Search

Resume Objectifs On observe dans l’Herault une nette augmentation de l’incidence des cancers urologiques. Le registre des tumeurs de l’Herault (RTH) a recueilli 1961 tumeurs urologiques en 2016, soit 21,4 % de l’ensemble des tumeurs de l’Herault pour cette annee-la. La creation d’un registre specialise en onco-urologie nous est apparue necessaire. L’objectif de cet article est de decrire le fonctionnement de RHESOU et de donner quelques exemples de resultats. Materiel et methodes En novembre 2018, RHESOU (Registre de l’herault specialise en onco-urologie) a ete cree sur le meme mode de fonctionnement qu’un registre. Il permet de completer les donnees du RTH sur beaucoup d’autres parametres oncologiques. Pour chaque type de cancer urologique et genital masculin et urologique feminin, une fiche de recueil a ete realisee pour recueillir le maximum de donnees presentes dans le dossier des cas signales. Cette etude a evalue les donnees concernant les patients domicilies dans l’Herault pour l’annee 2017. Resultats Nous avons denombre pour l’annee 2017, 970 cancers de la prostate, 581 tumeurs de vessie, 212 cancers du rein, 51 tumeurs de la voie excretrice superieure, 28 cancers du testicule et 9 cancers du penis. Le recueil de ces donnees permet de creer des requetes et de fournir des analyses pertinentes et detaillees sur les cancers urologiques et genitaux masculins. Nous rapportons les donnees analysees sur le rein, la vessie et la prostate. Conclusions RHESOU est un outil accessible pour permettre une vue d’ensemble sur les cancers en urologie dans l’Herault et leur prise en charge. Avec l’apparition de nouveaux traitements, il saura s’adapter en permettant une evolution des fiches. Niveau de preuve 3.

Background The EndoPredict (EP) test has been developed and validated for assessing recurrence risk in patients with estrogen receptor (ER)-positive HER2-negative breast cancer (BC). This test is based on the expression of 12 genes (molecular score), combined with clinicopathological criteria (i.e. tumor size and nodal status) (EPclin risk score). For node-positive patients, the weight given to the node status in the EPclin score is similar when considering pN1mi (]0.2-2mm]) or pN1 (>2mm, 1-3 positive lymph nodes). Our aim was to characterize the EPclin classification of the pN1mi subgroup in the French national registry for molecular signatures in ER+ BC. Methods Since April 2016, nine French laboratories using EP test in clinical practice prospectively implement a national registry for molecular prognostic signatures in ER+ BC. We analyzed the pN1mi subgroup with regards to their clinico-pathological characteristics, molecular EP score and EPclin risk score. Using the definition formula of the EPclin score [EPclin=0.35t + 0.64n + 0.28EP, with n=1 for pN0, 2 for pN1mi/pN1, 3 for pN2, 4 for pN3], we could calculate a hypothetical EPclin score if the pN1mi had been considered as pN0 [n factor=1]. Results By the end of 2017, the database included 1246 EP tests performed in routine practice, including 67 (5.4%) pN1mi. The pN1mi BC were ER+ HER2- (67/67, 100%), invasive carcinoma of no special type in 52/67 (78%), with a median tumor size of 18 mm (range 7-45; pT1c in 40/67). Among these, 22 were classified as EPclin low and 45 as EPclin high, with a median EP score of 6 (range 2-14), a median EPclin score of 3.70 (range 3-6), and a median relapse risk at 10-year of 15%(range 5-73). Most interestingly, 23/67 (34%; i.e. 1.8% of all EP tests performed) pN1mi BC displayed an EPclin score comprised between 3.4 and 4, just above the cut-off value of 3.3: these cases (and only these cases) would have been classified in a different risk category (i.e. EPclin low risk) if the node status would have been considered as negative. Conclusion With regards to EndoPredict test in pN1mi BC - and the persistent debate as to whether they should bear the same weight as node-positive (pN1) or negative (pN0) tumors - categorization in the EPclin class is not likely to be impacted by the node factor weight in the vast majority (>65%) of the pN1mi cases and >98% of all patients tested with EP. Only cases with an EPclin between 3.4 and 4 might be impacted. Citation Format: LaCroix-Triki M, Arnould L, MacGrogan G, Penault-Llorca F, Haudebourg J, Tas P, Garnier A, Vincent-Salomon A, Miquel C, Lehmann-Che J, Callens C, Quillien V, Cayre A, Lamy P-J, Rouleau E, De Cremoux P. EndoPredict prognostic signature in pN1mi, estrogen receptor-positive breast cancer: analysis of the French national registry for molecular signatures [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-08-23.

