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Background Few data are available on survival of breast cancer (BC) patients (pts) treated with neoadjuvant endocrine therapy (NET). Understanding how tumor response to NET is related to relapse risk would help clinicians make decisions about additional treatments for these pts. Methods The primary objective was to assess 5-years relapse-free survival (RFS) in previously published two sister phase II studies evaluating anastrozole and fulvestrant as NET in post-menopausal HR-positive/HER2-negative BC pts (CARMINA02 NCT00629616 ; HORGEN NCT00871858 ). Prognostic factors of RFS were explored by pooling the two databases : age ( 70), tumor and node staging, histological type and grade, clinical response, pathological response according to the Sataloff classification, baseline and surgical ER Allred score and Ki-67 expression, treatment arm, preoperative endocrine prognostic index (PEPI) score, adjuvant chemotherapy. The factor study (Horgen vs. Carmina02) was also introduced in the model as covariate. Univariate and multivariate Cox regression analysis (covariates from univariate model with P-value Results Intention-to-treat analysis is available for 217 of 236 pts included in the two trials. Post-menopausal pts with T2–T4, N0–N1, M0, HR-positive/HER2-negative BC were randomized to receive anastrozole (PO, 1 mg daily) or fulvestrant (IM, 500 mg on D1, D15 and D29 and then every 4 weeks) for 4 to 6 months before surgery. Mean age at diagnosis was 71.2 years. Baseline tumor characteristics were : 73.7 % T2, mean tumor size 44.3 mm, 66.4 % N0, 19.4 % SBR grade 1, 98.6 % ER Allred score 6-8, mean Ki67 score 17.5 % with Ki67 > 20 % in 29.5 % of cases. A clinical response (complete or partial) was observed in 50.2 % of pts and pathological response rate defined as TA or TB and NA or NB was 15.7 %. Mean Ki67 at surgery was 8.8 % (11.4 % of cases > 20 %). Among the pts, 12.4 % were classified in PEPI risk group I (risk score 0), 35.5 % in group II (score 1–3) and 30.4 % in group III (score > 4) (PEPI not available for 21.7 % of pts) ; 21.7 % of pts received adjuvant chemotherapy. Median follow-up is 65.2 months. RFS and overall survival at 5 years are 83.7 % [95 % CI : 77.9–88 %] and 92.7 [95 % CI : 88.2–95.6 %] respectively. On univariate analysis, tumor staging (T3–4 versus T2, P = 0.0001) and PEPI score (I + II versus III, P = 0.0004) are associated with RFS. So far, no relapses/death have been observed in pts with pathological response (n = 34, 15.7 %). Multivariate analysis (T, baseline Ki67, ER Allred score at surgery, PEPI and study) shows that PEPI group III is associated with significantly worse RFS (P = 0.0014, HR : 3.9 [95 % CI : 1.7–9.0]). Conclusion Post-menopausal HR-positive/HER2-negative BC pts receiving NET have a very favorable outcome. Within this population eligible for NET, the PEPI score identifies a subset of pts of poorer prognosis who are candidate for further additional treatment like chemo/or targeted therapies. The PEPI may be a tool routinely used for individualization of adjuvant treatment in NET setting. According to recent published studies, further analysis will be performed with Ki67 > 10 % and PEPI risk (group I versus groups II–III).

The new molecular classification of breast cancers defines cancer sub-groups with a distinct prognosis and response to treatment. Studies on the literature deal with the imaging of each tumour sub-type. The radiologist should be familiar with them in order to adapt the care of an aggressive sub-type. In view of the current knowledge, the following have been significantly more often observed: mammographical spiculated mass with echogenic halo in luminal A sub-type; architectural distortion in luminal B sub-type; an irregular mass with indistinct margin comprising microcalcifications, with an abrupt interface in the sonography, or non-sonographic mass in the HER2 sub-type; a very hypoechogenic, lobulated mass with indistinct or microlobulated margin, with an abrupt interface, sometimes pseudo-benign, in the triple-negative sub-type.

