Patterns of genomic change in residual disease after neoadjuvant chemotherapy for estrogen receptor-positive and HER2-negative breast cancer

Background: Treatment of patients with residual disease after neoadjuvant chemotherapy for breast cancer is an unmet clinical need. We hypothesised that tumour subclones showing expansion in residual disease after chemotherapy would contain mutations conferring drug resistance. Methods: We studied oestrogen receptor and/or progesterone receptor-positive, HER2-negative tumours from 42 patients in the EORTC 10994/BIG 00-01 trial who failed to achieve a pathological complete response. Genes commonly mutated in breast cancer were sequenced in pre and post-treatment samples. Results: Oncogenic driver mutations were commonest in PIK3CA (38% of tumours), GATA3 (29%), CDH1 (17%), TP53 (17%) and CBFB (12%); and amplification was commonest for CCND1 (26% of tumours) and FGFR1 (26%). The variant allele fraction frequently changed after treatment, indicating that subclones had expanded and contracted, but there were changes in both directions for all of the commonly mutated genes. Conclusions: We found no evidence that expansion of clones containing recurrent oncogenic driver mutations is responsible for resistance to neoadjuvant chemotherapy. The persistence of classic oncogenic mutations in pathways for which targeted therapies are now available highlights their importance as drug targets in patients who have failed chemotherapy but provides no support for a direct role of driver oncogenes in resistance to chemotherapy. ClinicalTrials.gov: EORTC 10994/BIG 1-00 Trial registration number NCT00017095.SCOPUS: ar.jDecretOANoAutActifinfo:eu-repo/semantics/publishe

Ki-67: level of evidence and methodological considerations for its role in the clinical management of breast cancer: analytical and critical review

Clinicians can use biomarkers to guide therapeutic decisions in estrogen receptor positive (ER+) breast cancer. One such biomarker is cellular proliferation as evaluated by Ki-67. This biomarker has been extensively studied and is easily assayed by histopathologists but it is not currently accepted as a standard. This review focuses on its prognostic and predictive value, and on methodological considerations for its measurement and the cut-points used for treatment decision. Data describing study design, patients’ characteristics, methods used and results were extracted from papers published between January 1990 and July 2010. In addition, the studies were assessed using the REMARK tool. Ki-67 is an independent prognostic factor for disease-free survival (HR 1.05–1.72) in multivariate analyses studies using samples from randomized clinical trials with secondary central analysis of the biomarker. The level of evidence (LOE) was judged to be I-B with the recently revised definition of Simon. However, standardization of the techniques and scoring methods are needed for the integration of this biomarker in everyday practice. Ki-67 was not found to be predictive for long-term follow-up after chemotherapy. Nevertheless, high KI-67 was found to be associated with immediate pathological complete response in the neoadjuvant setting, with an LOE of II-B. The REMARK score improved over time (with a range of 6–13/20 vs. 10–18/20, before and after 2005, respectively). KI-67 could be considered as a prognostic biomarker for therapeutic decision. It is assessed with a simple assay that could be standardized. However, international guidelines are needed for routine clinical use

Cancer risk management strategies and perceptions of unaffected women 5 years after predictive genetic testing for BRCA1/2 mutations

In a French national cohort of unaffected females carriers/non-carriers of a BRCA1/2 mutation, long-term preventive strategies and breast/ovarian cancer risk perceptions were followed up to 5 years after test result disclosure, using self-administered questionnaires. Response rate was 74%. Carriers (N=101) were younger (average age±SD=37±10) than non-carriers (N=145; 42±12). There were four management strategies that comprised 88% of the decisions made by the unaffected carriers: 50% opted for breast surveillance alone, based on either magnetic resonance imaging (MRI) and other imaging (31%) or mammography alone (19%); 38% opted for either risk reducing salpingo-oophorectomy (RRSO) and breast surveillance, based on MRI and other imaging (28%) or mammography alone (10%). The other three strategies were: risk reducing mastectomy (RRM) and RRSO (5%), RRM alone (2%) and neither RRM/RRSO nor surveillance (6%). The results obtained for various age groups are presented here. Non-carriers often opted for screening despite their low cancer risk. Result disclosure increased carriers' short-term high breast/ovarian cancer risk perceptions (P⩽0.02) and decreased non-carriers' short- and long-term perceptions (P<0.001). During follow-up, high breast cancer risk perceptions increased with time among those who had no RRM and decreased in the opposite case; high ovarian cancer risk perceptions increased further with time among those who had no RRSO and decreased in the opposite case; RRSO did not affect breast cancer risk perceptions. Informed decision-making involves letting women know whether opting for RRSO and breast MRI surveillance is as effective in terms of survival as RRM and RRSO

The Influence of Number and Timing of Pregnancies on Breast Cancer Risk for Women With BRCA1 or BRCA2 Mutations