Introduction: There has been increasing interest in the potential benefit of vitamin D to improve breast cancer outcomes. Pre-clinical studies suggest vitamin D enhances chemotherapy-induced cell death. We previously reported (Thomas A SABCS 2016) that low serum vitamin D levels were associated with not attaining a pathologic complete response (pCR) following breast cancer neoadjuvant chemotherapy (NAC). We report here the impact of vitamin D on survival parameters in an expanded cohort of patients. Methods: Patients from two Iowa registries who had serum vitamin D level measured before or during NAC were included. French patients enrolled in a previous study of the impact of NAC on vitamin D and bone metabolism were also eligible for this study. Vitamin D deficiency was defined as < 20 ng/mL. pCR was defined as no residual invasive disease in breast and lymph nodes. Survival was defined from the date of diagnosis to the date of relapse (PFS) or date of death (OS). Results: The study included 327 women. Median age was 51 years. Patients presented with HER2+, HR+/HER2- and triple negative (TN) tumors in 28.5%, 43.9% and 27.6% of the cases respectively. In this expanded cohort, vitamin D deficiency remained associated with the odds of not attaining pCR (OR 1.64; 95%CI: 1.02-2.66, p=0.04). Median follow-up was 5.33 years (range 0.5 to 9.8 years). Of these patients, there were 54 relapse and 52 deaths. In multivariate analysis, stage III disease, TN phenotype and the inability to achieve pCR were independently associated with a worse survival (Table 1). Table 1 PFS (Hazard Ratio, 95%CI)pOS (Hazard Ratio, 95%CI)pStage I - II1 1 III2.78 (1.56 – 4.95)0.0012.82 (1.57 - 5.05)0.001Tumor phenotype HR+/HER2-1 1 HER2+3.00 (1.28 – 7.06)0.0121.78 (0.76 – 4.08)0.174TN7.37 (3.26 – 16.69)< 0.0016.50 (3.07 – 13.76)< 0.001NAC response Non-pCR1 1 pCR0.19 (0.08 – 0.45)< 0.0010.22 (0.09 – 0.55)< 0.001Vitamin D < 20 ng/mL1 1 ≥ 20 ng/mL1.01 (0.57 – 1.78)0.971.03 (0.58 – 1.84)0.92 Vitamin D deficiency was not significantly associated with survival parameters in the general population; however a trend was seen in the TN population regarding the correlation with PFS (90 patients, 5-year PFS 60.4% vs. 72.3%, p=0.18). Conclusion: Vitamin D deficiency is associated with the inability to reach pCR in breast cancer undergoing NAC. A trend for worse survival was seen in the TN subgroup. The strong association between vitamin D deficiency and the inability to reach pCR warrant further evaluation in the TN subgroup. Prospective interventional studies are needed to elucidate if maintaining vitamin D levels during NAC, a highly modifiable variable, may be utilized to improve cancer outcomes, particularly in TN breast cancers. Citation Format: Viala M, Chiba A, Thezenas S, Delmond L, Lamy P-J, Mott SL, Schroeder MC, Thomas A, Jacot W. Clinical correlations of serum vitamin D in patients undergoing neoadjuvant systemic therapy and survival outcomes for operable breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-10-09.

Purpose: Intermediate-risk early breast cancer (EBC) is a heterogeneous group in which adjuvant chemotherapy decision prove to be difficult. Clinical and pathological criteria might be insufficient to determine the best therapeutic options for patients, and validated biomarkers are urgently needed to help decision making, such as the LOE-I uPA/PAI-1 biomarker. The aim of this study is to evaluate the clinical outcome of a large, unselected, ER+/HER2- pN0 EBC cohort of patients in whom the routine clinical decision process included a prospective uPA/PAI-1 determination. Methods: This monocentric retrospective study included 520 ER+/HER2- pN0/M0 EBC patients who had curative surgery in our center between 2006 and 2011. Adjuvant therapeutic strategy was decided based on clinico-pathological data, altogether with a routine prospective determination of uPA/PAI-1 tumor levels. We evaluated the correlation between uPA/PAI-1 levels, classical clinico-pathological variables and the patient's outcome (relapse free survival, RFS; overall survival, OS). Results: Median age was 54 years (range 27-85). 75% of tumors were classified T1, 25% T2 and above. We found 80.8% of ductal carcinomas, 12.3% of lobular carcinomas and 6.9% of other histological types. SBR grade 1-2 represented 82.5% of our cohort versus 17.5% of grade 3. Mitotic count was Conclusion: The individualization of patients' treatment using uPA/PAI-1 tumor levels allows the reversion of the well-known poor prognostic impact of high uPA/PAI-1 levels and strongly support the use of this LOE-I biomarker in clinical practice. PR status and mitotic activity remains independent major prognostic factors in optimally treated patients. The evaluation of the additional impact of multigene signature in this setting needs to be performed. Longer 10-years follow-up needs to be done in this ER+/HER2- subgroup, particularly to evaluate the risk of late relapse after endocrine therapy. Citation Format: Viala M, Alexandre M, Thézenas S, Lamy P-J, Bibeau F, Gutowski M, Colombo P-E, Romieu G, Jacot W, Guiu S. Prognostic impact of the inclusion of uPA/PAI-1 in ER+/Her2- pN0 early breast cancer adjuvant treatments decision-making [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-09-28.