Resume La nouvelle classification moleculaire des cancers du sein definit des sous-groupes de cancers de pronostic et reponse au traitement distincts. Des etudes abordent l’aspect a l’imagerie de chaque sous-type tumoral : le radiologue doit les connaitre pour adapter la prise en charge d’un sous-type agressif. Au vu des connaissances actuelles, il est observe de facon significativement plus frequente : un aspect de masse spiculee mammographique-avec halo echogene dans le sous-type luminal A ; de distorsion architecturale dans le sous-type luminal B ; de masse irreguliere a bord indistinct comportant des microcalcifications, a interface abrupt a l’echographie, ou de non-masse echographique dans le sous-type HER2 (human epidermal growth factor receptor 2 : recepteur 2 du facteur de croissance epidermique humain) ; de masse lobulee a bord indistinct ou microlobule, tres hypoechogene, a interface abrupt, parfois pseudo-benigne, dans le sous-type triple-negatif.

Resume Le type histologique de la tumeur selon l’OMS : canalaire, lobulaire, formes plus rares, est correle a des aspects a l’imagerie particuliers selon chaque type. Cette classification morphologique a ete amelioree par la connaissance des anomalies moleculaires des cancers du sein, aboutissant a definir des sous-groupes de cancers ayant des pronostics distincts et des reponses differentes au traitement : luminal A, luminal B, HER2 positif, basal-like, triple-negatif. Des etudes commencent a aborder l’aspect a l’imagerie de chaque sous-type tumoral : il est desormais important pour le radiologue de les connaitre.

Objectives Triple-negative breast cancers generally occur in young women and they have the potential to be aggressive. It is important for this subtype of tumour to be detected early. We studied the appearance of 73 tumours on mammography, sonography and MRI in order to determine what specific features they showed on imaging. Patients and methods From July 2009 to December 2010, we retrospectively reviewed mammogram and sonogram images of 73 triple-negative cancers. Colour Doppler had been used to depict vascularisation in 34 cases and elastography score calculated in 17 cases. Sixteen patients had undergone MRI. The radiological description of these different modalities draws on the BI-RADS lexicon and categorisation. Results On mammography, triple-negative cancers often presented as a round mass (59.3%) or an oval or lobulated mass (65%), with circumscribed (15%), microlobulated (12.5%), indistinct (55%) or occasionally spiculated margins (15%). On sonography, the vast majority of these cancers appeared as masses (92.8%) with occasional posterior acoustic attenuation (22.6%). MRI showed more suspicious images than the standard examinations, notably rim-enhancement (eight out of 12 masses). Conclusion . Radiological images appear as lobulated masses more readily, while on sonography posterior enhancement is shown more often than attenuation, and MRI finds rim-enhancement.

Resume Objectifs Les cancers mammaires triple negatifs surviennent plutot chez les femmes jeunes et ont un potentiel agressif. Il est important de detecter precocement ce sous-type tumoral. Nous avons etudie les aspects mammographiques, echographiques et IRM de 73 lesions afin de determiner leurs caracteristiques particulieres en imagerie. Patients et methodes De juillet 2009 a decembre 2010, nous avons revu retrospectivement la mammographie et l’echographie imageant 73 cancers triple negatifs. La vascularisation doppler couleur etait notee dans 34 cas et le score elastographique dans 17 cas. L’IRM avait ete pratiquee chez 16 patientes. La description radiologique de ces differentes modalites a utilise le lexique et la classification BI-RADS. Resultats En mammographie, les cancers triple negatifs se presentent souvent comme une masse (59,3 %) de forme ronde, ovale ou lobulee dans 65 % des cas et de contour circonscrit (15 %), microlobule (12,5 %) ou indistinct (55 %), rarement spicule (15 %). En echographie, ces cancers sont dans la grande majorite a type de masse (92,8 %) avec rarement une attenuation posterieure (22,6 %). L’IRM montre un aspect plus suspect que les examens conventionnels, notamment un rehaussement annulaire (huit des 12 masses). Conclusion Les aspects radiologiques sont plus volontiers a type de masse lobulee, avec a l’echographie plus souvent un renforcement posterieur qu’une attenuation et un rehaussement en anneau a l’IRM.

