had lower adjusted OS (adjusted HR [95% CI] = 1.54 [1.03-2.32]) and PFS1 (adjusted HR [95% CI] 1.58 [1.17-2.12]) compared to gBRCAwt patients. However, for patients who received frontline chemotherapy, neither OS nor PFS1 differed between gBRCAm carriers and the other groups (HR versus gBRCAwt for OS: 1.12 [0.88-1.41], p = 0.350; PFS1: 1.09 [0.90-1.31], p = 0.379). CONCLUSION: In this large cohort of HR+/HER2- MBC patients treated in a pre-CDK4/6 inhibitors era, gBRCAm status was associated with a lower OS and lower PFS following first-line endocrine therapy, but not following first-line chemotherapy.


Subject(s)
Breast Neoplasms , Humans , Female , Breast Neoplasms/pathology , BRCA1 Protein/genetics , Receptor, ErbB-2/genetics , BRCA2 Protein/genetics , Germ Cells/pathology , Mutation , Antineoplastic Combined Chemotherapy Protocols/therapeutic use
4.
Breast Cancer Res Treat ; 191(3): 577-587, 2022 Feb.
Article in English | MEDLINE | ID: mdl-34984582

ABSTRACT

PURPOSE: Older cancer patients are underrepresented in clinical trials. We aimed to evaluate the enrollment of older women aged 70 years old (yo) or over with metastatic breast cancer (MBC) in clinical trials. METHODS: We used the national Epidemio-Strategy and Medical Economics MBC Data Platform, a French multi-center real-life database. We selected MBC women over 70yo, without central nervous system metastases, with at least one line of systemic treatment, between January 1st, 2008 and December 31st, 2016, and had no other cancer in the 5 years before MBC. The primary objective was to evaluate the proportion of patients enrolled in clinical trials according to their age. Secondary objective was to identify variables associated with enrollment in older ones. RESULTS: 5552 women were aged ≥ 70 (median 74yo; IQR 72-77). 14,611 were less than 70. Of the older ones, 239 (4%) were enrolled in a clinical trial during first line of treatment, compared with 1529 (10.5%) for younger ones. Multivariable analysis of variables predicting for enrollment during first line of treatment in older patients were younger age (OR 0.50 [95%CI 0.33-0.76] for the 80-85yo class; OR 0.17 [95%CI 0.06-0.39] for the 85yo and more class), good ECOG Performance Status (PS 0-1) (OR 0.15 [95%CI 0.08-0.27] for the PS 2-4 class), HER2 + disease (OR 1.78 [95%CI 1.27-2.48]), type of treatment (chemotherapy/targeted therapy/immunotherapy OR 5.01 [95%CI 3.13-8.18]), and period (OR 1.65 [95%CI 1.22-2.26] for 2012-2016, compared to 2008-2011). CONCLUSION: In this large database, few older MBC patients were enrolled in a trial compared with younger ones.


Subject(s)
Breast Neoplasms , Neoplasms, Second Primary , Aged , Antineoplastic Combined Chemotherapy Protocols , Breast Neoplasms/drug therapy , Breast Neoplasms/epidemiology , Cohort Studies , Databases, Factual , Female , Humans , Receptor, ErbB-2 , Retrospective Studies
5.
Eur J Cancer ; 158: 181-188, 2021 Oct 21.
Article in English | MEDLINE | ID: mdl-34689042

ABSTRACT

INTRODUCTION: The estimated rate of de novo metastatic breast cancer (dnMBC) at the time of diagnosis is between 5 to 12%. International guidelines recommend metastatic work-up (MWU) only in women with advanced breast cancer. The purpose of this study was to describe the characteristics and prognosis of patients with dnMBC diagnosed without an initial indication for MWU. METHODS: We conducted a retrospective, comparative study in dnMBC patients selected from the ESME-MBC cohort. Patients were treated in France between 2008 and 2016. We compared two populations: patients in whom dnMBC was diagnosed by staging although not indicated by guidelines (non-guideline staging [NGS]) and those in whom dnMBC was diagnosed by guideline staging (GS). RESULTS: During the study period, 22,463 patients with MBC were included in the ESME cohort. Among them, 6698 were dnMBC patients. In 247 of these patients (6% of dnMBC and 1% of the overall population), dnMBC was diagnosed by non-guideline staging. Women in this group were significantly younger (57 vs. 59 years, p = 0.02) and had fewer metastatic sites at diagnosis than dnMBC-GS patients. The two groups were not significantly different in terms of the other characteristics. Overall survival (OS) and progression-free survival (PFS) were better in the dnMBC-NGS group than in the dnMBC-GS group. The impact on survival was confirmed by univariate and multivariate analysis (HR 1.83 [1.31-2.57], p < 0.01). CONCLUSION: This study provides the first description of a very specific population. These patients with dnMBC-NGS were younger and more likely to have oligometastatic disease with a better prognosis.