Introduction: Pathologic complete response (pCR) following neoadjuvant systemic chemotherapy (NAC) serves as a measure of tumor responsiveness and is a recognized surrogate for improved long-term outcomes. Some, but not all, studies have found a positive association between vitamin D (VD) and disease-free survival. We investigated if VD at diagnosis or during chemotherapy impacts pCR following neoadjuvant chemotherapy for operable breast cancer. Methods: Patients from Iowa were eligible if they were enrolled in one of two Iowa registries and had serum from before or during NAC tested for VD. French patients enrolled in a previous study of the impact of NAC on vitamin D and bone metabolism were considered for this study. VD deficiency was defined as Results: The final cohort included 144 women. 84.7% of VD levels were obtained before initiation of chemotherapy. There was no difference between the French and Iowa cohorts with regard to age (p=0.20), clinical stage (p=0.22), disease receptor status (HER2+ [Hormone receptor (HR)+ or HR-], HR+/HER2-, and Triple Negative) (p=0.32) and rate of pCR (p=0.34). French women had lower body mass index (mean 24.8 vs 28.8, p Conclusion: In this retrospective cohort, VD level before or during NAC was associated with pCR. Prospective trials could elucidate if maintaining VD levels during NAC, a highly modifiable variable, can be utilized to improve cancer outcomes in addition to benefiting other established health outcomes. Table 1: VD Deficient and Sufficient Groups Vitamin D (ng/ml) Deficient (< 20)Sufficient (≥ 20)pN 5391 BMIUnderweight-Normal27 (50.9)47 (51.6)0.93 Overweight-Obese26 (49.1)44 (48.4) VD LevelBefore Chemotherapy45 (84.9)77 (84.6)0.96 During Chemotherapy8 (15.1)14 (15.4) GradeG1-224 (47.1)41 (46.1)0.91 G327 (52.9)48 (53.9) Clinical StageI-II37 (69.8)61 (67)0.73 III16 (30.2)30 (33) Receptor StatusHER2+ (HR+ or HR-)12 (22.6)29 (32.2)0.20 HR+/HER2-30 (56.6)37 (41.1) Triple Negative11 (20.8)24 (26.7) SurgeryBreast Conserving32 (60.4)58 (63.7)0.69 Mastectomy21 (39.6)33 (36.3) pCRNo43 (81.1)53 (58.2) Table 2: Odds of Not Attaining a pCR: Multivariable Results NOdds Ratio95% CIp-valueCohortIowa661.170.522.630.71 France77Ref Vitamin D ( Citation Format: Thomas A, Thezenas S, Mott SL, Raman R, Viala M, Pouderoux S, Schroeder MC, Lamy P-J, Jacot W. Vitamin D level impacts odds of pathologic complete response following neoadjuvant therapy in operable breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-09-24.

Background Androgen receptor (AR) is expressed in 8-53% of triple negative breast cancer (TNBC). Its prognostic value in this subgroup is controverted. FOXA1 is essential for expression of 50% of estrogen receptor (ER)–related genes. Microarray studies identified the subgroup of molecular apocrine or luminal androgen receptor tumors that express AR and luminal genes including FOXA1 but nor ER. Preclinical data suggested that FOXA1 may direct AR to sites normally occupied by ER in luminal tumors, inducing an estrogen-like gene program stimulating proliferation. We have already shown that TNBC with AR/FOXA1 co-expression seem to behave like luminal tumors. We aimed at evaluating co-expression AR/FOXA1-associated profiles and its prognostic value in a large retrospective series of patients with non-metastatic TNBC with a long follow-up. Patients and methods AR and FOXA1 expression were evaluated by immunohistochemistry in tissue microarrays of 300 patients with non-metastatic TNBC treated in our center between 2002 and 2012. Positivity threshold was set at ≥10% staining. Results Median age was 57.7 years (range 28.5-98). 46.2% of tumors were classified T1 and 64% pN0. We found 83.2% of ductal carcinomas, 5% of lobular carcinomas and 11.8% of other histological types. SBR grade 1-2 represented 21.4%. A basal-like phenotype (cytokeratins 5/6 and/or EGFR+) was observed in 63.7% of cases. In 161 evaluable patients, a PIKCA mutation (exon 9 or 20) was observed in 16.2% of cases. In 124 evaluable patients, a deletion of PTEN was observed in 25% of cases. Adjuvant chemotherapy was delivered in 74.5% of patients. 37.7% of patients had AR+ tumors and 29.7% had AR+ and FOXA1+ tumors. AR+/FOXA1+ tumors were more frequently: found in older patients (p With a median follow-up of 5.5 years, recurrence-free survival (RFS) was significantly lower for patients with AR+/FOXA1+ tumors (p=0.046). 3-years RFS were 84.2% and 85.3% for AR+/FOXA1+ and the others TNBC, respectively. 5-years RFS were 67.4% and 79.4% for AR+/FOXA1+ and the others TNBC, respectively. Tumor size, nodal status and adjuvant chemotherapy were also statistically correlated to RFS. Tumor size, nodal status, histology and adjuvant chemotherapy were significantly associated with overall survival. Conclusions In this large series, almost 30% of TNBC had an AR/FOXA1 co-expression with distinct clinicopathological characteristics and a worse outcome than others TNBC with higher risk of late recurrences. These biomarkers could be useful to identify a subgroup of TNBC and could have therapeutic implications: anti-androgen are under investigation, FOXA1 could be another therapeutic target and PI3K inhibitors should be evaluated in this specific subgroup, alone or in association with anti-androgens. Citation Format: Guiu S, Charon-Barra C, Mollevi C, Boissiere F, Crapez E, Chartron E, Lamy P-J, Gutowski M, Bourgier C, Romieu G, Simony-Lafontaine J, Jacot W. Prognostic value of androgen receptor and FOXA1 co-expression in non-metastatic triple-negative breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-05-06.

