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Background: Following the PALOMA-3 study results, the combination of palbociclib, a CDK4/6 inhibitor, with fulvestrant, a selective estrogen receptor degrader, has become a standard therapy in women with estrogen receptor-positive (ER+) HER2-negative (HER2-) metastatic breast cancer (MBC). Palbociclib has been shown to increase the progression-free survival (PFS) overall but no predictive biomarker of palbociclib efficacy has been validated so far. We thus evaluated whether early changes of circulating tumor DNA (ctDNA) levels are associated with palbociclib plus fulvestrant efficiency., Methods: ER+ HER2- MBC patients were included in a prospective observational cohort before treatment initiation. Tumor response was assessed by radiological evaluation (RECIST v1.1) every 3 months. Plasma samples were collected before treatment (baseline), at day 15 (D15), at day 30 (D30), and at disease progression. We searched for somatic mutations from archived tumor tissues by targeted deep sequencing. For patients with somatic mutations identified, circulating tumor DNA (ctDNA) was tracked using digital droplet PCR. Ratios of ctDNA levels ([D15/baseline] and [D30/baseline]) were then correlated with prospectively registered patient characteristics and outcomes., Results: Twenty-five of the 61 patients enrolled had a somatic mutation testable in plasma (N PIK3CA  = 21, N TP53  = 2, N AKT1  = 2). At baseline, 84% of patients had detectable ctDNA levels but ctDNA levels had no prognostic impact on PFS (p = 0.10). Among those patients, ctDNA was still detected in 82% at D15 and 68% at D30. ctDNA clearance observed at day 30 was associated with longer PFS (HR = 7.2, 95% CI = 1.5-32.6, p = 0.004). On the contrary, a [D30/baseline] ctDNA ratio > 1 was associated with a shorter PFS (HR = 5.1, 95% CI = 1.4-18.3, p = 0.02) and all 5 patients with increased ctDNA levels at D30 showed disease progression after 3 months under palbociclib-fulvestrant. Finally, at the time of radiological tumor progression, ctDNA was detected in all patients tested., Conclusion: Our study demonstrates that the efficiency of palbociclib and fulvestrant can be monitored by serial analyses of ctDNA before radiological evaluation and that early ctDNA variation is a prognostic factor of PFS.

Background: Cervical cancer (CC) remains a leading cause of gynaecological cancer-related mortality with infection by human papilloma virus (HPV) being the most important risk factor. We analysed the association between different viral integration signatures, clinical parameters and outcome in pre-treated CCs., Methods: Different integration signatures were identified using HPV double capture followed by next-generation sequencing (NGS) in 272 CC patients from the BioRAIDs study [NCT02428842]. Correlations between HPV integration signatures and clinical, biological and molecular features were assessed., Results: Episomal HPV was much less frequent in CC as compared to anal carcinoma (p < 0.0001). We identified >300 different HPV-chromosomal junctions (inter- or intra-genic). The most frequent integration site in CC was in MACROD2 gene followed by MIPOL1/TTC6 and TP63. HPV integration signatures were not associated with histological subtype, FIGO staging, treatment or PFS. HPVs were more frequently episomal in PIK3CA mutated tumours (p = 0.023). Viral integration type was dependent on HPV genotype (p < 0.0001); HPV18 and HPV45 being always integrated. High HPV copy number was associated with longer PFS (p = 0.011)., Conclusions: This is to our knowledge the first study assessing the prognostic value of HPV integration in a prospectively annotated CC cohort, which detects a hotspot of HPV integration at MACROD2; involved in impaired PARP1 activity and chromosome instability.

Background: Cancer-related microangiopathic haemolytic anaemia (MAHA) is a rare but life-threatening paraneoplastic syndrome. Only single cases or small series have been reported to date. We set up a retrospective multicentre study focusing on breast cancer-related MAHA., Methods: Main inclusion criteria were known diagnosis of breast cancer, presence of schistocytes and either low haptoglobin or cytopenia and absence of any causes of MAHA other than breast cancer, including gemcitabine- or bevacizumab-based treatment. Patient characteristics, treatments and outcome were retrieved from digital medical records., Results: Individual data from 54 patients with breast cancer-related MAHA were obtained from 7 centres. Twenty-three (44%) patients had a breast tumour with lobular features, and most primary tumours were low grade (grade I/II, N = 39, 75%). ER+/HER2-, HER2+ and triple-negative phenotypes accounted for N = 33 (69%), N = 7 (15%) and N = 8 (17%) cases, respectively. All patients had stage IV cancer at the time of MAHA diagnosis. Median overall survival (OS) was 28 days (range 0-1035; Q1:10, Q3:186). Independent prognostic factors for early death (≤ 28 days) were PS > 2 (OR = 7.0 [1.6; 31.8]), elevated bilirubin (OR = 6.9 [1.1; 42.6]), haemoglobin < 8.0 g/dL (OR = 3.7 [0.9; 16.7]) and prothrombin time < 50% (OR = 9.1 [1.2; 50.0]). A score to predict early death displayed a sensitivity of 86% (95% CI [0.67; 0.96]), a specificity of 73% (95% CI [0.52; 0.88]) and an area under the curve of 0.90 (95% CI [0.83; 0.97])., Conclusions: Breast cancer-related MAHA appears to be a new feature of invasive lobular breast carcinoma. Prognostic factors and scores may guide clinical decision-making in this serious but not always fatal condition.