Stereotactically-guided procedures for diagnosis of breast lesions can avoid a lot of surgical biopsies. Stereotactic guidance is used for vacuum-assisted core biopsies and for stereotactic breast biopsies. Technical details of the procedures are described, and the benefits and the limits of these methods are discussed. Indications for breast sampling are proposed according to the Breast Imaging Reporting and Data System (BI-RADS) assessment categories.

The histological type of tumour according to the WHO: ductal, lobular, rare forms, is correlated with specific aspects of the imaging based on each type. This morphological classification was improved by knowledge of the molecular anomalies of breast cancers, resulting in the definition of cancer sub-groups with distinct prognoses and different responses to treatment: luminal A, luminal B, HER2 positive, basal-like, triple-negative. Studies are beginning to deal with the appearance of each sub-type in the imaging. It is now important for the radiologist to be familiar with them.

Introduction La CGH array (aCGH) est une technique moleculaire pangenomique detectant des rearrangements chromosomiques (gains ou pertes). Nous en presentons une nouvelle indication pour etablir un possible lien entre deux tumeurs synchrones (decouvertes ou survenues en meme temps) ou metachrones (survenues successivement). Observations Une patiente de 76 ans etait operee d’une tumeur de la jambe gauche apparue 6 mois auparavant. Elle n’avait pas d’antecedent de cancer profond. L’examen histologique etait en faveur d’un adenocarcinome sudoral eccrine. Les cellules tumorales n’exprimaient pas les recepteurs hormonaux aux estrogenes (RE) ou a la progesterone (RP) ni le GATA-3. Le bilan d’extension montrait une tumeur du quadrant supero-externe du sein gauche dont l’exerese a conclu a un adenocarcinome de type non specifique (ex. canalaire), de phenotype luminal, exprimant les RE et les RP. Une comparaison des profils chromosomiques par aCGH montrait des profils chromosomiques distincts ecartant un lien entre les 2 tumeurs. Devant ces resultats, la chimiotherapie etait arretee apres 6 cures. Un homme de 65 ans etait suivi depuis 1983 pour un carcinome basocellulaire (CBC) recidivant de l’hemiface droite traite par chirurgie iterative et radiotherapie. Au cours de son evolution, il avait developpe des nodules pulmonaires bilateraux dont l’exerese etait en faveur d’un carcinome peu differencie de type basaloide, exprimant Ber-EP4, comme le CBC. Une comparaison des profils chromosomiques etait realisee et montrait une perte du bras long du chromosome 9 (9q) dans les 2 tumeurs, avec point de cassure identique, confirmant leur parente. Un traitement par vismodegib s’averait inefficace. Devant la progression de la maladie, une prise en charge palliative etait decidee. Discussion Nos cas illustrent l’apport de l’aCGH pour differencier 2 tumeurs synchrones ou pour etablir une parente entre 2 tumeurs metachrones. Cette application a deja ete proposee dans les cancers de l’endometre et de l’ovaire. Dans le 1er cas, l’ aCGH a permis d’eliminer une metastase de cancer du sein et d’arreter la chimiotherapie apres 6 cures. Cette technique pourrait aussi permettre d’identifier des genes d’interet dans la physiopathologie de l’adenocarcinome eccrine. Pour le 2e patient, l’aCGH a confirme le lien entre les nodules pulmonaires et le CBC, et a montre une deletion de 9q qui comporte le gene PTCH1, de telles anomalies ayant ete observees chez des patients avec un syndrome de Gorlin. Ce gene est la cible de mutations inactivatrices dans les CBC sporadiques et constitue une cible du vismodegib. Conclusion Bien que couteuse, l’aCGH permet d’affirmer l’existence ou l’absence de parente entre 2 tumeurs synchrones ou metachrones pouvant modifier la prise en charge. Elle permet egalement d’identifier rapidement des regions chromosomiques remaniees comportant de potentiels genes d’interet.

