Magali Provansal

Cancer du sein triple-négatif : caractéristiques histocliniques et moléculaires, prise en charge et perspectives thérapeutiques

Triple-negative breast cancer (TNBC), as defined by the absence of estrogen and progesterone receptor expression, as well as the lack of HER2 overexpression/amplification, corresponds to 15% of breast cancer and represents an aggressive form of the disease. TNBC are frequently confounded with basal subtype in the molecular classification of breast cancer and also share some similarities with BRCA1-mutated tumors. Epidemiological and clinical characteristics are distinct from other subtypes, including a younger age at diagnosis, a higher risk of relapse in spite of increased chemosensitivity, and a higher incidence of lung and brain metastatic relapses. Conventional cytotoxics remain the mainstay of current systemic management but recent evaluation of more targeted therapeutics, including specific cytotoxics (such as the use of platinum salts), PARP and EGFR inhibition, and antiangiogenics have been performed, providing contrasted but rather disappointing results. Recent data indicate that TNBC represent a heterogeneous entity composed of multiple and distinct molecular subtypes, which should deserve specific targeted therapeutics.

Prognostic factors for ovarian epithelial cancer in the elderly: a case-control study.

Objectives Ovarian cancer is the leading cause of mortality by gynecologic cancers in Western countries. Many publications have suggested that age may be an independent prognostic factor in ovarian carcinoma. There are only few data concerning the impact of treatments and geriatric features within the elderly population. Methods/Materials We collected data of older (≥70 years old) patients treated in our institution for an invasive ovarian carcinoma between 1995 and 2011. First we described usual clinical and pathological features for these patients, as well as their outcome. We compared these parameters with that of young (<70 years old) patients treated during the same period. We then observed geriatric features in our set: Eastern Cooperative Oncology Group performance status, number of medications, Charlson index, body mass index, hemoglobin, and glomerular filtration rate. We finally looked for prognostic factors specific of the elderly population. Results One hundred nine elderly patients were identified and compared with 488 younger cases. There was no difference concerning clinicopathologic data. Surgery was more frequently complete in young women (58% vs 41.7%), and older patients received less chemotherapy courses and less taxanes (38.4% vs 67.1%). Young patients had a longer overall survival (median, 65.2 vs 26.2 months, P = 8.5E−10, log-rank test). Multivariate analyses confirmed that age was an independent prognostic factor and that within the elderly set the International Federation of Gynecology and Obstetrics stage, surgery results, number of chemotherapy cycles administered and performance status had a significant prognostic value. No clear correlation could be observed between geriatric characteristics and treatments administration. Conclusions Ovarian cancer prognosis is poorer for older women, but they are more frequently suboptimally treated. No correlation could be observed between geriatric factors and surgery or chemotherapy achievement. Treatment decision should be based on objective geriatric assessment in order to improve outcome in this population.

Prognostic impact of hormone receptor- and HER2-defined subtypes in inflammatory breast cancer treated with high-dose chemotherapy: a retrospective study

Purpose: Studies examining high-dose chemotherapy with autologous hematopoietic stem cell transplantation (HDC-AHSCT) strategies in inflammatory breast cancer (IBC), showed encouraging results in terms of disease-free survival (DFS), and overall survival (OS). The lack of data regarding HER2 status in all of these studies prevented any prognostic analysis involving breast cancer subtypes. Methods: All consecutive female patients treated for IBC with HDC and AHSCT at Institut Paoli-Calmettes between 2003 and 2012 were included. Since 2005, trastuzumab was included in initial treatment. Patient, tumor and treatment characteristics were collected. Patients were categorized in three subtypes based on hormonal receptor (HR) and HER2 status of the primary tumor: Luminal, (HR+/HER2-), HER2 (HER2+, any HR), and triple negative (TN) (HER2- and HR-). The main objective was the analysis of OS according to the IHC subtypes. Results: Sixty-seven patients were included. Eleven patients received trastuzumab. Median follow up was 80.04 months (95% CI 73.2-88.08). Five-year OS and DFS for the whole population patients were 74% (95% CI 61-83) and 65 % (95% CI 52-75), respectively. OS differed across subtypes (p=0.057) : HER2 subgroup appeared to have the best prognosis with a 5-year OS of 89% (95% CI 64-97) compared to 57% (95% CI 33-76) for the TN subgroup (HR 5.38, 95% CI 1.14-25.44; p=0.034). Conclusions: In IBC patients receiving HDC-AHSCT, OS favorably compares with data available in the literature on similar groups of patients. TN patients carried the least favourable OS and HER2 patients, half of them also receiving trastuzumab, had the best outcome. These findings provide additional information and options for patients with IBC and who could potentially benefit of HDC-AHSCT.