The prospective multicenter COMET trial followed a cohort of 306 consecutive metastatic breast cancer patients receiving bevacizumab and paclitaxel as first-line chemotherapy. This study was intended to identify and validate reliable biomarkers to better predict bevacizumab treatment outcomes and allow for a more personalized use of this antiangiogenic agent. To that end, we aimed to establish risk scores for survival prognosis dichotomization based on classic clinico-pathological criteria combined or not with single nucleotide polymorphisms (SNPs). The genomic DNA of 306 patients was extracted and a panel of 13 SNPs, covering seven genes previously documented to be potentially involved in drug response, were analyzed by means of high-throughput genotyping. In receiver operating characteristic (ROC) analyses, the hazard model based on a triple-negative cancer phenotype variable, combined with specific SNPs in VEGFA (rs833061), VEGFR1 (rs9582036) and VEGFR2 (rs1870377), had the highest predictive value. The overall survival hazard ratio of patients assigned to the poor prognosis group based on this model was 3.21 (95% CI (2.33-4.42); p < 0.001). We propose that combining this pharmacogenetic approach with classical clinico-pathological characteristics could markedly improve clinical decision-making for breast cancer patients receiving bevacizumab-based therapy.

Objective: MicroRNAs (miRNAs) are promising biomarkers in ovarian cancer. Their kinetics during treatment might be useful for monitoring disease burden, and guiding treatments in patients treated with peri-operative chemotherapy and interval debulking surgery (IDS)., Methods: Serial blood samples of patients enrolled in the randomized phase II CHIVA trial, comparing first line carboplatin-paclitaxel +/- nintedanib (NCT01583322) and IDS, were investigated to assess the kinetics of 11 relevant miRNAs. Their prognostic/predictive values regarding the likelihood of complete IDS, and the patient survival, were assessed and compared to those of CA125 kinetics. The selection of the miRNAs (miR-15b-5p, miR-16-5p, miR-20a-5p, miR-21-5p, miR-93-5p, miR-122-5p, miR-150-5p, miR-195-5p, miR-200b-3p, miR-148b-5p and miR-34a-5p) was based on the expression levels found with a large explorative panel, and on the literature data., Results: 756 serial blood samples from 119 patients were analyzed for a total of 8172 miRNA assays, and 1299 CA125 values. The longitudinal kinetics of the miRNA expressions were highly inconsistent, and were not related to CA125 dynamics. The miRNA changes during neoadjuvant treatment were not found associated with RECIST tumor response or IDS outcomes. Decreases of miR-34a-5p and miR-93-5p were associated with PFS benefit (p = .009) and OS benefits (p < .001), respectively, using univariate tests., Conclusions: The longitudinal kinetics of miRNA expressions during neoadjuvant treatment in ovarian cancer patients were inconsistent, and were not found to be associated with tumor burden changes. Although some prognostic value could be discussed, no predictive value regarding tumor responses or IDS quality could be identified., Competing Interests: Declaration of Competing Interest The authors declare no potential conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Young age is a poor prognostic factor in early stage breast cancer (BC) but its value is less established in metastatic BC (MBC). We evaluated the impact of age at MBC diagnosis on overall survival (OS) across three age groups (<40, 40 to 60 and > 60 years(y))., Methods: ESME MBC database is a national cohort, collecting retrospective data from 18 participating French cancer centers between January 01, 2008 and December 31, 2014., Results: Among 14 403 women included, 1077 (7.5%), 6436 (44.7%) and 6890 (47.8%) pts were <40, 40-60 and > 60 y respectively. Pts <40 had significantly more aggressive presentations than other age groups: more frequent HER2+ (25.7 vs 15.3% in >60y) and triple negative subtypes (27.4 vs 14.6% in >60y), and more frequent visceral involvement (36.3 vs 29.8% in >60y). At a median follow-up of 48 months, median OS differed across age groups: 38.8, 38.4 and 35.6 months for pts <40, 40-60 and > 60y, respectively (p < 0.0001). Compared to pts <40y, older pts had a statistically significant higher risk of death (all causes of death included), although of limited clinical value (HR = 1.1, IC 95%:1.01-1.20). There was a significant trend for better OS in pts <40y with HER2+ and luminal diseases. A possible explanation is a greater use of anti-Her2 therapies as first-line treatments: 86.6, 81.9 and 74.9% for pts <40, 40-60 and > 60y, respectively (p < 0.0001)., Conclusion: Although young age seems associated with more aggressive presentations at diagnosis of MBC, it has no deleterious effect on OS in this large series., Competing Interests: Declaration of competing interest Co-authors having declared no conflict of interests: Sophie Frank, Matthieu Carton, Coraline Dubot, Barbara Pistilli (GR), Audrey Mailliez (COL), Christelle Levy (CFB), Véronique D’Hondt (ICM), Marc Debled (IB), Thomas Vermeulin (CHB), Bruno Coudert (CGFL), Christophe Perrin (CEM), Anthony Gonçalves (IPC), Lionel Uwer (ICL), Jean-Marc Ferrero (CAL), Jean-Christophe Eymard (IJG), Thierry Petit (CPS), Marie-Ange Mouret-Reynier (CJP), Anne Patsouris (ICO PP), Tahar Guesmia (R&D Unicancer), Thomas Bachelot (CLB), Mathieu Robain (R&D Unicancer), Paul Cottu. Mario campone: Advisory Board: Consulting fees to my Institut:Astra ZENECA, Novartis, Abbvie, Sanofi, Pfizer, Sandoz, ACCORD. Personal fees to Lilly, G1 Therapeutic Consultant: Fees to my Institute: Pierre Fabre Oncology; Sanofi; Novartis; Servier. Speaker bureau: Personnal fees Novartis, Lilly Travel: Pfizer, Novartis, Roche, Astra Zeneca. Barbara Pistilli:P ersonal fees from AstraZeneca, Pfizer, Myriad, Pierre Fabre and non-financial support from Pfizer, Puma and Merus, Novartis outside the submitted work Florence Dalenc: Advisory Board: Novartis, Pfizer, Lilly Travel: Pfizer, Novartis, Roche, Astra Zeneca Paul Cottu: Advisory Board: Novartis, Pfizer, Lilly, Roche Travel: Pfizer, Novartis, Roche, Astra Zeneca., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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.