The Standards, Options and Recommendations (SOR) project, which started in 1993, is a collaboration between the Federation of French Cancer Centers (FNCLCC), the 20 French Regional Cancer Centers, and specialists from French public universities, general hospitals and private clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and the outcome of cancer patients.To elaborate practice guidelines for difficult diagnoses in surgical pathology or cytopathology in cancer patients.The methodology is based on a literature review and critical appraisal by a multidisciplinary group of experts who define the CPGs according to the definitions of the Standards, Options and Recommendations project. Once the guidelines has been defined, the document is submitted for review by independent reviewers.The main recommendations to prevent and reduce the number of difficult diagnoses in surgical pathology or cytopathology are: The main recommendations to detect lesions associated with difficult diagnosis in surgical pathology or cytopathology are: The main recommendations to solve difficult diagnosis in surgical pathology or cytopathology are

Stereotactically-guided procedures for diagnosis of breast lesions can avoid a lot of surgical biopsies. Stereotactic guidance is used for vacuum-assisted core biopsies and for stereotactic breast biopsies. Technical details of the procedures are described, and the benefits and the limits of these methods are discussed. Indications for breast sampling are proposed according to the Breast Imaging Reporting and Data System (BI-RADS) assessment categories.

The "Standards, Options and Recommendations" (SOR) project, started in 1993 is a collaboration between the Federation of the French Cancer Centres (FNCLCC), the 20 French Cancer Centres and specialists from French Public Universities, General Hospitals and Private Clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and outcome for cancer patients. The methodology is based on literature review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery.To develop clinical practice guidelines according to the definitions of the Standards, Options and Recommendations project for difficult diagnoses in surgical pathology or cytopathology in cancer patients.Data were identified by searching Medline and using the personal reference lists of members of the expert groups. Once the guidelines were defined, the document was submitted for review to 71 independent reviewers.The main recommendations to prevent and reduce the number of difficult diagnoses in surgical pathology or cytopathology are: 1) The development of quality insurance programs with use of written procedures in each pathology laboratory (standard). 2) The knowledge of clinical data in order to explain surgical pathology or cytopathology results (standard). 3) The availability of complementary patient informations (radiologic data . . .) can be useful to explain surgical pathology or cytopathology results (option). The main recommendations to detect lesions associated with difficult diagnosis in surgical pathology or cytopathology are: 1) Tumor types known as potential difficult diagnosis in surgical pathology or cytopathology should be reviewed by a second pathologist. 2) The systematic second reviewing for every case is expensive but has to be done when the difficulty is know (sarcoma, lymphoma . . .) by experienced pathologists. The main recommendations to solve difficult diagnosis in surgical pathology or cytopathology are: 1) Block recuts, use of special techniques (immunocytohistochemistry and molecular biology), additional data from clinicians, second opinion by a local pathologist, or new specimen can be required for establishing the diagnosis (options). 2) Outside second opinion by expert pathologist has to be considered once the other steps did not allow to establish surgical or cytopathology diagnosis (recommendations, expert agreement).

The purpose was to evaluate the interest of stereotaxic fine-needle aspiration for round opacities when the ultrasound and echoguided punctures are inefficient; especially when women are under menopausal hormonal replacement therapy. Sixty stereotactic guided fine-needle aspirations detected by mammography have been performed between january 1990 and august 1996. The stereotaxic procedure is performed with a DMR unit (GE with Stereotix II). Stereotaxic views are done to verify needle position. After aspiration, cytologic examination is realised. Cystic fluid was always obtained and cytologic examination proved benign cysts in all cases. In 50 cases, cysts completely disappeared. There were 2 relapses that received after a second. This method is reliable for evaluation of non palpable mammographically detected opacities. The use of this technique spares the patient a surgical biopsy. This procedure enables women under menopausal hormone replacement therapy to continue the treatment.

