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Summary Purpose In the ACOSOG Z0011 trial, patients with primary breast cancer and 1–2 tumor-involved sentinel lymph nodes (SLNs) undergoing breast-conserving surgery had no oncological outcome benefit after axillary lymph node dissection (ALND), despite a relevant rate of non-SLN metastases of 27%. According to the St Gallen expert consensus, and NCCN and ASCO clinical guidelines, ALND may be avoided in patients who meet all ACOSOG Z0011 inclusion criteria. This recommendation can also be extended to patients undergoing mastectomy, with 1 or 2 positive SLNs and an indication for chest wall radiation, in whom axillary radiotherapy can be proposed as an alternative to completion ALND. The aim of this study was to assess non-compliance with the NCCN and ASCO clinical guidelines and Z0011 criteria, namely the rate of performance of completion ALND when it was not recommended, and the rate of failure to perform completion ALND when recommended. Methods Data were prospectively analysed from T1-2 N0 breast cancer patients undergoing an SLN procedure and treated at the Georges-Francois Leclerc Cancer Center between November 2015 and May 2017. Factors associated with non-compliance treatment decisions were identified using logistic regression. Results Among 563 patients included, 122 (21.7%) had at least one positive SLN. ALND was not recommended for 76 patients (62.3%), and was recommended in 46 patients (37.7%). The rate of non-compliant treatment was 32% (39/122) overall: ALND was performed despite not being recommended in 16/76 patients (21.1%) and was not performed in 50% of patients in whom it was recommended (23/46). By multivariate analyses, lymphovascular invasion ((Odds Ratio (OR) = 6.1; 95% confidence interval (CI): 1.4-26.7; P = 0.02)) and only one SLN removed (OR = 9.1; 95%CI: 2.2-33.3; P = 0.002) were associated with performance of completion ALND when not recommended. Conversely, >1 SLN removed (OR = 5.1; 95%CI: 1.2-22.2; P = 0.03) was associated with the failure to perform completion ALND when recommended. Conclusion Almost one third of patients with invasive breast cancer receive treatment that is not in compliance with recommendations regarding completion ALND.

Background HER2 expression is often negative or low in primary breast cancers (BCs) but its changes with disease progression remain poorly known. We aimed to estimate them between primary and recurrent tumours, and identify predictive factors. Methods We compared the HER2 status, and clinical and pathological characteristics by its evolution category (stable or changed), between all primary BCs and matched recurrences registered in our database in 2000–2020 (n = 512). Results HER2-low tumours were the most prevalent at diagnosis (44.9%), followed by HER2-negative tumours (39.3%). HER2 status significantly changed in 37.3% of recurrences, mainly of HER2-negative and HER2-low tumours. HER2-negative tumours which relapsed as HER2-low significantly more frequently expressed oestrogen receptors (ER) and recurred later than stably HER2-negative tumours. Changed HER2 status in distant metastases correlated with lower proliferation rates and higher ER expression in primary tumours, and among metastases of hormone receptor-positive (HR+) tumours—with weak progesterone receptor (PR) expression in primary tumours. Conclusions HER2 status changes with BC progression, with enrichment of HER2-low tumours in advanced stages. The ER+/PR− status, low proliferation index and time to late recurrence correlated with these changes. These findings highlight the need of retesting recurrences, especially of HR + primary tumours, to identify candidates for new anti-HER2 therapies.

e12595 Background: The rate of pathologic complete response in the axilla (pCRAx) according to breast cancer biologic subtypes and the impact of nodal response on survival are lacking. Methods: Inclusion criteria were all T-stage breast cancers with initial lymph node involvement (determined by clinical palpation and radiological assessment by ultrasound and/or 18F-FDG PET scan), non-metastatic, treated with neoadjuvant chemotherapy followed by surgery with axillary lymph node dissection, managed at the George-François Leclerc Cancer Center in Dijon, France, between 2000 and 2018. pCRAx was defined as the absence of invasive cells in the axillary lymph nodes ( i.e. ypN0). The Sataloff classification was used as reference on each pathological report. Patients with a Sataloff NA classification ( i.e. evidence of therapeutic effect, and no residual disease) were classified as having pCRAx. Univariate and multivariate analysis were performed to identify factors predictive of pCRAx. Then, we analysed recurrence-free survival (RFS) and overall survival (OS) according to the type of nodal response of the different tumor subtypes. Survival curves were constructed using the Kaplan Meier method and compared using the log rank test. Results: Among 437 patients included, 227 (52%) were pathologically proven node-positive disease by biopsy. pCRAx rate was 35% (n=153) but varied according to tumor subtypes: 69.4% in HR(Hormone Receptor)-/HER2-positive, 47.4% in HR-/HER2-negative, 46.7% in HR+/HER2-positive, 8.5% in HR+/HER2-negative. By multivariate analysis, the factors significantly associated with pCRAx were HER2-positive profile (OR 4.48 (2.14-9.65), p