Background: Olaparib has shown significant clinical benefit as maintenance therapy in women with newly diagnosed advanced ovarian cancer with a BRCA mutation. The effect of combining maintenance olaparib and bevacizumab in patients regardless of BRCA mutation status is unknown., Methods: We conducted a randomized, double-blind, international phase 3 trial. Eligible patients had newly diagnosed, advanced, high-grade ovarian cancer and were having a response after first-line platinum-taxane chemotherapy plus bevacizumab. Patients were eligible regardless of surgical outcome or BRCA mutation status. Patients were randomly assigned in a 2:1 ratio to receive olaparib tablets (300 mg twice daily) or placebo for up to 24 months; all the patients received bevacizumab at a dose of 15 mg per kilogram of body weight every 3 weeks for up to 15 months in total. The primary end point was the time from randomization until investigator-assessed disease progression or death., Results: Of the 806 patients who underwent randomization, 537 were assigned to receive olaparib and 269 to receive placebo. After a median follow-up of 22.9 months, the median progression-free survival was 22.1 months with olaparib plus bevacizumab and 16.6 months with placebo plus bevacizumab (hazard ratio for disease progression or death, 0.59; 95% confidence interval [CI], 0.49 to 0.72; P<0.001). The hazard ratio (olaparib group vs. placebo group) for disease progression or death was 0.33 (95% CI, 0.25 to 0.45) in patients with tumors positive for homologous-recombination deficiency (HRD), including tumors that had BRCA mutations (median progression-free survival, 37.2 vs. 17.7 months), and 0.43 (95% CI, 0.28 to 0.66) in patients with HRD-positive tumors that did not have BRCA mutations (median progression-free survival, 28.1 vs. 16.6 months). Adverse events were consistent with the established safety profiles of olaparib and bevacizumab., Conclusions: In patients with advanced ovarian cancer receiving first-line standard therapy including bevacizumab, the addition of maintenance olaparib provided a significant progression-free survival benefit, which was substantial in patients with HRD-positive tumors, including those without a BRCA mutation. (Funded by ARCAGY Research and others; PAOLA-1 ClinicalTrials.gov number, NCT02477644.)., (Copyright © 2019 Massachusetts Medical Society.)

Background: In this prospective phase 2 trial, we assessed the efficacy of trastuzumab-emtansine (T-DM1) in HER2-negative metastatic breast cancer (MBC) patients with HER2-positive CTC., Methods: Main inclusion criteria for screening were as follows: women with HER2-negative MBC treated with ≥ 2 prior lines of chemotherapy and measurable disease. CTC with a HER2/CEP17 ratio of ≥ 2.2 by fluorescent in situ hybridization (CellSearch) were considered to be HER2-amplified (HER2 amp ). Patients with ≥ 1 HER2 amp CTC were eligible for the treatment phase (T-DM1 monotherapy). The primary endpoint was the overall response rate., Results: In 154 screened patients, ≥ 1 and ≥ 5 CTC/7.5 ml of blood were detected in N = 118 (78.7%) and N = 86 (57.3%) patients, respectively. ≥1 HER2 amp CTC was found in 14 patients (9.1% of patients with ≥ 1 CTC/7.5 ml). Among 11 patients treated with T-DM1, one achieved a confirmed partial response. Four patients had a stable disease as best response. Median PFS was 4.8 months while median OS was 9.5 months., Conclusions: CTC with HER2 amplification can be detected in a limited subset of HER2-negative MBC patients. Treatment with T-DM1 achieved a partial response in only one patient., Trial Registration: NCT01975142, Registered 03 November 2013.