Background: The dual blockade of HER2 signaling with trastuzumab (T) + pertuzumab (P) has been shown to be highly active with low toxicity in patients (pts) with HER2 positive breast cancer both in the neoadjuvant and metastatic setting even in the absence of chemotherapy. Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate combining the antitumor properties of trastuzumab with the cytotoxic agent DM1 via a stable linker. T-DM1 was more efficacious and less toxic than a combination of docetaxel and T in pts with metastatic breast cancer (MBC). Based on these data we decided to evaluate a potentially less toxic strategy of T+P without chemotherapy followed by T-DM1 in the context of a randomized phase 2 trial. It would be a major advantage for patients in terms of toxicity if the regimen of T+P followed by T-DM1 was equally effective with regard to overall survival to a strategy using a traditional chemotherapy-based regimen with T+P upfront followed by T-DM1. Trial design: In this multicenter, randomized, open-label phase 2 trial, pts with HER2 positive disease will be randomized to T + P alone or to T + P combined with chemotherapy (paclitaxel weekly or vinorelbine) for at least 4 months followed by maintenance treatment with T+P until progression. Pts with hormone receptor positive disease will receive endocrine treatment when treated without chemotherapy or after completion of chemotherapy. In case of progression pts of both treatment arms will receive T-DM1 as second line treatment. Eligibility: Eligibility criteria for the first-line part of the trial include a histologically confirmed BC with distant metastases, no prior chemotherapy, no anti-HER2 treatment for MBC. A biopsy from the primary tumor or a metastasis may be used for diagnosis. HER2 positive status must be confirmed by central testing. Prior neoadjuvant/adjuvant anti-HER2 treatment with T and/or lapatinib is allowed. Previous treatment with P is not allowed. For second-line treatment pts must have had at least one dose of trial therapy in the first-line phase and proven disease progression on first-line therapy. Objectives: The primary endpoint is to evaluate the efficacy in terms of overall survival (OS) at 24 months in both treatment arms. Secondary endpoints include progression-free survival (PFS) of first-line treatment ignoring first CNS lesion, PFS of second-line treatment and of both treatment lines, OS, adverse events of first- and second -line treatment, quality of life and duration of chemotherapy-free time. Statistical methods: For sample size calculation we estimated a median OS of 32 months corresponding to an expected survival proportion of 59.5% at 24 months under an exponential distribution. The two arms will be analyzed separately. Statistical comparisons by hypothesis tests between treatment arms are not planned. The hazard ratio for OS will be estimated with 95% confidence interval. Time-to-event endpoints are described by Kaplan-Meier plots and medians (with 95% confidence interval). Accrual: Target accrual is 104 pts per arm, first patient was enrolled in May 2013. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT1-1-05.