Abstract A118: PIKHER2: A phase Ib study evaluating oral BKM120 in combination with lapatinib in trastuzumab-resistant HER2-positive advanced breast cancer

Background: Phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR)-pathway is frequently activated in HER2-positive breast cancer and may play a major role in resistance to trastuzumab. Lapatinib is a dual anti-HER2/EGFR tyrosine kinase inhibitor with clinical activity after trastuzumab failure in HER2-positive advanced breast cancer (ABC). BKM120 is a pan-class I PI3K inhibitor with potent and selective activity against wild-type and mutant PI3K p110α. PIKHER2 phase Ib study aimed primarily to determine maximum tolerated dose (MTD) and propose a recommended phase II dose (RP2D) for BKM120 in combination with lapatinib in HER2-positive, trastuzumab-resistant, ABC. Secondary objectives included safety, antitumor activity, pharmacokinetics and biomarker assessments. Methods: PIKHER2 was a multi-center study, enrolling HER2 positive (IHC 3+ or FISH positive) ABC, with disease progressing either while on trastuzumab for metastatic disease or within 12 months of the last infusion for patients who received trastuzumab as adjuvant/neoadjuvant treatment. Oral BKM120 (B; 40, 60 or 80 mg) and lapatinib (L; 750, 1000 or 1250 mg) were administered daily. A modified CRM using an adaptive Bayesian model guided the dose escalation of both agents. PIK3CA mutational status and PTEN/hormone receptor expression IHC was evaluated on available tumor tissue. Results: A total of 24 HER2-positive ABC pts, with a median number of previous lines of cytotoxics = 2 (1-5) and previous lines of anti-HER2 = 2 (1-6) for advanced stage, were treated across 5 dose-levels (B,40 + L,750; B, 60 + L,750; B,80 + L,750; B,80 + L,1000; B,80 + L,1250). Following cycle 1, 5 pts experienced DLTs: G3 ALT elevation, G3 vomiting, G3 stomatitis, G3 hyperglycemia and G3 diarrhea. MTD was reached at B,80 + L,1250 but toxicities and early treatment discontinuation beyond cycle 1 led us to select B,80 + L,1000 as the RP2D. Main drug-related adverse events were: diarrhea (83% of pts, G3 in 21%), nausea/vomiting (83% of pts, G3 in 4%), skin toxicity (75% of pts, G3 in 21%), asthenia (70% of patients, no G3), depression (58% of pts, G3 in 4%), anxiety (42% of pts, no G3), transaminases increase (29% of pts, G3 in 17%). B and L PK parameters values were consistent with those already published for both drugs. A large inter-individual variability was observed for both drugs. There was no significant evidence for drug-drug PK interaction. Disease control rate (DCR) was 79% [57-92%], one patient obtained a complete remission and 6 additional patients experienced stable disease for ≥ 24 weeks (clinical benefit rate, CBR of 29% [12-51%]). PIK3CA mutations and PTEN loss were observed in 4 of 14 and 1 of 21 patients, respectively. DCR and CBR were higher in hormone receptor-negative tumors. C onclusion: Combining BKM120 and lapatinib in HER2-positive trastuzumab-resistant was feasible. Preliminary evidences of antitumor activity were observed in this heavily pre-treated population. Citation Format: Anthony Goncalves, Mathilde Guerin, Nicolas Isambert, Mario Campone, Keyvan Resai, Aurelie Autret, Jihane Pakradouni, Alexie Robert, Magali Provansal, Emmanuelle Charafe-Jauffret, Renaud Sabatier, Alice Hervieu, Jean-Marc Extra, Patrice Viens, Francois Lokiec, Jean-Marie Boher. PIKHER2: A phase Ib study evaluating oral BKM120 in combination with lapatinib in trastuzumab-resistant HER2-positive advanced breast cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A118.