6.
ESMO Open ; 6(5): 100241, 2021 10.
Article in English | MEDLINE | ID: mdl-34450475

ABSTRACT

BACKGROUND: There is growing evidence that a high neutrophil-to-lymphocyte ratio (NLR) is associated with poor overall survival (OS) for patients with metastatic castration-resistant prostate cancer (mCRPC). In the CARD study (NCT02485691), cabazitaxel significantly improved radiographic progression-free survival (rPFS) and OS versus abiraterone or enzalutamide in patients with mCRPC previously treated with docetaxel and the alternative androgen-receptor-targeted agent (ARTA). Here, we investigated NLR as a biomarker. PATIENTS AND METHODS: CARD was a multicenter, open-label study that randomized patients with mCRPC to receive cabazitaxel (25 mg/m2 every 3 weeks) versus abiraterone (1000 mg/day) or enzalutamide (160 mg/day). The relationships between baseline NLR [< versus ≥ median (3.38)] and rPFS, OS, time to prostate-specific antigen progression, and prostate-specific antigen response to cabazitaxel versus ARTA were evaluated using Kaplan-Meier estimates. Multivariable Cox regression with stepwise selection of covariates was used to investigate the prognostic association between baseline NLR and OS. RESULTS: The rPFS benefit with cabazitaxel versus ARTA was particularly marked in patients with high NLR {8.5 versus 2.8 months, respectively; hazard ratio (HR) 0.43 [95% confidence interval (CI) 0.27-0.67]; P < 0.0001}, compared with low NLR [7.5 versus 5.1 months, respectively; HR 0.69 (95% CI 0.45-1.06); P = 0.0860]. Higher NLR (continuous covariate, per 1 unit increase) independently associated with poor OS [HR 1.05 (95% CI 1.02-1.08); P = 0.0003]. For cabazitaxel, there was no OS difference between patients with high versus low NLR (15.3 versus 12.9 months, respectively; P = 0.7465). Patients receiving an ARTA with high NLR, however, had a worse OS versus those with low NLR (9.5 versus 13.3 months, respectively; P = 0.0608). CONCLUSIONS: High baseline NLR predicts poor outcomes with an ARTA in patients with mCRPC previously treated with docetaxel and the alternative ARTA. Conversely, the activity of cabazitaxel is retained irrespective of NLR.


Subject(s)
Prostatic Neoplasms, Castration-Resistant , Androstenes , Antineoplastic Combined Chemotherapy Protocols , Benzamides , Humans , Lymphocytes , Male , Neutrophils , Nitriles , Phenylthiohydantoin , Prognosis , Prostatic Neoplasms, Castration-Resistant/drug therapy , Taxoids
7.
Breast ; 49: 17-24, 2020 Feb.
Article in English | MEDLINE | ID: mdl-31675683

ABSTRACT

PURPOSE: The Time to First Metastatic Recurrence (TFMR) could be considered as an indirect reflection of the tumour growth kinetics which plays an important role in cancer. Molecular subtypes such as expression of estrogen receptor are known predictive factors of TFMR. The CinéBreast study aimed to identify predictive factors of the time to TFMR. METHODS: The French Epidemiological Strategy and Medical Economics (ESME) Metastatic Breast Cancer (MBC) Database (NCT03275311) was used, which contains data from a cohort of metastatic breast cancer patients from 2008 to 2016 using retrospective data collection. It is a national multi-centre database. The impact of TFMR on overall survival (OS) since first metastasis was also evaluated. RESULTS: Among 16 702 patients recorded in the ESME MBC database, 10 595 had an initially localised breast cancer with hormone receptor (HR) and HER2 status available, with a metastatic recurrence. Median follow up was 56 months. Median TFMR was 59 months (<24: 20%, 24-60: 31%, 60-120: 25%, >120: 24%). HER2+ and TNBC were respectively 4 times and 12 times (p < 0.0001) more likely to have a recurrence within 2 years when compared to the luminal subgroup. Short TFMR and HR-/HER2-subtype significantly correlated with a poor OS in multivariate analysis. Some patients with MBC (20% in HER2+, 10% in ER+/HER2-and <5% in the ER-/HER2-) were long-term survivors in all 3 subgroups. CONCLUSIONS: In this large-scale real-life data study, patients with a TNBC metastatic recurrence had a shorter TFMR. Short TFMR significantly correlated with worse overall survival.