BackgroundThe PTEN tumour suppressor gene is frequently inactivated in a wide range of cancers and encodes a nonredundant phosphatase which antagonizes the PI3K signalling pathway. Previous IHC analysis and genomic characterization (through BAC CGH array) of a series of 135 sporadic breast carcinomas identified some tumours with decreased or absent PTEN levels and/or loss at 10q23.3, including the PTEN locus. Comprehensive molecular genetic analysis of PTEN, in addition to PI3KCA and TP53 point mutation screening were performed on this large homogenous series of breast carcinomas, giving a molecular portrait of key players of sporadic breast carcinogenesis.Materials and methodsA series of 135 sporadic invasive ductal carcinomas resected between 1989 and 1992 at Institut Bergonie underwent PTEN molecular genetic screening through QMPSF to detect gross genomic rearrangements and the recently developed Enhanced Mismatch Mutation Analysis (EMMA) to detect point mutations and to confirm gross genomic rearrangements. Tumours with a suspected PTEN large deletion identified using these techniques, along with any additional tumours previously shown to have decreased or absent PTEN levels and/or loss at 10q23.3, were analyzed using Agilent 4x44K high density oligo CGH arrays. The TP53 status of all tumours was assessed through IHC and direct sequencing. In addition, molecular analysis of the recurrent point mutations of PI3KCA, the catalytic subunit of the PI3 kinase, was performed.ResultsGross PTEN gene rearrangements were detected in 48 tumours through QMPSF ; 19 biallelic large deletions, 21 monoallelic large deletions and 8 large duplications. Variant EMMA profiles indicating a PTEN point mutation have been identified in approximately 15% of tumours which are confirmed by direct sequencing. High density oligo CGH array performed on 54 tumours demonstrates 7 monoallelic large deletions and 9 biallelic large deletions to date (analysis to be completed). A total of 39 tumours were shown to have mutant TP53 on IHC and/or a TP53 mutation, which interestingly only includes 8/19 tumours with a biallelic PTEN large deletion. Finally, an overall assessment of the above gene status, including results of the PI3KCA point mutation screen will be presented.ConclusionThis study shows that the predominant mechanism of PTEN inactivation in sporadic breast carcinomas is through gross genomic rearrangements rather than deleterious point mutations, and that this is not restricted to BRCA1-mutated tumours. Furthermore, previous reports have suggested that biallelic inactivation of PTEN in tumours with wild-type TP53 would result in cell death and therefore not be advantageous for tumour growth. In this series, we did not observe a correlation between biallelic inactivation of PTEN and TP53 mutation status (p=0.31, chi-squared test). Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3151.

BackgroundBRCA1 and BRCA2 genes are known to be the target of germline mutations in familial breast cancers, which represent 5% of the total breast cancer population. Mutation screening of these genes is performed in suspected familial breast cancer cases but a causative mutation is found in only 30% of patients. Therefore the development of additional methods to identify good candidates for BRCA1 and BRCA2 analysis would increase the efficacy of diagnostic mutation screening. With this in mind, we developed a study to determine molecular signatures of BRCA1 - or BRCA2 - mutated breast cancers.Material and MethodsArray-CGH and transcriptomic analysis were performed on a series of 103 familial breast cancers. The series included 7 breast cancers with a BRCA1 mutation and 5 breast cancers with a BRCA2 mutation. The remaining 91 cases were obtained from 73 families selected on the bases of at least 3 affected first degree relatives or at least 2 affected first degree relatives with breast cancer at an average age of 45 years. Tumoral DNA was co-hybridized with pooled normal blooded DNA from 21 individuals on a 4407 BAC-array (CIT-V8) provided by the CIT program and manufactured by Integragen. Transcriptomic analyses were performed using an Affymetrix Human Genome U133 Plus 2.0 chip. Clinical, pathological and genomic data were retrieved through Annotator, the CIT cancer database and the analysis was performed by using the R statistical software along with the CIT R packages.ResultsUsing supervised clustering analyses we identified 2 transcriptomic signatures, one for BRCA1-mutated breast cancers consisting of 600 probes sets and another for BRCA2-mutated breast cancers also consisting of 600 probes sets. We also defined CGH-array signatures, based on a presence of specific genomic rearrangements, one for BRCA1-mutated breast cancers and one for BRCA2-mutated breast cancers.ConclusionThis study has identified molecular signatures of breast cancers with BRCA1 or BRCA2 germline mutations. Genes present in these signatures could be exploited to find new markers for such breast cancers. Moreover, we identified specific genomic rearrangements in these breast cancers which could be screened for in a diagnostic setting using FISH thus improving patient selection for BRCA1 and BRCA2 molecular genetic analysis. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6132.