Objectifs L’objectif de notre etude a ete d’evaluer les performances diagnostiques du test Xpert®Bladder Cancer Monitor en comparaison au couple de reference cystoscopie–cytologie pour le suivi de recidives des tumeurs de la vessie n’infiltrant pas le muscle. Ce marqueur a ete developpe afin de repondre aux inconvenients majeurs de ces 2 examens : invasivite et sensibilite mediocre pour les tumeurs de bas grade. Methodes Les urines de patients (âge median : 70 ans, intervalle : 34–93) ont ete recueillies avant leur cystoscopie de suivi et analysees prospectivement avec le test Xpert® Monitor et/ou par cytologie selon les pratiques en vigueur. L’analyse intermediaire porte sur 178 patients, ayant des resultats disponibles. Les resultats Xpert® Monitor ont ete obtenus apres amplification et quantification de 5 cibles ARNm (ABL1, CRH, IGF2, UPK1B, ANXA10) par RT-PCR sur le systeme GeneXpert® et etaient rendus positifs (score ≥ 0,5), negatifs (score Resultats Vingt des 178 patients ont eu une recidive du cancer de la vessie prouvee par histologie (9 bas grades, 10 hauts grades, +1 CIS ?), 18 etant positifs pour Xpert® Monitor (sensibilite : 90 %), 4 pour la cytologie (sensibilite : 28,5 %). La specificite etait de 93,4 % (119/158) pour Xpert® Monitor et 93,3 % (85/91) pour la cytologie. Huit sur 8 des patients avec cystoscopie positive et cytologie negative etaient positifs au test ( Tableau 1 , Tableau 2 ). Conclusion Le test Xpert®Bladder Cancer Monitor semble etre efficace pour la detection des recidives du cancer de la vessie, et pourrait remplacer les cytologies. Notre etude se poursuit pour evaluer si ce test pourrait limiter le nombre de cystoscopies en augmentant le delai entre elles (alternance Xpert® Monitor et cystoscopie) voire (dans certaines conditions) les remplacer.

Purpose: Only a minority of patients with early breast cancer (EBC) treated with adjuvant or neoadjuvant chemotherapy have sufficient baseline vitamin D. The current recommendations regarding daily vitamin D supplementation appears too low to correct this deficiency in this population. Optimal vitamin D dosing has yet to be determined in this setting. The current randomized phase III study address the issue of the effectiveness and safety of a tailored high dose oral vitamin D supplementation as a means for restoring normal 25-hydroxy vitamin D (25OHD) levels in a large population of chemotherapy-treated EBC patients. Methods: Chemotherapy-treated EBC patients were stratified according to the degree of Vitamin D deficiency, time between chemotherapy initiation and inclusion (0 to 6 months versus 6 to 12 months), hormone receptors status and menopausal status. Participants were randomly assigned to receive a 6-months conventional (C) vitamin D and calcium supplementation or a 6-months high dose oral vitamin D regimen tailored on the degree of deficiency (T) associated with a conventional calcium supplementation. Primary endpoint was the efficacy (6-months percentage of 25OHD serum levels normalization) in the T arm compared with the C arm. Statistical analyses were performed on an intent to treat basis. Results: The trial accrued 215 patients, among which 197 patients presented with vitamin D deficiency, and randomized 195 patients (T, 100; C, 95) from July 2011 to January 2013. The groups were well balanced in regard to the stratification characteristics, as well as in regard of median weight and neoadjuvant or adjuvant chemotherapy status. Compliance to the daily oral supplementation was low in both arms, 64% of the patients in both arms taking less than 80% of the planned oral supplementation dose. Compliance to the tailored high dose vitamin D schedule appeared better (78%). After 6 months of treatment, at the primary endpoint analysis time, significantly more patients in the T arm presented with normalised serum vitamin D levels compared to the C arm (30% vs. 12.6%; p = 0.003). Vitamino-calcic supplementation was well tolerated, with no difference in the treatment-related toxicity between the 2 arms. Conclusion: In this randomized phase III study, a tailored high dose oral vitamin D supplementation allowed a statistically higher percentage of serum 25OHD levels normalization compared to a conventional regimen, without any increase in side effects, in a large population of chemotherapy-treated EBC patients. Observance of a daily oral supplementation remains poor in this setting, advocating for an adaptation of the schedule and dosage of this supplementation in a population of patients subject to chemotherapy-induced emesis. Clinical trial number NCT01480869. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-09-10.

Purpose: BRCA1 gene mutation is closely associated with familial hereditary breast cancer. Decreased expression of BRCA1 could be detected in certain types of sporadic breast cancer without BRCA1 mutations. Aberrant hypermethylation of DNA promoter CpG islands is one of the mechanisms by which tumor suppressor gene expression and function could be lost. We investigated BRCA1 methylation status and BRCA1 immunohistochemistry (IHC) expression and their clinic-pathological significance in triple negative breast cancers (TNBC). Patients and methods: We analyzed BRCA1 promoter hypermethylation using a methylation specific PCR assay and BRCA1 IHC expression using the MS110 monoclonal antibody and Garg and Meisel scoring classification. Their clinicopathological and prognostic implications were analyzed in a TMA of TNBC samples from European patients. Results: To date, 123 TNBC have been analyzed. 25 tumors (20%) presented a BRCA1 promoter hypermethylation. BRCA1 IHC expression was retained, equivocal and lost in 73 (59%), 17 (14%) and 33 (27%) cases respectively. No significant correlation was found between promoter hypermethylation and protein expression (p=0.28). A significant association was found between promoter hypermethylation and basal staining (CK5/6 and/or EGFR IHC staining), while using either a 10% or 1% cut-off for basal definition (p= 0.04 and 0.03, respectively). No significant association was found between BRCA1 expression and a basal phenotype. With a median follow-up of 6.3 years (range [0.01 – 11.8]), 35 relapses and deaths occurred (71.2% 5-years RFS and 77.8 5-years OS). RFS was significantly associated with T and N stage, and a trend was seen for a better prognosis of BRCA1 promoter hypermethylated tumors (5-years RFS: 84% vs. 68%, p=0.07). OS was significantly associated with T and N stage, and adjuvant chemotherapy. Conclusion: BRCA1 promoter hypermethylation is associated with basal-like features and seems to be associated with a better prognosis in TNBC. BRCA1 IHC expression is not a good surrogate marker for evaluation of the methylation status of the tumors, and did not appear associated with prognosis in our series. The data will be updated for the meeting in term of number of analyzed tumors in order to strengthen the statistical analysis. Citation Format: Jacot W, Simony-Lafontaine J, Mollevi C, Boissierre F, Lopez-Crapez E, Chartron E, Lamy P-J, Guiu S. BRCA1 promoter hypermethylation, but not BRCA1 expression, is associated with basal-like features and good prognosis in triple negative breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-06-08.