Background: Nivolumab and pembrolizumab targeting programmed cell death protein 1 (PD-1) have recently been approved among patients with recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC) who failed platinum therapy. We aimed to evaluate the prognostic value of selected immune gene expression in HNSCC., Patients and Methods: We retrospectively assessed the expression of 46 immune-related genes and immune-cell subpopulation genes including immune checkpoints by real-time polymerase chain reaction among 96 patients with HNSCC who underwent primary surgery at Institut Curie between 1990 and 2006. Univariate and multivariate analyses were performed to assess the prognostic value of dysregulated genes., Results: The Median age of the population was 56 years [range: 35-78]. Primary tumour location was oral cavity (45%), oropharynx (21%), larynx (18%) and hypopharynx (17%). Twelve patients (13%) had an oropharyngeal human papillomavirus-positive tumour. Most significantly overexpressed immune-related genes were TNFRSF9/4-1BB (77%), IDO1 (75%), TNFSF4/OX40L (74%) and TNFRSF18/GITR (74%), and immune-cell subpopulation gene was FOXP3 (62%). Eighty-five percent of tumours analysed overexpressed actionable immunity genes, including PD-1/PD-L1, TIGIT, OX40/OX40L and/or CTLA4. Among the immune-related genes, high OX40L mRNA level (p = 0.0009) and low PD-1 mRNA level (p = 0.004) were associated with the highest risk of recurrence. Among the immune-cell subpopulation genes, patients with high PDGFRB mRNA level (p < 0.0001) and low CD3E (p = 0.0009) or CD8A mRNA levels (p = 0.004) were also at the highest risk of recurrence., Conclusions: OX40L and PDGFRB overexpression was associated with poor outcomes, whereas PD-1 overexpression was associated with good prognosis in patients with HNSCC treated with primary surgery, suggesting their relevance as potential prognostic biomarkers and major therapeutic targets., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: There is a lack of information as to which molecular processes, present at diagnosis, favor tumour escape from standard-of-care treatments in cervical cancer (CC). RAIDs consortium (www.raids-fp7.eu), conducted a prospectively monitored trial, [BioRAIDs (NCT02428842)] with the objectives to generate high quality samples and molecular assessments to stratify patient populations and to identify molecular patterns associated with poor outcome., Methods: Between 2013 and 2017, RAIDs collected a prospective CC sample and clinical dataset involving 419 participant patients from 18 centers in seven EU countries. Next Generation Sequencing has so far been carried out on a total of 182 samples from 377 evaluable (48%) patients, allowing to define dominant genetic alterations. Reverse phase protein expression arrays (RPPA) was applied to group patients into clusters. Activation of key genetic pathways and protein expression signatures were tested for associations with outcome., Findings: At a median follow up (FU) of 22 months, progression-free survival rates of this FIGO stage IB1-IV population, treated predominantly (87%) by chemoradiation, were65•4% [CI95%: 60•2-71.1]. Dominant oncogenic alterations were seen in PIK3CA (40%), while dominant suppressor gene alterations were seen in KMT2D (15%) and KMT2C (16%). Cumulative frequency of loss-of-function (LOF) mutations in any epigenetic modulator gene alteration was 47% and it was associated with PIK3CA gene alterations in 32%. Patients with tumours harboring alterations in both pathways had a significantly poorer PFS. A new finding was the detection of a high frequency of gains of TLR4 gene amplifications (10%), as well as amplifications, mutations, and non-frame-shift deletions of Androgen receptor (AR) gene in 7% of patients. Finally, RPPA protein expression analysis defined three expression clusters., Interpretation: Our data suggests that patient population may be stratified into four different treatment strategies based on molecular markers at the outset. FUND: European Union's Seventh Program grant agreement No 304810., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Febrile neutropenia (FN) is one of the most common and most critical adverse effects of chemotherapy. Despite many existing guidelines based on the use of granulocyte-colony stimulating factor (G-CSF), FN continues to impair the quality of life and interfere with the treatment of many patients. The purpose of this study was to assess the incidence and management of FN associated with chemotherapy for early breast cancer in routine clinical practice., Methods: All patients with early-stage breast cancer (ESBC) treated by chemotherapy at Institut Curie, Hôpital René Huguenin, in 2014 were retrospectively included. The incidence and management of FN were reported. Risk factors associated with FN were studied by robust-error-variance Poisson regression., Results: A total of 524 patients received either neoadjuvant (N = 130) or adjuvant chemotherapy (N = 394). Most patients (80%) were treated with a combination of 5-fluorouracil, epirubicin, and cyclophosphamide (FEC100; 3 cycles) followed by docetaxel 100 mg/m 2 (D; 3 cycles). The overall incidence of FN was 17%. Eighteen percent of patients received primary prophylaxis (PP) for FN with G-CSF, using pegfilgrastim in 64% of cases and 74% of patients over the age of 70 received PP. Less than 5% of patients who received PP experienced FN. Recurrent FN after secondary prophylaxis was observed in 9% of patients. Forty-seven percent of cases of FN occurred after the first cycle and 30% occurred after the fourth cycle, corresponding to D ± trastuzumab (T). The FEC100 regimen was associated with a relative risk of FN of 1.98 (p = 0.09). Autoimmune (AI) and inflammatory diseases were associated with a higher risk of FN (RR 3.08; p < 0.01). No significant difference in the incidence of FN was observed between adjuvant and neoadjuvant chemotherapy. FN was managed on an outpatient basis in 72% of cases. Outpatients with FN were mainly treated by a combination of amoxicillin-clavulanic acid and ciprofloxacin. Dose reduction or chemotherapy regimen modification were necessary in 25% of patients after FN. No toxic death was reported., Conclusion: The incidence of FN induced by adjuvant/neoadjuvant chemotherapy in ESBC is higher in routine clinical practice than in clinical trials. AI or inflammatory diseases were significant independent risk factors for FN. Primary prophylaxis in patients at risk (elderly, comorbid patients), especially treated with the FEC regimen, is the keystone of management of this adverse effect. Prevention and management of FN to ensure the patient's safety and quality of life are a major issue for both medical oncologists and supportive care physicians.