Subject(s)
Breast Neoplasms/pathology , Progression-Free Survival , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/metabolism , Breast Neoplasms/metabolism , Breast Neoplasms/mortality , Databases, Factual , Female , Follow-Up Studies , France/epidemiology , Humans , Middle Aged , Neoplasm Metastasis , Neoplasm Recurrence, Local , Retrospective Studies , Risk Factors , Survival Analysis , Time Factors , Triple Negative Breast Neoplasms/metabolism , Triple Negative Breast Neoplasms/mortality , Triple Negative Breast Neoplasms/pathology
8.
Eur J Cancer ; 125: 31-37, 2020 01.
Article in English | MEDLINE | ID: mdl-31835236

ABSTRACT

BACKGROUND: Options in second-line therapy after doxorubicin-based chemotherapy for metastatic/advanced leiomyosarcoma include gemcitabine (G), trabectedin and pazopanib (P) monotherapy. Currently, no combination therapy is better than monotherapy. LMS03 is an open-label multicentre single-group phase II study designed to assess the efficacy and tolerance of G + P in the second-line setting. PATIENTS AND METHODS: Patients (pts), ECOG ≤2, with metastatic leiomyosarcomas (LMS) after first-line doxorubicin chemotherapy failure were eligible. Pts were treated with G 1000 mg/m2 on days 1 and 8 of each 21 days (maximum eight cycles), in combination with oral daily P (800 mg), until disease progression/toxicity. 9-month progression-free survival (PFS) rate was the primary endpoint. Inacceptable and promising 9-month PFS rates were defined, in the intent-to-treat population, as 32% and 44%. RESULTS: 106 pts were included with a mean age of 59.8 years and an ECOG 0 in 63.5%; the primary tumour site was uterus in 61%. Pts were treated with P + G for a median of 3.8 mo, and P for a median of 4.2 mo. The 9-month PFS rate was 32.1% (95% CI 23.1-41.1). After a median follow-up of 14.2 months, the PFS was 6.5 months (95% CI 5.6-8.2), and the overall survival was 22.4 months (95% CI 16.9-26.5). The best response was 23.8%. The most frequent reported grade 3-4 adverse events were haematological. CONCLUSIONS: LMS03 failed to show that second-line therapy, with gemcitabine combined with pazopanib, followed by pazopanib alone, was beneficial for advanced LMS patients. Eudract N°2011-001308-36 and NCT01442662.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Deoxycytidine/analogs & derivatives , Leiomyosarcoma/drug therapy , Pyrimidines/therapeutic use , Sulfonamides/therapeutic use , Adult , Aged , Aged, 80 and over , Antimetabolites, Antineoplastic , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Deoxycytidine/pharmacology , Deoxycytidine/therapeutic use , Female , Humans , Indazoles , Male , Middle Aged , Pyrimidines/pharmacology , Sulfonamides/pharmacology , Gemcitabine
9.
Radiat Oncol ; 13(1): 115, 2018 Jun 20.
Article in English | MEDLINE | ID: mdl-29925410

ABSTRACT

BACKGROUND: Granular cell or Abrikossoff's tumors are usually benign however rare malignant forms concern 1 to 3% of cases reported. Pelvic locations are exceptional. CASE PRESENTATION: We report a case of a 43-years-old patient who had a benign Abrikossoff's tumor localized in the right femoral triangle diagnosed at the biopsy. The patient underwent a surgical tumorectomy and inguinal lymph nodes resection. Histologically, the tumor showed enough criteria to give diagnosis of malignancy: nuclear pleomorphism, tumor cell spindling, vesicular nuclei with large nucleoli. Moreover, five lymph nodes were metastatic. Immunohistochemistry findings confirmed the diagnosis of granular cell tumor which is positive for S100 protein and CD68 antibodies. The mitotic index was nevertheless low with a Ki67 labeling index of 1-2%. A large surgical revision with an inguinal curage following radiotherapy were decided on oncology committee. Adjuvant radiotherapy on the tumor bed and right inguinal area of ​​50 Gy in conventional fractionation was delivered with the aim of reducing local recurrence risk. There was no recurrence on longer follow-up (10 months post radiotherapy). CONCLUSIONS: Adjuvant radiotherapy seems an appropriate therapeutic approach, even if controversial, given that some authors report effectiveness on local disease progression.


Subject(s)
Granular Cell Tumor/radiotherapy , Lymph Node Excision , Adult , Female , Granular Cell Tumor/pathology , Granular Cell Tumor/surgery , Groin , Humans , Immunohistochemistry , Pregnancy , Radiotherapy, Adjuvant
10.
Eur J Cancer ; 87: 140-146, 2017 12.
Article in English | MEDLINE | ID: mdl-29149760