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Caspases are well known for their role in apoptosis. Recently, nonapoptotic roles of caspases have been identified, however, these noncanonical roles are not well documented and the mechanisms involved are not fully understood. Here, we studied the role of cleaved caspase-3 using human- and mouse-proficient caspase-3 cancer cell lines and human-deficient caspase-3 cancer cells. Cleaved caspase-3 functioned as a transcription factor and directly bound to DNA. A DNA-binding domain was identified in the small subunit of caspase-3 and an active conformation was essential for caspase-3 transcriptional activity. Caspase-3 DNA binding enhanced angiogenesis by upregulating the expression of proangiogenic genes and by activating pathways that promoted endothelial cell activation. Some proapoptotic genes were downregulated in caspase-3–proficient cells. Inhibiting caspase-3 increased the efficacy of chemotherapy and decreased spontaneous tumor development. These data highlight a novel nonapoptotic role of caspase-3 and suggest that cleaved caspase-3 could be a new therapeutic target in cancer.Significance:These findings report a noncanonical function of caspase-3 by demonstrating its ability to transcriptionally regulate the VEGFR pathway.

Resume Les strategies de prise en charge en cas de ganglion(s) sentinelle(s) micro ou macrometastatique(s) dans les cancers du sein ont ete profondement modifiees depuis une dizaine d’annees et la publication de cinq essais randomises : ACOSOG Z0011, IBCSG 23-01, et AATRM comparant curage axillaire versus abstention ; et AMAROS et OTOASOR comparant curage axillaire versus radiotherapie axillaire. Malgre les limites methodologiques de certains de ces essais, notamment de l’ACOSOG Z0011, les recommandations internationales (ASCO, NCCN) et le consensus d’experts de St Gallen ne preconisent pas la realisation d’un curage axillaire complementaire en cas d’envahissement macro ou micrometastatique des ganglions sentinelles si l’ensemble des criteres d’inclusions de l’ACOSOG Z0011 sont reunis. De plus, en cas de mastectomies avec un ou deux ganglions sentinelles envahis et une indication d’irradiation de paroi, la realisation d’une radiotherapie axillaire peut etre proposee en alternative au curage axillaire. En dehors de ces indications, un curage axillaire reste indique, notamment lorsque trois ou plus ganglions sentinelles sont metastatiques, ou en cas de rupture capsulaire. Ce changement de strategie a conduit a une diminution importante du nombre de curage axillaire et l’abandon de l’examen extemporane des ganglions sentinelles. Se pose egalement la question de la pertinence de systematiquement realiser une microbiopsie ou une cytologie des ganglions axillaires suspects lors du bilan initial. En France, il n’existe pas de recommandations nationales sur la prise en charge axillaire en cas d’envahissement du ganglion sentinelle. A l’inverse, une multitude de referentiels tous plus differents les uns que les autres conduisent dans notre pays a des pratiques tres heterogenes. La prochaine evolution dans la strategie de prise en charge axillaire sera la realisation d’une procedure du ganglion sentinelle apres chimiotherapie neoadjuvante pour les patientes ayant un envahissement ganglionnaire prouve avant chimiotherapie neoadjuvante et chez qui la chimiotherapie neoadjuvante a permis un downstaging axillaire.