Purpose: Precision medicine trials constitute a precious source of molecular data with prospective clinical annotations allowing the exploration of patients' subpopulations according to specific clinical or biological questions. Using the SHIVA01-the first randomized trial comparing molecularly targeted therapy on the basis of tumor molecular profiling versus conventional chemotherapy in metastatic cancer patients who failed standard of care therapy-annotated database, we report cases of patients treated in the trial with targeted therapy who experienced an objective response or prolonged disease stabilization in light of patients' molecular alterations., Patients and Methods: We selected all patients included in SHIVA01 treated with a molecularly targeted agent (MTA) who experienced an objective response or disease stabilization that lasted longer than 6 months according to Response Evaluation Criteria in Solid Tumors version 1.1., Results: Among the 170 patients who received MTAs in the SHIVA01 trial, 15 patients (9%) experienced an objective response (n = 3) or disease stabilization that lasted longer than 6 months (n = 12). The most frequent histologic subtypes were breast cancer (27%) and cervical cancer (20%). Six patients, including three patients with breast cancer, were treated with abiraterone on the basis of androgen receptor protein overexpression. Five patients were treated with everolimus on the basis of a PTEN heterozygous deletion with loss of protein expression, PIK3CA mutation, or both alterations. The remaining four patients were treated with tamoxifen, erlotinib, imatinib, and vemurafenib on the basis of progesterone receptor expression, EGFR amplification, KIT mutation, and BRAF mutation, respectively. TP53 mutations were absent in responder patients., Conclusion: Analysis of patients who experienced objective responses or disease stabilization that lasted longer than 6 months allowed the identification of potential biomarkers of sensitivity and resistance to MTAs., Competing Interests: Clinical trials information: NCT01771458.The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Clémence BasseNo relationship to discloseClaire MorelNo relationship to discloseCéline CallensNo relationship to discloseGaëlle PierronNo relationship to discloseVincent ServoisNo relationship to discloseAnne Vincent-SalomonHonoraria: Roche, AstraZeneca Research Funding: NanoString Technologies (Inst) Travel, Accommodations, Expenses: NanoString Technologies, GenentechAude JobardTravel, Accommodations, Expenses: BayerMarie AltNo relationship to discloseFrancesco RicciNo relationship to discloseDelphine LoiratConsulting or Advisory Role: Roche, MSD Oncology, Bristol-Myers SquibbMarie-Paule SablinNo relationship to discloseMarie BretagneNo relationship to discloseMathilde Saint-GhislainNo relationship to discloseSégolène HescotNo relationship to discloseAnthony GonçalvesResearch Funding: MSD Oncology (Inst), Bristol-Myers Squibb (Inst), Novartis (Inst), Cascadian Therapeutics (Inst), Nektar (Inst), Boehringer Ingelheim (Inst), Eli Lilly (Inst), AbbVie (Inst) Travel, Accommodations, Expenses: Pfizer, Novartis, Genentech, CelgeneOlivier TredanConsulting or Advisory Role: Roche, Pfizer, Novartis, Eli Lilly, AstraZeneca, MSD Oncology, Roche Research Funding: Novartis, Pfizer, Eli Lilly, Bristol-Myers Squibb, MSD Oncology, AstraZeneca Travel, Accommodations, Expenses: Roche, Novartis, Pfizer, Eli Lilly, AstraZenecaCoraline DubotNo relationship to discloseCéline GavoilleNo relationship to discloseJean-Pierre DelordNo relationship to discloseMario CamponeHonoraria: Novartis, Servier, Menarini Consulting or Advisory Role: Novartis (Inst), Servier (Inst), Menarini, Sanofi (Inst), Eli Lilly (Inst), Pfizer (Inst), AstraZeneca (Inst), MedImmune (Inst) Speakers' Bureau: Novartis, Amgen Research Funding: Novartis (Inst) Travel, Accommodations, Expenses: Novartis Other Relationship: RocheNicolas IsambertTravel, Accommodations, Expenses: Celgene, PharmaMar, Novartis, AstraZeneca, MedImmune, GenentechLisa BelinNo relationship to discloseIvan BiecheNo relationship to discloseMaud KamalNo relationship to discloseChristophe Le TourneauHonoraria: Novartis, Bristol-Myers Squibb Consulting or Advisory Role: Amgen, MSD Oncology, Bristol-Myers Squibb, Merck Serono, AstraZeneca Travel, Accommodations, Expenses: MSD Oncology, Bristol-Myers Squibb, AstraZeneca, (© 2018 by American Society of Clinical Oncology.)

Introduction: Ovarian cancer is mostly diagnosed at advanced stage. Better survival is achieved through complete debulking surgery and chemotherapy. Historically, neoadjuvant chemotherapy (NAC) has been introduced for unresectable disease to decrease tumor load and perform a unique complete surgery. Four randomized control trials have compared primary debulking surgery to NAC, but there is still controversy about the use of neoadjuvant chemotherapy and questions about its modalities. Areas covered: We made a review of knowledge on benefits of NAC compared to primary debulking chemotherapy, in terms of survival and morbidity, methods of administration, new drugs in early and late phase trials, the selection of patients. Similar survival was observed after NAC and interval debulking surgery or primary debulking surgery. Morbidity of surgery was decreased after interval debulking compared primary debulking surgery. Conventional drugs are carboplatin and paclitaxel. Safety of bevacizumab was evaluated in phase 2 trials associated with conventional drugs. Immunotherapy trials are enrolling patients in phase 1 study. Expert commentary: NAC followed by debulking surgery is the best treatment for patients with advanced ovarian cancer.

Purpose: Leptomeningeal carcinomatosis (MC) is commonly associated with HER2-positive breast cancer (HER2-BC), with a poor prognosis and no standardised treatment. We conducted a phase I dose-escalation study of intrathecal (IT) administration of trastuzumab in HER2-BC patients with MC to determine the maximum tolerated dose (MTD), which was based on both the achievement of a trastuzumab intra-cerebrospinal fluid concentration close to a conventional therapeutic plasma concentration (30 mg/L) and/or dose-limiting toxicity (DLT)., Methods: The protocol planned IT administration of trastuzumab (30 mg, 60 mg, 100 mg or 150 mg dose levels) once a week, over the course of at least 4 weeks. Sixteen patients with MC from HER2-BC received IT trastuzumab. Intra-cerebrospinal fluid samples were obtained before each injection for pharmacokinetics., Results: We did not observe DLT of IT trastuzumab. Eleven patients had no toxicity attributed to IT trastuzumab. For 60 mg or higher dose levels, minor toxicities attributed to IT trastuzumab included headache (2 patients), nausea (2 patients), vomiting (1 patient), cervical pain (1 patient) and peripheral neuropathy (1 patient). Two patients experienced immediate toxicity including headache or vomiting. The mean residual intra-cerebrospinal fluid concentration of trastuzumab was 27.9 mg/L for the 150 mg dose level. Three patients achieved a clinical response, seven patients had stable disease and four patients had progressive disease., Conclusions: The MTD and recommended phase II weekly dose of IT trastuzumab in patients with HER2-BC and MC is 150 mg. A phase II trial using this dose regimen in MC from HER2-BC is ongoing., Registration Identification: ClinicalTrials.gov Identifier: NCT01373710 (https://clinicaltrials.gov/ct2/show/NCT01373710?term=trastuzumab+intrathecal&rank=1)., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: High throughput molecular screening techniques allow the identification of multiple molecular alterations, some of which are actionable and can be targeted by molecularly targeted agents (MTA). We aimed at evaluating the relevance of using this approach in the frame of Institut Curie Molecular Tumor Board (MTB) to guide patients with cancer to clinical trials with MTAs., Patients and Methods: We included all patients presented at Institut Curie MTB from 4 October 2014 to 31 October 2017. The following information was extracted from the chart: decision to perform tumour profiling, types of molecular analyses, samples used, molecular alterations identified and those which are actionable, and inclusion in a clinical trial with matched MTA., Results: 736 patients were presented at the MTB. Molecular analyses were performed in 442 patients (60%). Techniques used included next-generation sequencing, comparative genomic hybridisation array and/or other techniques including immunohistochemistry in 78%, 51% and 58% of patients, respectively. Analyses were performed on a fresh frozen biopsy in 91 patients (21%), on archival tissue (fixed or frozen) in 326 patients (74%) and on both archival and fresh frozen biopsy in 25 patients (6%). At least one molecular alteration was identified in 280 analysed patients (63%). An actionable molecular alteration was identified in 207 analysed patients (47%). Forty-five analysed patients (10%) were enrolled in a clinical trial with matched MTA and 29 additional patients were oriented and included in a clinical trial based on a molecular alteration identified prior to the MTB analysis. Median time between date of specimen reception and molecular results was 28 days (range: 5-168)., Conclusions: The implementation of an MTB at Institut Curie enabled the inclusion of 10% of patients into a clinical trial with matched therapy., Competing Interests: Competing interests: None declared.