ABSTRACT

BACKGROUND: The GETUG 13 phase III trial tested personalised chemotherapy based on tumour marker decline in patients with poor-prognosis germ-cell tumour (GCT) and demonstrated that a dose-dense regimen improves progression-free survival in patients with an unfavourable decline. We investigated the pattern of relapse for patients included in GETUG 13. METHODS: We conducted an analysis of relapse events in patients from GETUG 13. Baseline procedures before inclusion in the trial comprised a thoraco-abdomino-pelvic computed tomography scan and a magnetic resonance imaging of the brain. RESULTS: With a median follow-up of 4.1 years (0.3; 8.8 years), a progression event was observed in 109/254 patients (43%). First event consisted in a marker progression only in 47 patients (43%), a radiographic progression only in 35 patients (32%), a mix progression on both markers and imaging in 12 patients (11%) and death in 15 patients (14%). In patients with radiographic progression only, brain was the predominant site (n = 19/35, 54%). Among patients with unfavourable decline who experienced a radiographic progression (as first and subsequent progression event, n = 58), brain was a site of progression in 28 patients (48%): 12/30 (40%) in patients treated with cisplatin, bleomycin and etoposide and 16/28 (57%) in those treated with dose-dense chemotherapy. CONCLUSIONS: Brain metastases develop often, early and frequently as the only site of relapse in the course of poor-prognosis GCT. This raises the question of early detection and optimal treatment of brain metastases in these patients, e.g. by integrating a systematic brain MRI after 2-3 months of chemotherapy.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Brain Neoplasms/secondary , Neoplasms, Germ Cell and Embryonal/drug therapy , Neoplasms, Germ Cell and Embryonal/secondary , Testicular Neoplasms/drug therapy , Testicular Neoplasms/pathology , Brain Neoplasms/diagnostic imaging , Brain Neoplasms/mortality , Clinical Trials, Phase III as Topic , Disease Progression , Disease-Free Survival , France , Humans , Kaplan-Meier Estimate , Magnetic Resonance Imaging , Male , Multicenter Studies as Topic , Neoplasms, Germ Cell and Embryonal/diagnostic imaging , Neoplasms, Germ Cell and Embryonal/mortality , Proportional Hazards Models , Retrospective Studies , Risk Factors , Testicular Neoplasms/diagnostic imaging , Testicular Neoplasms/mortality , Time Factors , Tomography, X-Ray Computed , Treatment Outcome , United States
11.
Ann Oncol ; 28(1): 103-109, 2017 01 01.
Article in English | MEDLINE | ID: mdl-28177480

ABSTRACT

Background: We present a pooled analysis of predictive and prognostic values of circulating tumour cells (CTC) and circulating endothelial cells (CEC) in two prospective trials of patients with inflammatory breast cancer (IBC) treated with neoadjuvant chemotherapy combined with neoadjuvant and adjuvant bevacizumab. Patients and methods: Nonmetastatic T4d patients were enrolled in two phase II multicentre trials, evaluating bevacizumab in combination with sequential neoadjuvant chemotherapy of four cycles of FEC followed by four cycles of docetaxel in HER2-negative tumour (BEVERLY-1) or docetaxel and trastuzumab in HER2-positive tumour (BEVERLY-2). CTC and CEC were detected in 7.5 and 4 ml of blood, respectively, with the CellSearch System. Results: From October 2008 to September 2010, 152 patients were included and 137 were evaluable for CTC and CEC. At baseline, 55 patients had detectable CTC (39%). After four cycles of chemotherapy, a dramatic drop in CTC to a rate of 9% was observed (P < 0.01). Pathological complete response (pCR) rate was 40%. No correlation was found between CTC or CEC levels and pCR rate. Median follow-up was 43 months. CTC detection (≥1 CTC/7.5 ml) at baseline was associated with shorter 3-year disease-free survival (39% versus 70% for patients without CTC, P < 0.01, HR 2.80) and shorter 3-year overall survival (OS) (P < 0.01). In multivariate analysis, independent prognostic parameters for shorter survival were absence of hormonal receptors, no pCR and CTC detection at baseline. CEC level at baseline or variations during treatment had no prognostic value. Conclusion: In this pooled analysis of two prospective trials in nonmetastatic IBC, detection rate of CTC was 39% with a strong and independent prognostic value for survival. Combination of pCR after neoadjuvant treatment with no CTC detection at baseline isolated a subgroup of IBC with excellent OS (94% 3-year OS), suggesting that CTC count could be part of IBC stratification in prospective trials.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Inflammatory Breast Neoplasms/drug therapy , Inflammatory Breast Neoplasms/pathology , Neoplastic Cells, Circulating/drug effects , Neoplastic Cells, Circulating/pathology , Adult , Aged , Bevacizumab/administration & dosage , Chemotherapy, Adjuvant , Cyclophosphamide/administration & dosage , Disease-Free Survival , Docetaxel , Epirubicin/administration & dosage , Female , Humans , Inflammatory Breast Neoplasms/blood , Inflammatory Breast Neoplasms/surgery , Middle Aged , Neoadjuvant Therapy , Prognosis , Receptor, ErbB-2/metabolism , Taxoids/administration & dosage , Trastuzumab/administration & dosage , Young Adult
12.
Ann Oncol ; 26(8): 1692-7, 2015 Aug.
Article in English | MEDLINE | ID: mdl-25943350