Targeted NGS, array-CGH, and patient-derived tumor xenografts for precision medicine in advanced breast cancer: a single-center prospective study

Background Routine feasibility and clinical impact of genomics-based tumor profiling in advanced breast cancer (aBC) remains to be determined. We conducted a pilot study to evaluate whether precision medicine could be prospectively implemented for aBC patients in a single center and to examine whether patient-derived tumor xenografts (PDX) could be obtained in this population. Results Thirty-four aBC patients were included. Actionable targets were found in 28 patients (82%). A targeted therapy could be proposed to 22 patients (64%), either through a clinical trial (n=15) and/or using already registered drugs (n=21). Ten patients (29%) eventually received targeted treatment, 2 of them deriving clinical benefit. Of 22 patients subjected to mouse implantation, 10 had successful xenografting (45%), mostly in triple-negative aBC. Methods aBC patients accessible to tumor biopsy were prospectively enrolled at the Institut Paoli-Calmettes in the BC-BIO study (ClinicalTrials.gov, NCT01521676). Genomic profiling was established by whole-genome array comparative genomic hybridization (aCGH) and targeted next-generation sequencing (NGS) of 365 candidate cancer genes. For a subset of patients, a sample of fresh tumor was orthotopically implanted in humanized cleared fat pads of NSG mice for establishing PDX. Conclusions Precision medicine can be implemented in a single center in the context of clinical practice and may allow genomic-driven treatment in approximately 30% of aBC patients. PDX may be obtained in a significant fraction of cases.

Immunohistochemical subtypes predict survival in metastatic breast cancer receiving high-dose chemotherapy with autologous haematopoietic stem cell transplantation

INTRODUCTION The objective of this study was to evaluate the outcome of patients affected with different subtypes of metastatic breast cancer (MBC) following treatment with high-dose chemotherapy (HDC) and autologous haematopoietic progenitor cell transplantation (AHSCT). METHODS All consecutive female patients treated for MBC with HDC and AHSCT at the Institut Paoli-Calmettes between 2003 and 2012 were included. Patient, tumour and treatment characteristics were collected. Patients were categorised in three subtypes based on hormonal receptor (HR) and human epidermal growth factor receptor 2 (HER2) status of the primary tumour: luminal (L), (HR+/HER2-), HER2 (HER2+, any HR), and triple negative (TN) (HER2- and HR-). The main objective was the analysis of overall survival (OS) according to the immunohistochemical (IHC) subtypes. RESULTS A total of 235 patients were included, median age was 46 (range 21-62). Median follow up was 53.28 months (95% confidence interval [CI] 45.12-57.6). The TN subtype appeared to have the worst prognosis with a median OS of 19.68 months (95% CI 11.76-44.4) compared to 44.64 months (95% CI 40.32-67.56) for the luminal subtype and a median OS not reached for the HER2 subtype (p < 0.01). In the multivariate analysis, the TN subtype retained an independent poor prognosis value compared to the luminal subtype, with a hazard ratio of 2.03 (95% CI 1.26-3.29, p = 0.037). CONCLUSION HDC-AHSCT does not change the prognostic value of IHC subtypes in MBC patients. OS favourably compares with data available in the literature on similar groups of patients. These findings provide additional information and options for patients with MBC and who could potentially benefit of HDC-AHSCT.