Background The aim of this study was to compare the value of 18F-fluorodesoxyglucose positron emission tomography (18F-FDG PET/CT) with CGFL/Curie nomogram to predict a pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) in women with human epidermal growth factor 2 (HER2)-positive breast cancer treated by trastuzumab. Methods Fifty-one women with HER2-positive breast cancer treated with trastuzumab plus taxane-based NAC, were retrospectively included from January 2005 to December 2015. For 18F-FDG PET/CT, the analyzed predictor was the maximum standardized uptake value of the primary tumor and axillary nodes after the first course of NAC (PET2.SUVmax). pCR was defined by no residual infiltrative tumor but in situ tumor was accepted. Accuracy of CGFL/Curie nomogram and PET2.SUVmax was evaluated measuring sensitivity (Se), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV). For each predictor, receiver operating characteristic (ROC) curve was created. To evaluate the correlation between predictors, the Spearman coefficient was calculated. Combined prediction was evaluated testing predictor’s associations. Results For CGFL/Curie nomogram’s performances, Se, Sp, PPV and NPV were respectively: 76% (CI95%: 58-90%), 57% (CI95%: 43-66%), 55% (CI95%: 42-65), 77% (CI95%: 59-90%). For PET2.SUVmax’s performances, Se, Sp, PPV and NPV were respectively: 67% (CI95%: 48-81%), 77% (CI95%: 64-97%), 67% (CI95%: 48-82%), 77% (CI95%: 64-87%). ROC curves for these predictors were similar; the areas under the curve were 0.6 (CI95%: 0.56-0.64) for PET2.SUVmax and 0.55 (CI95%: 0.50-0.59) for CGFL/Curie nomogram. Spearman coefficient was 0.23. Combined prediction was more efficient with Se at 80%, VPN at 76%, Sp at 78% and VPP at 81 %. Conclusions CGFL/Curie nomogram and PET2.SUVmax were two efficient predictors of pCR in patients with HER2-positive breast cancer. Combined prediction has an improved accuracy. Citation Format: Laura Vincent, Clémentine Jankowski, Marion Cortet, Laurent Arnould, Sylvain Ladoire, Bruno Coudert, Isabelle Desmoulins, Céline Charron-Barra, Françoise Beltjens, Roman Rouzier, Fabien Reyal, Olivier Humbert, Alexandre Cochet, Charles Coutant. HER2-positive breast cancer: Combined 18F-FDG PET and CGFL/Curie nomogram to predict pathologic complete response after preoperative chemotherapy with trastuzumab [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-16-14.

Molecular testing is extremely important in cancer care, starting as early as at diagnosis. In order to address the challenge of providing reliable results within the timeframe adapted to patient management and suitable to guide clinical decisions, a capture‑based next‑generation sequencing (NGS) panel focusing on ten genes known to harbor genetic variations which may be targeted by approved drugs in patients with cancer was designed and validated. Very favorable analytical performances were obtained for both solid and liquid biopsies. For solid biopsies, a low read depth (80X per nucleotide) led to the genotype detection accuracy of 100%. The read of raw data for liquid biopsies resulted in the 91.19% result concordance between paired solid and liquid samples. The present method met all the requirements for the ISO15189 certification. During our three‑year experience of routinely using this panel, almost 2,300 samples from lung and colorectal cancers, melanomas and gastrointestinal stromal tumors have been analyzed. It was found that our panel detected slightly more gain‑of‑function variants than described in the literature. Surprisingly, loss‑of‑function variants were also detected in certain of the analyzed genes. Finally, liquid biopsy data revealed statistically different mutated allele frequencies between tumor types, but also between mutated genes and variants themselves. In conclusion, the use of our capture‑based NGS panel is perfectly adapted to perform relevant molecular diagnosis in a time frame compatible with patient care.

Caspases are well known for their role in apoptosis. Recently, nonapoptotic roles of caspases have been identified, however, these noncanonical roles are not well documented and the mechanisms involved are not fully understood. Here, we studied the role of cleaved caspase-3 using human- and mouse-proficient caspase-3 cancer cell lines and human-deficient caspase-3 cancer cells. Cleaved caspase-3 functioned as a transcription factor and directly bound to DNA. A DNA-binding domain was identified in the small subunit of caspase-3 and an active conformation was essential for caspase-3 transcriptional activity. Caspase-3 DNA binding enhanced angiogenesis by upregulating the expression of proangiogenic genes and by activating pathways that promoted endothelial cell activation. Some proapoptotic genes were downregulated in caspase-3–proficient cells. Inhibiting caspase-3 increased the efficacy of chemotherapy and decreased spontaneous tumor development. These data highlight a novel nonapoptotic role of caspase-3 and suggest that cleaved caspase-3 could be a new therapeutic target in cancer. Significance: These findings report a noncanonical function of caspase-3 by demonstrating its ability to transcriptionally regulate the VEGFR pathway.