ABSTRACT

BACKGROUND: Inflammatory breast cancer (IBC) is a rare and aggressive disease requiring a multimodal treatment. We evaluated the benefit of adding docetaxel-5-fluorouracil (D-5FU) regimen after preoperative dose-intense (DI) epirubicin-cyclophosphamide (EC) and locoregional treatment in IBC patients. PATIENTS AND METHODS: PEGASE 07 was a national randomized phase III open-label study involving 14 hospitals in France. Women with nonmetastatic IBC were eligible and randomly assigned to receive either four cycles of DI EC (E 150 mg/m(2) and C 4000 mg/m(2) every 3 weeks with repeated hematopoietic stem cell support), then mastectomy with axillary lymph node dissection, and radiotherapy (arm A) or the same treatment followed by four cycles of D-5FU (D 85 mg/m(2), day 1 and 5FU 750 mg/m(2)/day continuous infusion, days 1-5 every 3 weeks) administered postradiotherapy (arm B). Patients with hormone receptor-positive tumors received hormonal therapy. Disease-free survival (DFS) was the primary end point. Secondary end points included tolerance, pathological complete response (pCR) rate, and overall survival (OS). RESULTS: Between January 2001 and May 2005, 174 patients were enrolled and treated (87 in each arm). Median follow-up was similar in both arms: 59.6 months [95% confidence interval (CI) 58.4-60.3] in arm A and 60.5 months (95% CI 58.3-61.4) in arm B. The estimated 5-year DFS rates were not different: 55% (95% CI 43.9-64.7) in arm A and 55.5% (95% CI 44.3-65.3) in arm B [hazard ratio (HR) = 0.94 (0.61-1.48); P = 0.81]. Identical results were observed for 5-year OS: 70.2% (95% CI 59.1-78.8) in arm A and 70% (95% CI 58.8-78.7) in arm B [HR = 0.93 (0.55-1.60); P = 0.814]. Following DI EC induction, in-breast and global (breast plus nodes) pCR were 28.9% and 20.1%, respectively. Estrogen receptor and pCR status were independently associated with survival. CONCLUSION: The addition of D-5FU after preoperative DI EC and standard local therapy did not improve DFS in IBC. CLINICAL TRIAL NUMBER: ClinicalTrials.gov identifier: NCT02324088.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Ductal, Breast/drug therapy , Carcinoma, Lobular/drug therapy , Inflammatory Breast Neoplasms/drug therapy , Mastectomy , Neoadjuvant Therapy/methods , Adult , Antineoplastic Agents, Hormonal/administration & dosage , Axilla , Chemoradiotherapy, Adjuvant/methods , Chemotherapy, Adjuvant/methods , Cyclophosphamide/administration & dosage , Disease-Free Survival , Docetaxel , Epirubicin/administration & dosage , Female , Fluorouracil/administration & dosage , Humans , Inflammatory Breast Neoplasms/metabolism , Lymph Node Excision , Middle Aged , Receptor, ErbB-2/metabolism , Receptors, Estrogen/metabolism , Receptors, Progesterone/metabolism , Taxoids/administration & dosage
13.
Ann Oncol ; 26(1): 120-125, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25361980

ABSTRACT

BACKGROUND: Everolimus is an agent frequently associated with specific toxicities. Predictive markers of efficacy are needed to help define which patients could benefit from it. The goal of this exploratory study was to identify potential predictive biomarkers in the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) activation pathway using primary tumor samples collected during the phase II tamoxifen plus everolimus (TAMRAD) trial. PATIENTS AND METHODS: Tumor tissues were collected retrospectively from the TAMRAD trial. Immunohistochemistry was carried out using specific antibodies directed toward proteins that result in mTORC1 activation [canonical phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mTOR or alternative pathways]. DNA was extracted from the tumor tissue; mutation screening in the PIK3CA gene (exons 9 and 20) and the KRAS gene (exons 2 and 3) was first carried out using Sanger direct sequencing, and then completed by next-generation sequencing for PIK3CA. An exploratory analysis of everolimus efficacy in terms of a time-to-progression (TTP) increase was carried out in each biomarker subgroup (high versus low expression referring to the median percentage of marked cells). RESULTS: A total of 55 primary tumor samples from the TAMRAD trial­25 from the tamoxifen-alone group and 30 from the tamoxifen/everolimus group­were evaluated for biomarkers. The subgroups most likely to have an improvement in TTP with tamoxifen/everolimus therapy, compared with tamoxifen alone, were patients with high p4EBP1, low 4EBP1, low liver kinase B1, low pAkt, and low PI3K. Among the 45 samples screened for mutation status, nine samples (20%; 95% CI 9.6-34.6) had a PIK3CA mutation. KRAS mutation was observed in one patient. CONCLUSIONS: A positive correlation between late effectors of mTORC1 activation, a positive correlation between Akt-independent mTORC1 activation, and an inverse correlation between canonical PI3K/Akt/mTOR pathway and everolimus efficacy were observed in this exploratory analysis. However, these correlations need to be validated in larger studies before applying the findings to routine clinical practice.