International guidelines have set the frame and methods of patients' surveillance after early breast cancer (BC) treatment. Since 1998, delegation of low-risk BC patients follow-up to nonhospital practitioners has been developed within a care network in the Paris region. We used the Gynecomed care network digital database to describe the characteristics of oncological events which occurred in the cohort, and to assess the quality of BC follow-up in relapsing patients. Events were defined as any local, contralateral, or metastatic recurrence, as well as second cancer or death due to any cause. We developed a ranked evaluation method of our surveillance program. Among the 3019 patients followed in the network, 116 (4.3%) patients had 116 events. Median follow-up was 7.1 years (0-51). First events were local-regional relapses, contralateral BCs, metastatic events, second primaries in respectively 52, 26, 14, 24 cases. During the first 5 years, 68.4% of surveillance visits were performed on time, 13.5% were behind schedule and 18.1% were not performed, while 79.1% of mammographies were performed on time, 7.7% behind schedule, and 13.2% were not performed. On schedule examinations allowed diagnosis of 77% of the local-regional, ipsilateral relapses or contralateral BCs, including 38 (69%) discovered by mammographies and 17 (31%) by clinical examination. A nonhospital practitioner care network is able to comply with good surveillance practices and deliver high quality surveillance, in accordance with international guidelines. Delegation of low-risk BC surveillance to nonhospital practitioners is reliable., (© 2017 Wiley Periodicals, Inc.)

Purpose: The Prosigna® breast cancer prognostic gene signature assay identifies a gene-expression profile that permits the classification of tumors into subtypes and gives a score for the risk of recurrence (ROR) at 10 years. The primary objective of this multicenter study was to evaluate the impact of Prosigna's assay information on physicians' adjuvant treatment decisions in patients with early-stage breast cancer. Secondary objectives were to assess confidence of practitioners in their therapeutic recommendations before and after the added information provided by the Prosigna assay; and to evaluate the emotional state of patients before and after the Prosigna test results., Methods: Consecutive patients with invasive early-stage breast cancer were enrolled in a prospective, observational, multicenter study carried out in 8 hospitals in France. The Prosigna test was carried out on surgical specimens using the nCounter® Analysis System located at the Institut Curie. Both before and after receiving the Prosigna test results, physicians completed treatment confidence questionnaires and patients completed questionnaires concerning their state of anxiety, the difficulties felt in face of the therapy and quality of life. Information was also collected at 6 months regarding the physicians' opinion on the test results and the patients' degree of anxiety, difficulties with therapy and quality of life., Results: Between March 2015 and January 2016, 8 study centers in France consecutively enrolled 210 postmenopausal women with estrogen receptor (ER) positive, human epidermal growth hormone-2 (HER-2) negative, and node negative tumors, either stage 1 or stage 2. Intrinsic tumor subtypes as assessed by the Prosigna test were 114 (58.2%) Luminal A, 79 (40.3%) Luminal B, 1 (0.5%) HER-2 enriched (HER-2E), and 2 (1.0%) basal-like. Before receiving the Prosigna test results, physicians categorized tumor subtypes based on immunohistochemistry (IHC) as Luminal A in 126 (64%) patients and Luminal B in 70 (36%) patients, an overall discordance rate of 25%. The availability of Prosigna assay results was significantly associated with the likelihood of change in treatment recommendations, with 34 patients (18%) having their treatment plan changed from Adjuvant Chemotherapy to No Adjuvant Chemotherapy or vice versa (p<0.001, Fisher's exact test). Prosigna test results also decreased patients' anxiety about the chosen adjuvant therapy, and improved emotional well-being and measures of personal perceptions of uncertainty., Conclusions: The results of this prospective decision impact study are consistent with 2 previous, identically designed studies carried out in Spain and Germany. The availability of Prosigna test results increased the confidence of treating physicians in their adjuvant treatment decisions, and led to an 18% change in chemotherapy treatment plan (from Adjuvant Chemotherapy to No Adjuvant Chemotherapy or vice versa). Prosigna testing decreased anxiety and improved measures of health-related quality of life in patients facing adjuvant therapy. The 25% discordance between Prosigna test and IHC subtyping underlines the importance of molecular testing for optimal systemic therapy indications in early breast cancer.