International audience; Objectives: To determine whether small cell neuroendocrine prostate cancers (NEPCa) emerging after anti-androgen treatments are different from the rarest cases diagnosed de novo, and to identify effective predictive markers.Material and methods: The expression of neuroendocrine markers, androgen receptor (AR) and androgen-regulated genes, as well as markers of aggressiveness, were analyzed by immunohistochemistry on a tissue microarray containing samples of 30 sNEPCa, either pure or admixed with conventional PCa, and including 14 cases diagnosed de novo and 16 cases subsequent to prior androgen deprivation.Results: Chromogranin A is a better marker of NE differentiation than synaptophysin in post-treatment NEPCa, with 94% and 44% of positive tumors, respectively, while both markers are equally expressed in de novo cases. Despite the acquisition of a NE phenotype, more than half of NEPCa expressed AR and the androgen-regulated gene NKX3.1, more frequently in cases admixed with conventional PCa. TTF1 staining, present in half of NEPCa, was associated with loss of androgen-regulated genes and with markers of aggressiveness, including increased proliferation, Zeb1 expression and PTEN loss. In multivariate analysis, only TTF1 expression was significantly associated with shorter overall survival.Conclusion: These results suggest the persistence of androgen signaling in a number of NEPCa cases, and the interest of TTF1 staining as a predictive biomarker.

Determining the status of steroid hormone receptors [oestrogen (ER) and progesterone receptors (PR)] is a crucial part of the breast cancer workup. Thereby, breast cancers can be classified into four subtypes. However, the existence of ER-/PR+ tumours, often reported to be ill-classified due to technical errors, remains controversial. In order to address this controversy, we reviewed the hormone receptor status of 49 breast tumours previously classified as ER-/PR+ by immunohistochemistry, and compared clinical, pathological and molecular characteristics of confirmed ER-/PR+ tumours with those of ER+ and triple-negative tumours. We unequivocally confirmed the ER-/PR+ status in 27 of 49 tumours (0.3% of all breast cancers diagnosed in our institution between 2000 and 2014). We found that ER-/PR+ were morphologically and histologically similar to triple-negative tumours, but very distinct from ER+ tumours, with more aggressive phenotypes and more frequent basal marker expression than the latter. On the molecular level, RNA sequencing revealed different gene expression profiles between the three groups. Of particular interest, several genes controlled by the suppressor of zest 12 (SUZ12) were upregulated in ER-/PR+ tumours. Overall, our results confirm that ER-/PR+ breast cancers are an extremely rare but 'real' tumour subtype that requires careful diagnosis and has distinct features warranting different responsiveness to therapies and different clinical outcomes. Studies on larger cohorts are needed to further characterise these tumours. The likely involvement of SUZ12 in their biology is an interesting finding which may - in a long run - give rise to the development of new therapeutic alternatives.

Primary triple-negative invasive lobular breast carcinomas (TN-ILCs), which do not express hormone receptors and HER2 at diagnosis, are rare and poorly known. In this study, we analyzed the largest TN-ILC series ever reported in the literature, in comparison to phenotypically similar breast tumor subtypes: triple-negative invasive ductal carcinoma (TN-IDC) and hormone receptor-positive invasive lobular carcinoma (HR + ILC). All primary TN-ILCs registered in our database between 2000 and 2018 (n = 38) were compared to tumors from control groups, matched by stage and Elston/Ellis grade, with regard to clinical, pathologic, and immunohistochemical characteristics. A comparative molecular analysis (whole-exome and RNA sequencing using next-generation technology) was also performed. We found that TN-ILC patients were older than those with HR + ILC (P = 0.002) or TN-IDC (P

Background The incidence and incidence trends of breast cancer according to molecular subtype are unknown at a population level in France. The registry data enables this study and may give this information, that is crucial to describe and understand breast cancer epidemiology. Methods We estimated the incidence rates of breast cancer for each molecular subtype using data from three cancer registries in France for the period from 2007 to 2012. Molecular subtypes were defined with immunohistochemical data. Poisson models were estimated to modelize the course of breast cancer incidence and to test the trends. Results The study included 12,040 patients diagnosed between 2007 and 2012 in the three administrative areas covered by the registries. There was no significant trends in the proportion of each molecular subtype year by year. The age distribution of incident cases was different depending on the molecular subtypes (p

Metaplastic breast carcinoma is a rare subtype of breast cancer. This subtype is mostly found in association with poorly differentiated ductal breast carcinomas and rarely with other breast carcinoma types. We report the case of a 69-year-old woman with an exceptional invasive lobular breast carcinoma associated with metaplastic squamous cell bone metastasis occurring 2 years after the initial breast cancer diagnosis. Whole-exome sequencing and subsequent immunohistochemistry of the lesions were used to link the squamous cell bone metastasis of unknown origin to the primary breast carcinoma initially diagnosed. Searching for primary carcinoma when metastatic lesions of unknown origin occur can be complex. Current molecular biology techniques may help pathologists in associating metastasis with the primary carcinoma by identifying shared specific gene mutations, even when different morphological and immunohistochemical profiles are observed between the tumours.