Subject(s)
Antineoplastic Agents/therapeutic use , Biomarkers, Tumor/genetics , Breast Neoplasms/drug therapy , Multiprotein Complexes/genetics , Sirolimus/analogs & derivatives , TOR Serine-Threonine Kinases/genetics , Adaptor Proteins, Signal Transducing/metabolism , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Base Sequence , Breast Neoplasms/mortality , Cell Cycle Proteins , Class I Phosphatidylinositol 3-Kinases , Everolimus , Female , Humans , Mechanistic Target of Rapamycin Complex 1 , Middle Aged , Phosphatidylinositol 3-Kinases/genetics , Phosphatidylinositol 3-Kinases/metabolism , Phosphoproteins/metabolism , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins c-akt/metabolism , Proto-Oncogene Proteins p21(ras) , Retrospective Studies , Sequence Analysis, DNA , Sirolimus/therapeutic use , TOR Serine-Threonine Kinases/metabolism , Tamoxifen/therapeutic use , ras Proteins/genetics
14.
Ann Oncol ; 26(2): 378-85, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25467013

ABSTRACT

BACKGROUND: Although sequential targeted therapy is standard in patients with metastatic clear-cell renal cell carcinoma (m-ccRCC), the choice of drugs and optimal administration sequence have yet to be established. The objective of this study was to explore whether it is preferable to rechallenge a long-term responder to a first-line tyrosine kinase inhibitor (TKI) with a TKI or whether to switch to a mammalian target of rapamycin inhibitor (mTORi); to determine whether second-line treatment response depends on duration of first-line response (TD1). PATIENTS AND METHODS: Retrospective multicenter study (2004-2011) of 241 consecutive mRCC patients (clear-cell histology) who received a first-line TKI for ≥6 months followed by a second-line TKI (n = 118) or mTORi (n = 123). END POINTS: Progression-free survival (PFS) and time-to-treatment failure (TTF) on second-line therapy. Multivariable full-model: second-line drug, TD1, ECOG-PS before first- and second-line, best objective response (first-line), Fuhrman grade, number of metastatic sites, and presence of bone metastases. Adjustment covariable: International mRCC Database Consortium (IMDC) risk score. Multiple propensity score and missing data methods were used. Any correlation between first-line and second-line PFS was investigated using censored quantile regression models (CQRM). RESULTS: Sequence effect in the overall cohort was in favor of the TKI-TKI sequence over the TKI-mTORi sequence on using TD1 as continuous covariable (HR ≈ 0.75 for PFS and TTF). TKI-TKI superiority was attributed in large part to the 11-22 month (TD1) subgroup of patients which displayed significantly better outcomes [HR ≈ 0.5; median PFS (months): 9.4 (5.9-12.2) versus 3.9 (3.0-5.5), P = 0.003; TTF(months): 8.0 (5.5-11.0) versus 3.6 (3.0-4.6), P = 0.009]. Upon full CQRM, long-term second-line responders were more likely to have received a second TKI than an mTORi and to have been long-term responders to first-line TKI. CONCLUSIONS: m-ccRCC patients who remained on first-line TKI between 11 and 22 months benefited from a TKI rechallenge rather than from second-line mTORi.


Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Renal Cell/drug therapy , Protein Kinase Inhibitors/therapeutic use , Salvage Therapy/methods , Aged , Carcinoma, Renal Cell/mortality , Disease-Free Survival , Female , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Proportional Hazards Models , Protein-Tyrosine Kinases/antagonists & inhibitors , Retrospective Studies , TOR Serine-Threonine Kinases/antagonists & inhibitors , Treatment Outcome
15.
Prostate Cancer Prostatic Dis ; 17(4): 348-52, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25311767