The objective of this literature review is to describe the types of tumor heterogeneity in breast cancer and their clinical implication. Two kinds of tumor heterogeneity are described: intertumor heterogeneity and intra-tumor heterogeneity. In breast cancer, inter-tumor heterogeneity was best characterized in the 2000s thanks to high throughput analyses. These analyzes resulted in a molecular classification of breast cancers distinguishing four subtypes: Luminal A, Luminal B, HER 2+ and basal like. This variability may be observed between the primary tumor and metastases, namely the temporal intratumor heterogeneity. The average discrepancy for the progesterone receptor, estrogen, and between HER2 status appears to be 33%, 20% and 8%, respectively. It is then interesting to study the heterogeneity within the primary tumor: this spatial intra-tumor heterogeneity is poorly known. Physiopathology of intra-tumor heterogeneity light be deciphered by studies on cancer stem cells and clonal evolution model. In addition, the tumor microenvironment seems to actively contribute to this heterogeneity. The major interest to study this heterogeneity is the clinical implication that could result. While precision medicine is emerging, it is important to capture the heterogeneity of each specific tumor type. These new biological knowledge will allow us to anticipate such heterogeneity and individualize the management of breast cancer.

Background: We aimed at identifying druggable molecular alterations at the RNA level from untreated HNSCC patients, and assessing their prognostic significance., Methods: We retrieved 96 HNSCC patients who underwent primary surgery. Real-time quantitative RT-PCR was used to analyze a panel of 42 genes coding for major druggable proteins. Univariate and multivariate analyses were performed to assess the prognostic significance of overexpressed genes., Results: Median age was 56 years [35-78]. Most of patients were men (80%) with a history of alcohol (70.4%) and/or tobacco consumption (72.5%). Twelve patients (12%) were HPV-positive. Most significantly overexpressed genes involved cell cycle regulation (CCND1 [27%], CDK6 [21%]), tyrosine kinase receptors (MET [18%], EGFR [14%]), angiogenesis (PGF [301%], VEGFA [14%]), and immune system (PDL1/CD274 [28%]). PIK3CA expression was an independent prognostic marker, associated with shorter disease-free survival., Conclusions: We identified druggable overexpressed genes associated with a poor outcome that might be of interest for personalizing treatment of HNSCC patients., Competing Interests: No conflicts to disclose

Objective: The "Institut national du cancer" has established since 2007 a minimum threshold of 20 patients per year per center to treat patients with gynecologic cancer. This review aims to assess whether the literature data validate this approach, and specifically for ovarian cancer., Methods: A search of the MEDLINE database was conducted, to reference all relevant articles evaluating one hand the links between the survival of patients with ovarian cancer and the average volume of patients per center and by operator; and secondly the relationship between quality of oncological surgery and these volumes., Results: Nineteen studies met our inclusion criteria; seventeen were retrospective and two were prospective; population samples ranged from 476 to 96,802 patients. The most important data, quantitatively and qualitatively, concern the evaluation of survival based on the average volume per center, with 8 out of 13 studies finding a statistically significant correlation between average volume per center and survival. Data on the quality of surgery are less abundant and more heterogeneous, depending on the definition of the "optimal" surgery by the authors., Conclusion: The establishment of threshold centers appears to be an effective way to improve survival in ovarian cancer. However, these thresholds would have to be specific to ovarian cancer and not extended to "gynecological cancers.", (Copyright © 2016 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

The poor outcome of patients with recurrent ovarian cancer constitutes a continuous challenge for decision-making in clinical practice. In this setting, molecular targets have recently been identified, and novel compounds are now available. Bevacizumab has been introduced for the treatment of patients with ovarian cancer and is, to date, the most extensively investigated targeted therapy in this setting. However, potential toxicities are associated with the use of this monoclonal antibody. These toxicities have been reported in clinical trials, and can also be observed outside of trials. As limited data is currently available regarding the safety of bevacizumab treatment in daily clinical practice, the current retrospective study was designed to evaluate this. Data from 156 patients with recurrent ovarian cancer who had received bevacizumab treatment between January 2006 and June 2009 were retrospectively identified from the institutional records of five French centers. In contrast to clinical trials, the patients in the present study were not selected and had a heterogeneous profile according to their prior medical history, lines of treatment prior to bevacizumab introduction and number of relapses. The results first confirm the effect of heavy pretreatment on the occurrence of serious and fatal adverse events in clinical practice, as previously reported for clinical trials and for other retrospective cohort studies. Importantly, the data also demonstrates, for the first time, that medical history of hypertension is an independent predictive risk factor for the development of high-grade hypertension during bevacizumab treatment. These results thus suggest that treating physicians must consider all risk factors for managing bevacizumab toxicity prior to its introduction. Such risk factors include the time of bevacizumab introduction, a patient's history of hypertension and a low incidence of pre-existing obstructive disease.