Safety Results and Analysis of Eribulin Efficacy according to Previous Microtubules-Inhibitors Sensitivity in the French Prospective Expanded Access Program for Heavily Pre-treated Metastatic Breast Cancer

Purpose Eribulin is approved for advanced breast cancers refractory to anthracyclines and taxanes. Efficacy according to sensitivity to previous therapies has been poorly explored. Materials and Methods Safety data were collected prospectively and we retrospectively collected efficacy data from the five French centres that participated in the Eribulin E7389-G000-398 expanded access program. Our main objectives were exploration of safety and analysis of eribulin efficacy (progression-free survival [PFS] and overall survival [OS]) according to sensitivity to the last microtubule-inhibiting agent administered. Results Median eribulin treatment duration was 3.3 months for the 250 patients included in this prospective single-arm study. Two hundreds and thirty-nine patients (95.6%) experienced an adverse event (AE) related to treatment including 129 (51.6%) with grade ≥ 3 AEs. The most frequently observed toxicities were cytopenias (59.6% of included patients), gastro-intestinal disorders (59.2%), and asthenia (56.4%). The most frequent grade 3-4 AE was neutropenia (37.2% with 4.8% febrile neutropenia). Median PFS and OS were 4.6 and 11.8 months, respectively. Patients classified as responders to the last microtubule-inhibiting therapy had a longer OS (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.51 to 0.94; p=0.017), and tended to display a better PFS (HR, 0.78; 95% CI, 0.58 to 1.04; p=0.086). OS improvement was still significant in multivariate analysis (adjusted HR, 0.53; 95% CI, 0.35 to 0.79; p=0.002). Conclusion This work based on a prospective study suggests that identification of patients likely to be more sensitive to eribulin could be based on their previous response to microtubules inhibitors.

Abstract 2049: Pharmacokinetic drug-drug interaction: a phase Ib dose escalation study of LY2780301 in combination with weekly paclitaxel

Introduction: LY2780301 is an orally available small molecule dual inhibitor of p70 S6 kinase and AKT. LY2780301 is an inhibitor of CYP3A4. By the one hand, Paclitaxel (PXL) undergoes extensive metabolism via CYP450 2C8 and CYP450 3A4 pathways. By the other hand, PXL induces weakly CYP3A4 activity. In this study we investigated for the first time, the potential pharmacokinetic (PK) drug-drug interaction (DDI) related to the combination of both drugs LY2780301 and PXL. Methods: Women with HER2- locally advanced or metastatic breast cancer, with and without PI3/AKT pathway activation, were treated with weekly administration of PXL on day1 (D1), D8 and D15. LY2780301 was administered by a daily flat dosing regimen starting at D3. Dose levels [DL, LY2780301 (mg/day)/PXL (mg/m2/week)] ranged from 400/70 to 500/80. For PK analysis, 7 time point samples were collected on D1 and D3 of cycle 1 for PXL and LY2780301 respectively. 7 samples were collected on D8 for both drugs. LY2780301 plasma concentrations were measured using Ultra Performance Liquid Chromatography (UPLC) coupled with tandem mass spectrometry validated method. PXL plasma concentrations were measured using UPLC coupled with UV validated method. A joint population PK (PK-POP) model has been developed for LY2780301 and its main metabolite. PK-POP modelling has been performed with a non linear mixed effect model program (Monolix version 4.3.2). Results: 12 patients, 35 to 67 years old, were treated. A total of 160 and 157 concentrations for LY2780301 and its metabolite were used respectively for PK-POP modeling. A one compartment open model adequately described LY2780301 and its metabolite concentration versus time courses respectively with the estimation of the fraction of absorbed dose (fm) of LY2780301 metabolised in that metabolite. The interindividual variabilities (ISV) could be well estimated for all structural parameters (clearance: CL, volume of distribution: V, L and the absorption constant: Ka). The population PK parameters obtained for the structural model were: Ka = 0.536 h−1, CL/F = 3.57 L/h, V/F = 85.2 L, CL/(F*fm) = 13.2 L/h, V2/(F*fm) = 13.2 L, fm = 0.747 for LY2780301 and its metabolite respectively. PXL increases LY2780301 CL from 3.57 to 4.4 L/h (p = 0.016). Conclusions: We have demonstrated a PK DDI between LY2780301 and PXL. PXL increases LY2780301 CL and decreases LY2780301 AUC. PXL PK modeling is ongoing in order to verify the effect of LY2780301 on PXL PK. Citation Format: Keyvan Rezai, Samuel Huguet, Olivier Madar, Jean-Marc Extra, Magali Provansal, Carole Tarpin, Nicolas Isambert, Jihane Pakradouni, Anthony Goncalves, Francois Lokiec. Pharmacokinetic drug-drug interaction: a phase Ib dose escalation study of LY2780301 in combination with weekly paclitaxel. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2049.