ABSTRACT

BACKGROUND: During the last 30 years, there has been a major shift in initial staging in prostate cancer (CaP) in Western countries, with the incidence of metastases at diagnosis decreasing from over 50% in the 1970s to currently less than 10%. Yet, CaP is still the second cause of cancer death in men. We used two monthly curated databases of patients with castration-resistant prostate cancer (CRPC) to describe the natural history of patients dying of CaP in the modern era. METHODS: The outcome of 190 men with metastatic CRPC treated from 2008 to 2011 was studied. The characteristics of the patients who died from CaP (n = 113 patients, 61%) were analyzed. RESULTS: All 113 patients who died of CaP were assessable for the presence of metastases at diagnosis. Sixty-three patients (56%) had detectable metastases at diagnosis: 67%, 11% and 43% had bone, visceral and lymph node metastases, respectively. The median time to CRPC was 16 months and median overall survival (OS) was 5.2 years.Among the patients with localized CaP at diagnosis (n = 50, 44%), 46% had T stage ⩾ 3 and 38% had a Gleason score ⩾ 8. Overall, 64% of patients were classified as having a high-risk CaP. Only 26% who died from CaP had a Gleason score ⩽ 6. Median OS was 8.8 years. CONCLUSIONS: In the modern era, approximately half of the patients who die from CaP have metastases at diagnosis. The paradigm of progression from localized disease to metastasis and eventually death is only represented in the other half, although possible initial screening and staging errors ought to be taken into consideration. More efforts are needed to conduct trials in patients with newly diagnosed metastatic CaP.


Subject(s)
Prostatic Neoplasms, Castration-Resistant/mortality , Prostatic Neoplasms, Castration-Resistant/pathology , Aged , Aged, 80 and over , Databases, Factual , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Neoplasm Metastasis/pathology , Retrospective Studies
16.
Ann Oncol ; 25(5): 987-91, 2014 May.
Article in English | MEDLINE | ID: mdl-24595454

ABSTRACT

BACKGROUND: The standard treatment of patients with metastatic germ-cell tumor (GCT) relapsing after first-line chemotherapy is based on a cisplatin and ifosfamide-containing three-drug regimen, which usually yields a complete response (CR) rate <50%. As gemcitabine consistently displayed activity in patients with advanced GCT and as synergy with cisplatin was reported, we integrated this drug into the salvage triplet regimen and assessed its activity in this phase II study. PATIENTS AND METHODS: The GIP regimen consisted in gemcitabine 1000 mg/m(2) day 1 and 5, ifosfamide 1200 mg/m(2)/day day 1-5, cisplatin 20 mg/m(2)/day day 1-5, and granulocyte colony-stimulating factor 263 µg/day day 7-15, repeated every 3 weeks for four cycles. Eligibility criteria were that patients had favorable prognostic factors to conventional-dose salvage chemotherapy including a testis primary tumor and a previous CR to first-line chemotherapy for metastatic disease. The primary end point was the CR rate and a two-stage Simon design was used. RESULTS: Thirty-seven patients were accrued and 29 (78%) achieved a favorable response, including a CR in 20 (54%) and a partial response with normalization of tumor markers (PRm-) in 9 (24%). With a median follow-up of 53 months (13-81), the 2-year overall survival rate is 73% (57%-84%) and the continuous progression-free survival rate is 51% (35%-66%). Myelosuppression was the main toxicity including febrile neutropenia in 8 (22%) patients and 18 (50%) cases required platelet infusion. No grade 3 and 4 peripheral neurotoxicity or renal toxicity occurred. Two patients died of treatment-related toxicity, one of them with cancer progression. CONCLUSION: In a multicenter context, four cycles of the GIP regimen achieved a high CR rate in patients with relapsed testicular GCT. The GIP regimen avoided severe neurotoxicity and yielded a high survival rate. CLINICAL TRIAL NUMBER: NCT00127049.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neoplasm Recurrence, Local/drug therapy , Neoplasms, Germ Cell and Embryonal/drug therapy , Testicular Neoplasms/drug therapy , Adult , Cisplatin/administration & dosage , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Drug Administration Schedule , Humans , Ifosfamide/administration & dosage , Kaplan-Meier Estimate , Lymphatic Metastasis , Male , Middle Aged , Neoplasms, Germ Cell and Embryonal/mortality , Neoplasms, Germ Cell and Embryonal/secondary , Prospective Studies , Salvage Therapy , Testicular Neoplasms/mortality , Testicular Neoplasms/pathology , Treatment Outcome , Young Adult , Gemcitabine
17.
Ann Oncol ; 23(3): 714-721, 2012 Mar.
Article in English | MEDLINE | ID: mdl-21653681