Purpose: Patients with early-stage breast cancer treated with neoadjuvant chemotherapy (NCT) are at risk of bone metabolism changes, resulting in loss of bone mass. Cancer treatment-induced bone loss (CTIBL) increases the risk for skeletal morbidity. An understanding of CTIBL is critical for determining the risk, identifying which patients may benefit from preventive therapy, and for screening patients for early intervention with therapies such as bisphosphonates or anti-RANKL therapies. In addition, considering the bone metabolism profile in early breast cancer patients, only a minority of women had vitamin D levels in the range considered sufficient for optimal health. This vitamin D deficiency may be associated with poor outcomes in breast cancer. In order to study the variation of the bone metabolism markers during NCT, we evaluated 78 early breast cancer patients homogeneously treated in our centre. Patients and methods: We studied the serum level of a panel of bone metabolism biomarkers (calcium, vitamin D, TRAIL, RANK-Ligand, Osteoprotegerin (OPG), serum bone trap, serum crosslap and DKK1), in a population of 78 early breast cancer patients treated by the association of 3 cycles of FEC100 then 4 taxane cycles between March 2007 and August 2008. Serum samples were withdrawn before the first CT cycle and before surgery. Time course and correlations between these biomarkers levels were evaluated. All computations were carried out using Stata. Two-sided P-values below 0.05 were considered to be statistically significant. Results: The clinicopathological characteristics of the population were classical of a neoadjuvant setting. 23% of the patients achieved a pCR. At baseline, 79.5% of the patients presented with vitamin D insufficiency (< 30 ng/ml). This proportion increased to nearly all the patients before surgery (97.4%, p < 0.0001). The same significant decrease in serum levels was found for calcium and RANK-ligand, while a significant increase in serum OPG level was noted, resulting in an increase of the OPG/RANK-Ligand ratio. Serum calcium and vitamin D levels were significantly correlated (Spearman's coefficient = 0.023), while there was a trend (Spearman's coefficient = 0.1) for correlation between serum calcium and RANK-Ligand levels. Conclusion: To our knowledge, this is the first clinical study comprehensively evaluating the changes in bone metabolism during early stage breast cancer NCT. In our study, nearly all the patients suffered from vitamin D insufficiency by the end of NCT. This insufficiency was associated with changes in the calcium / Rank-Ligand / OPG axis, evocative of a functional regulatory mechanism. These results require further analyses in order to define the role of pharmacologic modulation of this regulatory mechanism in the bone wellbeing of early breast cancer patients. A study evaluating the best medical intervention to correct this highly prevalent vitamin D insufficiency in this population is ongoing. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-14-14.

Purpose: A strong prognostic impact of urokinase type plasminogen activator (uPA) and its inhibitor plasminogen activator inhibitor type 1 (PAI-1) as individual factors is well established, with a level of evidence I according to the ASCO recommendations, and can be used in early breast cancer (EBC) adjuvant treatments discussions. However, the association or independence of these factors with other determinant clinicopathological parameters remains unclear in this setting. The independence or correlation of these factors in the adjuvant population is evaluated here. Patients and methods: 556 EBC patients operated between January 2006 and December 2009 (mastectomy, 99 patients; breast conservative surgery, 457 patients) were analyzed in this retrospective study. Inclusion criteria were: (i) patient curatively operated for EBC, (ii) no previous diagnosis of EBC or another malignant disease, (iii) no neoadjuvant treatment, (iv) no evidence of distant metastasis, (v) unilateral disease. Classical clinicopathological prognostic and predictive factors were considered, namely age, sex, type of surgery, tumor size, nodal status, histological subtype, SBR grade, mitotic activity, peritumoral vascular invasion, hormonal receptor status (ER, PgR), HER-2 expression, KI67 staining and follow-up informations. The levels of uPA and PAI-1 were centrally measured in our specialized laboratory using the Femtelle ELISA Kit. The positivity limits were those commonly used (uPA >3ng/mg of cytosolic protein and/or PAI-1 >14ng/mg of cytosolic protein). Correlations of the classical clinicopathological parameters with the levels of uPA and PAI-1 were analyzed in order to find statistical associations precluding their concomitant use in adjuvant decision making. Two-sided P-values below 0.05 were considered to be statistically significant. Results: A total of 556 patients were analyzed. Median patients age was 54 years (range 26-85 years). 424 patients (76.3 %) were node negative. Peritumoral vascular invasion was found in 30% of the population (162 patients). uPA and PAI-1 levels were elevated in 254 (45.7%) and 302 (57.6%) of the samples respectively. 206 tumors (37.1%) presented an elevation of UPA and PAI-1 levels. In multivariate analysis, SBR grade, mitotic count, ER status, HER-2 over-expression and triple negative status were found to be significantly associated with the uPA and/or PAI-1 levels. No statistically significant association was found between uPA and/or PAI-1 levels and other classical prognostic factors such as age, tumour size, menopausal status and nodal status. Interestingly, uPA and PAI-1 levels were not statistically associated with the presence of peritumoral vascular invasion, with P-values of 0.39, 0.60 and 0.66 for uPA, PAI-1 and the association uPA and PAI-1 levels respectively. Conclusion: To our knowledge, this is the first clinical study reporting the absence of statistical association of UPA and/or PAI-1 levels and peritumoral vascular invasion. Considering the prognostic and decision-making impact of these two parameters, the absence of statistical association allow to considered these parameters altogether in adjuvant treatment discussion. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-06-04.