Objective: We report our experience on fertility sparing treatment in young women affected by cervical cancer of more than 2cm., Methods: Between July 2012 and February 2014, five patients presenting cervical tumors larger than 2cm (IB1>2cm) (23-35) and wishing to preserve fertility have been treated at our institution. Laparoscopic pelvic and para-aortic lymphadenectomy was performed for all patients. When lymph nodes were free of disease, patients had neoadjuvant chemotherapy followed by surgical conservative treatment., Results: Four patients underwent a cisplatin based neoadjuvant chemotherapy before conservative surgery: radical trachelectomy or simple trachelectomy. One patient with nodal involvement underwent a 3cycle chemotherapy followed by concurrent radiochemotherapy. Hematologic toxicity grade 3 was observed in one patient leading to a change of chemotherapy. Two patients showed complete disappearance of tumor and two a partial response to neoadjuvant treatment. After a mean follow up of 20.5months (14-33), no relapse was observed. To date, no pregnancy was obtained., Conclusion: Lymph node staging followed by neoadjuvant chemotherapy and radical trachelectomy seems to be a promising treatment scheme for patients with cervical tumors IB1>2cm pN0 seeking parenthood., (Copyright © 2015 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Background: Molecularly targeted agents have been reported to have anti-tumour activity for patients whose tumours harbour the matching molecular alteration. These results have led to increased off-label use of molecularly targeted agents on the basis of identified molecular alterations. We assessed the efficacy of several molecularly targeted agents marketed in France, which were chosen on the basis of tumour molecular profiling but used outside their indications, in patients with advanced cancer for whom standard-of-care therapy had failed., Methods: The open-label, randomised, controlled phase 2 SHIVA trial was done at eight French academic centres. We included adult patients with any kind of metastatic solid tumour refractory to standard of care, provided they had an Eastern Cooperative Oncology Group performance status of 0 or 1, disease that was accessible for a biopsy or resection of a metastatic site, and at least one measurable lesion. The molecular profile of each patient's tumour was established with a mandatory biopsy of a metastatic tumour and large-scale genomic testing. We only included patients for whom a molecular alteration was identified within one of three molecular pathways (hormone receptor, PI3K/AKT/mTOR, RAF/MEK), which could be matched to one of ten regimens including 11 available molecularly targeted agents (erlotinib, lapatinib plus trastuzumab, sorafenib, imatinib, dasatinib, vemurafenib, everolimus, abiraterone, letrozole, tamoxifen). We randomly assigned these patients (1:1) to receive a matched molecularly targeted agent (experimental group) or treatment at physician's choice (control group) by central block randomisation (blocks of size six). Randomisation was done centrally with a web-based response system and was stratified according to the Royal Marsden Hospital prognostic score (0 or 1 vs 2 or 3) and the altered molecular pathway. Clinicians and patients were not masked to treatment allocation. Treatments in both groups were given in accordance with the approved product information and standard practice protocols at each institution and were continued until evidence of disease progression. The primary endpoint was progression-free survival in the intention-to-treat population, which was not assessed by independent central review. We assessed safety in any patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, number NCT01771458., Findings: Between Oct 4, 2012, and July 11, 2014, we screened 741 patients with any tumour type. 293 (40%) patients had at least one molecular alteration matching one of the 10 available regimens. At the time of data cutoff, Jan 20, 2015, 195 (26%) patients had been randomly assigned, with 99 in the experimental group and 96 in the control group. All patients in the experimental group started treatment, as did 92 in the control group. Two patients in the control group received a molecularly targeted agent: both were included in their assigned group for efficacy analyses, the patient who received an agent that was allowed in the experimental group was included in the experimental group for the purposes of safety analyses, while the other patient, who received a molecularly targeted agent and chemotherapy, was kept in the control group for safety analyses. Median follow-up was 11·3 months (IQR 5·8-11·6) in the experimental group and 11·3 months (8·1-11·6) in the control group at the time of the primary analysis of progression-free survival. Median progression-free survival was 2·3 months (95% CI 1·7-3·8) in the experimental group versus 2·0 months (1·8-2·1) in the control group (hazard ratio 0·88, 95% CI 0·65-1·19, p=0·41). In the safety population, 43 (43%) of 100 patients treated with a molecularly targeted agent and 32 (35%) of 91 patients treated with cytotoxic chemotherapy had grade 3-4 adverse events (p=0·30)., Interpretation: The use of molecularly targeted agents outside their indications does not improve progression-free survival compared with treatment at physician's choice in heavily pretreated patients with cancer. Off-label use of molecularly targeted agents should be discouraged, but enrolment in clinical trials should be encouraged to assess predictive biomarkers of efficacy., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The delegation of low-risk breast cancer patients' follow-up to non-hospital practitionners (NHP), including gynaecologists and general practitioners, has been assessed prospectively within a care network in the Paris region. Patients with early stage breast cancer were eligible. The follow-up protocol was built according to international guidelines. By 2012, 289 NHPs were following 2266 patients treated in 11 centres. Median follow-up time was 7.4 years. The mean intervals between two consecutive consultations were 9.5 [9.2-9.8] months for women supposed to be monitored every 6 months and 12.5 [12.2-12.8] for those requiring annual monitoring. The relapse rate was 3.2% [2.1-4.3] at 5 years and 7.8% [5.9-9.7] at 10 years. Seventy one percent of relapses were diagnosed on a scheduled assessment. Only 6% were lost-to-follow-up. Delegating follow-up after low risk breast cancer to NHPs in a care network is feasible, well accepted and provides an alternative to follow-up in specialized centres., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Doublet chemotherapy with cisplatin is the reference for the treatment of recurrent cervical cancer. However, those tumors are little chemo-sensitive and overall survival remains poor. Moreover, because of pelvic irradiation, toxicities, especially hematologic toxicities, are increased and require a drug dose reduction. Finally, these treatments are rarely effective in radiation areas. Given all these elements, the development of new therapies is a prominent issue. This article reviews the results of the major targeted therapies in cervical cancer. Anti-EGFRs are disappointing despite of a strong biological rational. On the other hand, bevacizumab is the first targeted therapy to show a significant increase of overall survival. A major effort must be made in translational research for a better understanding of tumor biology of these tumors.

Because of increasing breast cancer incidence and improvement in long-term prognosis, follow-up of patients cannot be carried out entirely in specialized cancer centres. The Réseau Gynécomed was created to transfer the follow-up of patients to primary care physicians (PCP). In 2009, to evaluate the quality of PCP follow-up, a satisfaction study was performed for the 1,245 women followed after breast cancer. Sixty-four percent of the women participate in the study. Before starting follow-up, 87% were informed about its purpose and 93% about its schedule. The satisfaction score was excellent (91%). Old age, perception of a good health status, a high quality of information about and a confident relationship with their PCP were associated with a better satisfaction level. Forty-eight percent of patients thought easy to accept the PCP follow-up. Considering this data, PCP monitoring seems to provide a good follow-up and may be developed. Nonetheless, conditions of patients' choice should be improved and particularly exclude patients with financial difficulties. It would facilitate the growing transfer of follow-up to the PCP.