ABSTRACT

BACKGROUND: Sunitinib is a standard of care for metastatic renal cell carcinoma (mRCC). Hypothyroidism is frequently observed under sunitinib therapy. This study was conducted to prospectively determine the correlation between thyroid function and progression-free survival (PFS) in this population. PATIENTS AND METHODS: One hundred and eleven mRCC patients treated with sunitinib were evaluated for serum thyroid-stimulating hormone (TSH) and T4 levels before treatment and every 6 weeks during treatment. Survival was analysed according to a landmark method with a cut-off of 6 months, excluding early progressive or early-censored patients. RESULTS: Out of the 102 patients with normal baseline thyroid function, 53% developed thyroid dysfunction, including 95% hypothyroidisms out of which 90.9% received L-thyroxine replacement. Median time to TSH alteration was 5.4 months. Median PFS was 11.7 months for the entire population. Median PFS was not different between the groups with abnormal or normal thyroid function after 6 months of treatment (18.9 and 15.9 months, respectively, log-rank P = 0.94, hazard ratio = 1.02, 95% confidence interval = 0.54-1.93). There was no difference even after adjustment for Memorial Sloan-Kettering Cancer Centre classification and therapy line. CONCLUSIONS: Abnormal thyroid function with hormonal substitution did not increase survival in our population, independent of initial prognosis and previous treatments. Larger comparative studies are deserved to validate these conclusions.


Subject(s)
Carcinoma, Renal Cell/mortality , Hypothyroidism/chemically induced , Hypothyroidism/epidemiology , Kidney Neoplasms/mortality , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Carcinoma, Renal Cell/drug therapy , Disease-Free Survival , Female , Humans , Incidence , Indoles/adverse effects , Kaplan-Meier Estimate , Kidney Neoplasms/drug therapy , Male , Middle Aged , Proportional Hazards Models , Pyrroles/adverse effects , Sunitinib , Treatment Outcome
19.
Prog Urol ; 20(1): 24-9, 2010 Jan.
Article in French | MEDLINE | ID: mdl-20123524

ABSTRACT

Chemotherapy is indicated in metastatic castration-refractory prostate cancer. It aims at alleviating symptoms and increasing survival, without impairing quality of life. Docetaxel is considered as the reference treatment in this indication. However, several studies demonstrated the relevance of associating estramustin with docetaxel, due to the synergistic effect of the combination and the action of estramustin on resistance mechanisms. Moreover, the addition of estramustin to chemotherapy demonstrated a survival benefit for patients. Thrombotic events are frequent in patients with advanced prostate cancer and estramustine is known to increase the risk. Optimization of treatment requires a thorough assessment of the individual risk in each patient as well as the prescription of an anti-thrombotic prophylaxis, which should be currently based on low molecular weight heparin.


Subject(s)
Antineoplastic Agents, Hormonal/therapeutic use , Estramustine/therapeutic use , Prostatic Neoplasms/pathology , Humans , Male , Neoplasm Metastasis
20.
Br J Cancer ; 96(11): 1633-8, 2007 Jun 04.
Article in English | MEDLINE | ID: mdl-17505516

ABSTRACT

The aim of the study was to compare our reference adjuvant chemotherapy, FEC100 (fluorouracil 500 mg m(-2), epirubicin 100 mg m(-2) and cyclophosphamide 500 mg m(-2), six cycles every 21 days), to an epirubicin-vinorelbine (Epi-Vnr) combination for early, poor-prognosis breast cancer patients. Patients (482) were randomised to receive FEC100, or Epi-Vnr (epirubicin 50 mg m(-2) day 1 and vinorelbine 25 mg m(-2), days 1 and 8, six cycles every 21 days). The 7-year disease-free survival rates were 59.4 and 58.8%, respectively (P=0.47). The relative dose intensity of planned epirubicin doses was 89.1% with FEC100 and 88.9% with Epi-Vnr. There were significantly more grades 3-4 neutropenia (P=0.009) with Epi-Vnr, and significantly more nausea-vomiting (P<0.0001), stomatitis (P=0.0007) and alopecia (P<0.0001) with FEC100. No cases of congestive heart failure were reported, whereas four decreases in left ventricular ejection fraction occurred after FEC100 and five after Epi-Vnr. One case of acute myeloblastic leukaemia was registered in the FEC100 arm. After 7 years of follow-up, there was no difference between treatment arms. Epi-Vnr regimen provided a good efficacy in such poor-prognosis breast cancer patients, and could be an alternative to FEC100, taking into account respective safety profiles of both regimens.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Carcinoma/drug therapy , Cyclophosphamide/administration & dosage , Epirubicin/administration & dosage , Fluorouracil/administration & dosage , Vinblastine/analogs & derivatives , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Breast Neoplasms/mortality , Breast Neoplasms/pathology , Breast Neoplasms/surgery , Carcinoma/mortality , Carcinoma/pathology , Carcinoma/surgery , Chemotherapy, Adjuvant/adverse effects , Cyclophosphamide/adverse effects , Disease Progression , Epirubicin/adverse effects , Female , Fluorouracil/adverse effects , France , Humans , Lymphatic Metastasis , Mastectomy , Middle Aged , Survival Analysis , Vinblastine/administration & dosage , Vinblastine/adverse effects , Vinorelbine
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