Background: HT resistance occurs in nearly all patients with mBC. The identification of early predictive biomarkers of HT failure could help tailoring monitoring or an early change in HT. Circulating biomarkers would allow, a global evaluation of all the metastatic sites without the need of invasive biopsies. Mutation in the phosphatidylinositol 3 phosphate kinase gene (PIK3CA) is one of the most frequent events in ER+ BC and has been involved in HT resistance. We evaluated the early predictive value of cell free DNA (cfDNA) PIK3CA detection in a population of first line HT BC patients. Material and methods: 39 patients treated for an ER+/HER2- metastatic BC by first line HT in 2 French Comprehensive Cancer Centers were prospectively included in a dedicated clinical trial (NCT01612871) between June 2012 and January 2014. Serial blood sampling was performed before the initiation of HT (T0), 4 weeks (T1), 3 months (T3), 6 months (T6) and at tumor progression. Patients were followed until progression or end of the study (2 years follow-up). cfDNA was isolated from plasma using the QiaAmp circulating nucleic acid isolation kit (Qiagen). Mutation detection was performed using droplet digital PCR on a QX100TM system (Bio-Rad). The assay targeted wild type PIK3CA and mutations p.E542K, p.E545K in exon 9 and p.H1047R in exon 20. Target concentration was calculated as copies/reaction and cfDNA concentrations were reported as number of copies/mL of plasma. To assess the limit of detection of the three assays, isogenic reference DNA with known mutant allele frequency was used (Horizon Diagnostics). Based on confidence interval for Poisson parameter, a sample was considered positive if the average mutant copies detected was 4 copies and above per reaction. Results: Median age of the population was 63 (range 40-86). HT was as follow: letrozole 32, tamoxifen 5, anastrozole 1 and exemestane 1 patients, respectively. Most patients (28, 71.8%) presented with non-measurable disease, precluding a relevant evaluation of predictive factors for response. Progression-free survival (PFS) was used instead as primary endpoint. Serum samples results were available for 37 and 35 patients at T0 and T1 respectively. PIK3CA mutations were present in 10 (27.8%) and 5 (14.3%) cases at T0 and T1 respectively. While presence of a cfDNA PIK3CA mutation in the T0 sample was not associated with PFS, the persistence of a detectable circulating mutation at T1 was highly significant of a worse PFS (40% vs. 76.7% at 1 year; p=0.0053). Conclusions: In this dedicated clinical trial, 4-weeks persistence of cfDNA PIK3CA mutation appears highly correlated with PFS. Early identification of this mutated population could allow the evaluation of therapies targeting the PI3K/AKT/mTOR pathway in a selected population affected with an unfavorable prognosis. Dedicated studies and ancillary studies of such targeted therapies are warranted. Citation Format: Jacot W, Dalenc F, Lopez-Crapez E, Chaltiel L, Durigova A, Gros N, Lacaze J-L, Pouderoux S, Gladieff L, Romieu G, Roché H, Filleron T, Lamy P-J. Persistence of PIK3CA mutations detection in cell free tumor DNA as surrogate markers for hormonosensibility in patients with hormone receptor-positive breast cancer. The miRho clinical study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-02-05.

Resume Objectif La 18F-FDG TEP/TDM est un atout majeur dans la prise en charge de differents cancers. Certaines formes de cancers differencies, comme les cancers differencies de la thyroide (CDT), presentent une avidite moindre au 18F-FDG rendant leur exploration par cette technique moins sensible. Cependant, la TEP au 18FDG est reconnue comme interessante dans les suspicions de recidive de CDT en cas de scintigraphie a l’iode 131 (I131) negative et d’elevation des marqueurs (thyroglobuline [Tg] ou anticorps anti-thyroglobuline [ATg]). L’impact des examens TEP au 18FDG sur la prise en charge de patients suspects de recidive de CDT a ete analyse de facon retrospective dans cette etude. Methode Cinquante-cinq 18F-FDG TEP/TDM ont ete realisees chez 45 patients presentant une suspicion de recidive ou de maladie residuelle soit en raison d’un taux de Tg ou d’ATg eleve (n = 45), soit en raison d’un bilan d’imagerie conventionnelle douteux (n = 10) comprenant une scintigraphie corps entier I131, une echographie cervicale et eventuellement une tomodensitometrie. Les resultats de la 18F-FDG TEP/TDM ont ete compares aux donnees histologiques ou a defaut au suivi avec evaluation de l’impact sur la prise en charge. Resultats Vingt-neuf examens etaient positifs (53 %). Parmi eux, 20 ont ete etiquetes vrais positifs (VP) (14 recidives locoregionales et six a distance) et neuf faux positifs (FP) (tous cervicaux). La valeur mediane du SUVmax des foyers hypermetaboliques est significativement plus elevee dans les VP (5,1) que dans les FP (2,8). De facon globale, 20 examens sur 55 (36 %) ont directement influe sur la prise en charge avec dans deux tiers des cas (13/20) une nouvelle chirurgie d’exerese ganglionnaire cervicale. Les sensibilite (Se), specificite (Sp), valeur predictive positive (VPP), negative (VPN) et precision diagnostique ont ete evaluees de facon globale (Se 83 % ; Sp 71 % ; VPP 69 % ; VPN 85 % ; precision diagnostique 76 %) et dans deux sous-groupes en fonction du taux de Tg (superieur et inferieur a 1,2 ng/mL). Discussion et conclusion Notre etude confirme l’interet de la TEP-FDG chez les patients porteurs de CDT suspects de recidive/maladie residuelle. Cet examen d’imagerie hybride peut etre propose systematiquement en cas d’elevation isolee de la Tg basale superieure a 1,2 ng/mL au cours du suivi, en vue notamment de guider une eventuelle reprise chirurgicale.