Abstract 2036: A phase Ib pharmacokinetic drug-drug interaction evaluation of oral buparlisib in combination with lapatinib in HER2+/PI3K-activated, trastuzumab-resistant locally advanced, recurrent and metastatic breast cancer (MBC)

Background: A novel combination of oral lapatinib (LPT), a selective dual ErbB1/ErbB2 targeted drug, + oral buparlisib (B) a pan-class I PI3K inhibitor, could provide a synergestic antitumor activity in trastuzumab resistant disease. LPT has been shown to be a potent CYP3A4 inhibitor which is also mainly involved in BKM120 metabolism. In this study we investigated the potential pharmacokinetic (PK) drug-drug interactions (DDI) related to the association of B and LPT. Methods: Trastuzumab-resistant HER2 + metastatic breast cancer (MBC) patients were treated with a continuous once daily dosing schedule of LPT + B. Dose levels [DL, LPT (mg)/B (mg)] ranged from 750/40 to 1,250/80. For PK analysis, 2 time point samples were collected on D1 and D8 and 10 time point samples were collected on D15 of cycle 1 for LPT and B assays. Plasma concentrations of B and LPT, were measured using UPLC coupled with tandem mass spectrometry validated methods. Population PK was modeled using a non linear mixed effect model program (Monolix version 4.3s) by computing the maximum likelihood estimator of the parameters without any approximation of the model (no linearization). Results: 343 and 322 plasma concentrations were available for PK analysis of LPT and B respectively. A two-compartment open model adequately described B concentration versus time courses. The inter-individual variabilities (ISV) could be well estimated for all stuctural parameters (clearance: CL, volume of distribution: V, inter-compartmental clearance: Q) except for absorption constant: Ka. The population PK parameters obtained for the structural model were: Ka = 0.985 h−1, CL/F = 10.5L/h, V1/F = 54.8 L, Q/F = 46.3 L/h, V2/F = 582 L. Mean AUC0-24h(CV%) values for B were 10130 (34%), 15450 (29%), and 20560 (38%) ng*hr/mL for 40 mg, 60 mg and 80 mg dose level respectively. A one-compartment model adequately fitted the LPT plasma concentration-time data. The population PK parameters were CL/F = 25.7 L/h, V/F = 291 L and the absorption constant, Ka = 0.214 h−1. B has no significant effect on the PK of LPT and vice versa. Conclusions: B AUC increased proportionally with increasing dose. LPT PK parameters are consistent with those already published. There is no significant evidence for drug-drug PK interaction between LPT and B. Intra-occasion variabilities will be discussed. Citation Format: Francois Lokiec, Anthony Goncalves, Fanny Bret, Jihane Pakradouni, Magali Provansal, Renaud Sabatier, Jean-Marc Extra, Carole Tarpin, Nicolas Isambert, Mario Campone, Keyvan Rezai. A phase Ib pharmacokinetic drug-drug interaction evaluation of oral buparlisib in combination with lapatinib in HER2+/PI3K-activated, trastuzumab-resistant locally advanced, recurrent and metastatic breast cancer (MBC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2036.

New Therapeutic Targets

Cervical cancer occurs in approximately 500,000 women and kills 288,000 women worldwide each year. Prognosis is highly dependent on disease stage at diagnosis. When detected early, cervical cancer is generally curable. Early lesions are treated surgically and locally advanced lesions are managed with concurrent cisplatin chemotherapy and pelvic radiation. Unfortunately, responses to chemoradiation are partial and are of short duration.