International audienceBACKGROUND:Full-term pregnancy (FTP) is associated with a reduced breast cancer (BC) risk over time, but women are at increased BC risk in the immediate years following an FTP. No large prospective studies, however, have examined whether the number and timing of pregnancies are associated with BC risk for BRCA1 and BRCA2 mutation carriers.METHODS:Using weighted and time-varying Cox proportional hazards models, we investigated whether reproductive events are associated with BC risk for mutation carriers using a retrospective cohort (5707 BRCA1 and 3525 BRCA2 mutation carriers) and a prospective cohort (2276 BRCA1 and 1610 BRCA2 mutation carriers), separately for each cohort and the combined prospective and retrospective cohort.RESULTS:For BRCA1 mutation carriers, there was no overall association with parity compared with nulliparity (combined hazard ratio [HRc] = 0.99, 95% confidence interval [CI] = 0.83 to 1.18). Relative to being uniparous, an increased number of FTPs was associated with decreased BC risk (HRc = 0.79, 95% CI = 0.69 to 0.91; HRc = 0.70, 95% CI = 0.59 to 0.82; HRc = 0.50, 95% CI = 0.40 to 0.63, for 2, 3, and ≥4 FTPs, respectively, P trend < .0001) and increasing duration of breastfeeding was associated with decreased BC risk (combined cohort P trend = .0003). Relative to being nulliparous, uniparous BRCA1 mutation carriers were at increased BC risk in the prospective analysis (prospective hazard ration [HRp] = 1.69, 95% CI = 1.09 to 2.62). For BRCA2 mutation carriers, being parous was associated with a 30% increase in BC risk (HRc = 1.33, 95% CI = 1.05 to 1.69), and there was no apparent decrease in risk associated with multiparity except for having at least 4 FTPs vs. 1 FTP (HRc = 0.72, 95% CI = 0.54 to 0.98).CONCLUSIONS:These findings suggest differential associations with parity between BRCA1 and BRCA2 mutation carriers with higher risk for uniparous BRCA1 carriers and parous BRCA2 carriers

Correction to: Risk-reducing salpingo-oophorectomy, natural menopause, and breast cancer risk: an international prospective cohort of BRCA1 and BRCA2 mutation carriers.

After publication of the original article [1], we were notified that columns in Table 2 were erroneously displayed

Tumeurs cérébrales primitives malignes et phytosanitaires (matrices emploi-exposition, mise au point de la bibliographie. Fonctionnement du groupe de travail dans le cadre de l'enquête cas-témoins interrégionale de l'Est de la France)

Après avoir présenté dans une revue de bibliographie l'intérêt des matrices emploiexposition dans l'étude des effets sur l'homme des champs électromagnétiques et des produits phytosanitaires, l'auteur expose les principes de l'élaboration d'une matrice dans le cadre d'une enquête cas-témoins menée dans la région Est de la France sur les tumeurs cérébrales malignes primitives chez l'adulte et l'exposition professionnelle aux phytosanitaires. Une forte présomption de relation causale existe entre excès de risque de cancer du cerveau et exposition à ces substances mais également aux champs électromagnétiques, aux solvants, et aux nitrosamines. Une revue de littérature épidémiologique est mise à jour et conforte l'hypothèse d'un lien entre l'exposition professionnelle à certains de ces facteurs et la survenue de tumeurs cérébrales : les rapports de cause à effet entre exposition aux champs électromagnétiques ct ces lésions semblent à ce jour trop inconsistants, particulièrement vis-à-vis de ceux émis par les téléphones cellulaires, mais en revanche les liens avec l'exposition aux phytosanitaires, aux solvants et aux nitrosamines semblent plus solides. La responsabilité d'une substance précise est cependant difficile à cerner. Certains solvants et des nitrosamines contaminent en effet fréquemment la composition des phytosanitaires et pourraient avoir une toxicité supérieure vis-à-vis de ces derniers. Les études font d'autre part état de la nocivité de solvants spécifiques dont certains sont parfois présents dans les peintures. L'auteur présente enfin le protocole mis en place pour évaluer et valider les expositions professionnelles et extra-professionnelles aux facteurs de risque décrits plus haut dans le cadre de l'enquête cas-témoins. Une première ébauche de matrice emploi-exposition est présentée en annexe qui évalue l'exposition à ces facteurs selon les catégories socioprofessionnelles notées dans les historiques professionnels de sujets inclus dans l'étude.NANCY1-Bib. numérique (543959902) / SudocSudocFranceF

Aspects anatomo-cliniques et pronostiques des cancers du sein et de l'ovaire liés aux mutations du gène BRCA1

5 à 10 % des cancers du sein et de l'ovaire sont liés aux gènes BRCA1 et BRCA2. Des différences phénotypiques anatomo-cliniques et pronostiques sont observées dans notre étude concernant 54 cancers du sein et 21 cancers de l'ovaire liés au gène BRCA1. Les cancers du sein surviennent précocement, sont de haut grade, sans récepteurs hormonaux et évoluent fréquemment vers une récidive controlatérale. Il existe une sur-représentation du sous-type médullaire et un taux plus faible d'envahissement ganglionnaire. Leur survie est relativement élevée, mais ceci pourrait être lié au caractère rétrospectif de notre série. Les cancers de l'ovaire ne possèdent pas de caractéristiques anatomo-cliniques particulières à part l'apparition à un plus jeune âge et une sous-représentation des tumeurs borderline et mucineuses. Leur survie semble améliorée. Ces spécificités phénotypiques pourraient être liées à une histoire naturelle et à un comportement biologique différent des cancers sporadiques.NANCY1-SCD Medecine (545472101) / SudocPARIS-BIUM (751062103) / SudocNANCY1-Bib. numérique (543959902) / SudocSudocFranceF

Hormonothérapie adjuvante du cancer du sein avant la ménopause de 1896 à 2005 : un long chemin de doutes pour quelques certitudes

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