With the widespread use of prostate specific antigen (PSA) prescription and despite the automatization of PSA assessment, clinicians should not forget the analytical interference of PSA immunoassays due to the presence of heterophilic autoantibodies in a patient.This article details some clinical cases, mechanisms involved in the interference and how to overcome this problem.The reported and documented interferences led to useless explorations even erroneous diagnosis.Before any unexpected PSA value in relation to the clinical symptomatology, it is strongly recommended to verify the absence of any interference before any invasive procedure or therapy modification.

International audience; CONTEXT AND AIMS:Breast cancer prognosis and predictive biomarkers development would allow sparing some patients from chemotherapy or identifying patients for whom chemotherapy would be indicated. In this context, in 2009, the French National Cancer Institute, a National Health and Science Agency dedicated to cancer, in collaboration with the French society of senology and breast pathology (SFSPM) published a report on the assessment of the prognostic and the predictive clinical validity of tissular biomarkers, uPA/PAI-1, Oncotype DX™ and MammaPrint(®), in breast cancer management. They concluded that only the uPA/PAI-1 prognosis value reached the highest level of evidence (LOE I according to Hayes 1998 classification). In 2012, it was decided to update this report since new data have emerged and because information disparities among clinicians have been identified. This article aims to present the main conclusions together with the levels of evidence associated with those conclusions.METHODS:The updating process was based on literature published since 2009 appraisal and on multidisciplinary and independent experts' opinion. The levels of evidence (LOE) used are those of the classification defined by Simon in 2009 (updated Hayes 1998 classification): LOE IA and LOE IB: high level of evidence; LOE IIB and LOE IIC: intermediate level of evidence; LOE IIIC and LOE IV-VD: low level of evidence.CONCLUSIONS:Among patients without lymph-node involvement, uPA/PAI-1, invasion process biomarkers, reach the highest level of evidence for 10 years recurrence free survival prognosis (LOE IA according to Simon). The predictive value to anthracyclins chemotherapy remains to be confirmed. Oncotype DX™ and MammaPrint(®) prognosis and predictive value do not reach the LOE I level. This updating' process confirms the 2009 levels of evidence for all the three biomarkers prognosis value. Besides, concerning Oncotype DX™ and MammaPrint(®), new data do not allow to conclude neither to their complementary clinical information to other clinicopathological existing biomarkers nor to a favorable cost-efficiency ratio in therapeutic decision making and this because of the methodological weakness and uncertainty that are identified in the selected studies. Practically, beyond the prognosis and predictive biomarkers validity, the clinical utility of a new biomarker for chemotherapy indication depends on its clinical added information with regard to validated biomarkers (HR, HER2 and Ki67) and to clinicopathological parameters. Since they are the sole validated biomarkers of the invasion process, uPA/PAI-1 could complete clinical information of other clinicopathological factors and consequently could confer an added clinical value. However, data concerning the impact of this information on chemotherapy clinical indication are lacking.Copyright © 2014. Published by Elsevier Masson SAS.; IntroductionDans le cancer du sein, le développement des marqueurs biologiques pronostiques ou prédictifs a pour objectif de mieux identifier les patientes pour lesquelles un traitement par chimiothérapie pourrait être évité ou a contrario indiqué. Dans ce contexte, en 2009, l’Institut national du cancer (INCa), agence sanitaire et scientifique de l’État chargée de coordonner les actions de lutte contre le cancer, avait publié en partenariat avec la Société française de sénologie et de pathologie mammaire un rapport sur l’état des connaissances relatives aux biomarqueurs uPA/PAI-1, Oncotype DX™ et MammaPrint® dans la prise en charge du cancer du sein. Ce rapport avait montré que seule la valeur pronostique d’uPA/PAI-1 atteignait le plus haut niveau de preuve (LOE I selon la grille de Hayes 1998). En 2012, devant la parution de nouvelles publications et la divergence des messages diffusés sur les signatures moléculaires, il a été décidé d’actualiser le rapport de 2009. Cet article présente les principales conclusions accompagnées de leurs niveaux de preuve.MéthodeLe processus de mise à jour s’est appuyé sur l’analyse des données publiées depuis la recherche bibliographique de 2009, complétée par l’avis d’un groupe de travail multidisciplinaire indépendant. Les niveaux de preuve employés sont ceux de la classification définie par Simon en 2009 (grille de Hayes 1998 après mise à jour) : LOE IA et LOE IB : niveau de preuve élevé ; LOE IIB and LOE IIC : niveau de preuve intermédiaire ; LOE IIIC and LOE IV-VD : niveau de preuve faible.ConclusionsChez les patientes sans envahissement ganglionnaire (pN0), uPA/PAI-1, marqueurs d’invasion, ont un niveau de preuve élevé (LOE IA selon Simon) pour la valeur pronostique de la survie sans récidive à 10 ans. Il reste à confirmer leur valeur prédictive de réponse aux anthracyclines. Pour Oncotype DX™ et MammaPrint®, les valeurs pronostique et prédictive n’ont pas atteint à ce jour le niveau de preuve LOE I. Ce travail confirme les niveaux de preuve précédemment établis dans le rapport de 2009. Par ailleurs, les données ne permettent pas de conclure à une valeur ajoutée de Oncotype DX™ et MammaPrint® par rapport aux outils existants. Les données médico-économiques ne permettent pas de statuer sur le rapport coût/efficacité des stratégies utilisant ces tests dans la décision thérapeutique compte tenu d’un niveau de qualité insuffisant pour la plupart des études et d’une forte incertitude mise en évidence par les quelques études bien menées. En pratique, au-delà des niveaux de preuve attribuables à la valeur pronostique et prédictive d’un biomarqueur, l’utilité clinique d’un nouveau marqueur dans l’aide à la prescription d’une chimiothérapie repose sur sa valeur ajoutée par rapport aux marqueurs validés (RH, HER2 et les marqueurs de prolifération comme Ki67) et aux critères anatomo-cliniques. Puisqu’ils sont les seuls marqueurs validés à témoigner du processus d’invasion, uPA/PAI-1 peuvent apporter une information complémentaire et donc avoir une valeur ajoutée par rapport aux marqueurs existants. Les données de la littérature manquent pour apprécier le poids de cette valeur ajoutée dans la décision de prescrire ou non une chimiothérapie.

uPA et PAI-1 ont ete valides comme des facteurs pronostiques de niveau de preuve 1 par l’ASCO, l’INCa et la SFSPM dans le cadre de la prise en charge adjuvante du cancer du sein localise (CSL) [1]. Leur elevation predit de plus un benefice augmente a une chimiotherapie adjuvante contenant des anthracyclines [2]. Leur association avec certains marqueurs pronostiques, ainsi que l’impact de leur utilisation meritent d’etre precises.

La valeur pronostique de l’activateur de type urokinase du plasminogene (uPA) et de son inhibiteur (PAI-1) dans les cancers du sein sans envahissement ganglionnaire a ete etablie avec un niveau de preuve maximum (level of evidence I) [1]. Il est, avec les recepteurs hormonaux et le statut HER2, le seul test decisionnel sur la mise en place des traitements adjuvants, recommande au niveau international et accessible en pratique clinique de routine en Europe. L’independance de l’information apportee par le test uPA-PAI-1 analyse prospectivement et la correlation avec les autres parametres clinicopathologiques a ete etudiee sur une population atteinte de cancers du sein operes au centre val d’Aurelle-Paul Lamarque entre janvier 2006 et decembre 2009.

The several options for therapy in breast cancer underline the difficulties to determine the reliable population which can be treated by a specific adjuvant therapy, and the population in which that therapy could generate morbidity, mortality, "medical surcharge" without prognosis improvement. This problem is particularly accurate in node-negative breast cancer patients. Adjuvant therapy has been proved to be more efficient, so a better definition of the prognosis and the response to adjuvant treatments could allow the selection of a sub-group of patients who can be spared chemotherapy. The quantification of the uPA/PAI-1 tumor content is one of the most relevant prognostic factors in this clinical setting. The integration of the uPA/PAI-1 prognostic information gathered in the multidisciplinary medical consensus meetings could be used to select the node-negative good/prognosis population in which chemotherapy could be avoided. This review will focus on the uPA/PAI-1 system, its biological role and its clinical implications in breast oncology. The different ways to analyse the uPA and PAI-1 content in tumor cells will be also presented and commented.

Estrogen receptor (ER) content is the most useful parameter for predicting hormone response therapy in breast cancer. Assays available for detecting ER in breast tumor cytosol are ligand-binding assay (LBA), which detects both ERalpha and ERbeta, and the enzymatic immunoassay (EIA), in which monoclonal antibodies are directed against ERalpha. As shown in several studies, the 2 assays correlate and both are used routinely. However, some discrepancies between the 2 assays were found and explanations remain controversial. We evaluated ERalpha and ERbeta mRNA coexpression in breast tumors in order to study whether the presence of ERbeta could account for differences between LBA and EIA in the determination of ER protein level. Using HeLa cell lines transfected with either ERalpha or ERbeta, we confirmed that EIA, using H222 and D547 monoclonal antibodies, recognizes only ERalpha expression, whereas LBA detects both isoforms. In 119 breast tumor cytosols, the correlation between ER-EIA and ER-LBA was high (r = 0.72), although some discrepancies were found. When analyzing ER mRNA expression of samples with higher LBA values, no overexpression of ERbeta mRNA relatively to ERalpha mRNA were observed. There was a difference in ERbeta/ERalpha ratio between ER-negative and ER-positive samples, with a 10-fold increased median ratio in ER-negative samples (p = 0.01). We thus confirmed that the major form of ER in breast cancer is the ERalpha at both the protein and mRNA levels. Moreover, our data do not support the hypothesis that ERbeta expression could explain differences between LBA and EIA in the determination of ER protein level.