Management strategy of micro or macro metastatic sentinel lymph node(s) (SLNs) in breast cancer has dramatically changed over the past ten years and the publication of five randomized trials results: ACOSOG Z0011, IBCSG 23-01, and AATRM comparing axillary lymph node dissection (ALND) versus SLNs biopsy alone; and AMAROS and OTOASOR comparing ALND versus axillary radiotherapy. Despite methodological limitations of several of these trials, notably ACOSOG Z0011, the international recommendations (ASCO, NCCN) and the expert consensus of St Gallen do not recommend the performance of a complementary ALND in case of macro or micro metastatic SLN, if all ACOSOG Z0011 inclusion criteria are met. Moreover, in the context of a mastectomy, with one or two positive SLN and a wall irradiation indication, an axillary radiotherapy can be proposed as an alternative to ALND. Additionally, ALND is also indicated in extracapsular involvement or when three or more SLNs are metastatic. This change in strategy led to a significant decrease on the number of ALNDs performed and resulted on the abandon of SLNs extemporaneous examination. In France, there are no national recommendations on axillary management in the context of SLN involvement. Moreover, a multitude of different local guidelines, led to very heterogeneous practices in our country. The next evolution on axillary management strategy will be the implementation of a SLNs procedure after neoadjuvant chemotherapy (NAC) for patients with lymph node involvement proven before NAC and for whom NAC has allowed axillary downstaging.

e17537 Background: The management of ovarian cancer is based on a combination of surgery and chemotherapy. The aim of surgery is to achieve zero residual tumour at the end of the procedure. In advanced stage ovarian cancer, two therapeutic approaches are possible: primary debulking surgery, or primary chemotherapy followed by interval debulking surgery. The primary objective of this study was to describe overall survival (OS) in FIGO stage III and IV ovarian cancers according to the therapeutic sequence (i.e. primary surgery or interval surgery). Methods: We performed a retrospective, observational study using data from the gynecological cancer registry of the Cote d’Or, for patients diagnosed with FIGO stage III or IV ovarian cancer between 1998 and 2015. We recorded FIGO stage, histological type, treatment and completeness of cytoreduction. Results: In total, 460 patients were included. OS at 5 years was 47% in patients with primary surgery, versus 38% in patients with interval surgery (p = 0.06). Five-year OS was 45% in patients with complete cytoreduction, versus 30% in those with incomplete cytoreduction (p < 0.001). The rate of complete cytoreduction was 43% in patients with primary surgery, versus 55% in those with interval surgery. Conclusions: OS appears to be slightly better in patients receiving primary surgery, and when cytoreduction is complete. Every effort should be made during surgery to achieve complete cytoreduction, by an experienced team. Primary surgery should be preferred in these patients.

Resume Cette etude retrospective evalue l’interet du dosage de l’ACE pour la detection precoce des recidives des cancers du sein. Sur une population de 804 patientes porteuses d’un cancer du sein invasif, nous avons etudie 260 patientes dont 97 patientes sans recidive (SR) depuis plus de 5 ans, 32 patientes avec une recidive locale (RL) isolee et 131 patientes avec au moins une metastase a distance (MAD). Des concentrations elevees d’ACE et de CA 15-3 (> 3,1 μg/L et > 26 kU/L) ont ete trouvees chez 6 et 22 % des patientes avec une RL et chez 49 et 69 % des patientes avec MAD respectivement. L’ACE et le CA 15-3 ont une valeur predictive independante au diagnostic de MAD. Les elevations de l’ACE et du CA 15-3 sont etroitement correlees a la positivite des recepteurs hormonaux. Les sensibilites de l’ACE et du CA 15-3 sont respectivement de 23 et 65 % dans le groupe des tumeurs de profil triple negatif, de 58 et 75 % pour les tumeurs de type luminal, 56 et 78 % chez les tumeurs luminal-HER2, 50 et 30 % chez les tumeurs HER2 -enriched ( p = 0,0094 et 0,0252 respectivement). La combinaison de l’ACE et du CA 15-3 augmente la sensibilite de CA 15-3 dans les profils luminal et HER2 -enriched . En conclusion, l’elevation de l’ACE et du CA 15-3 au diagnostic de MAD est tres correlee a la positivite des recepteurs hormonaux et au profil moleculaire de la tumeur. L’association de l’ACE et du CA 15-3 apparait utile specialement dans les profils luminal et HER2 -enriched .

Breast sonography is required with mammogram to explore clinical breast mass (grade B), colored unipore breast nipple discharge (grade C), or mastitis (grade C). Bi-RADS system is recommended to describe and classify breast-imaging abnormalities. For breast abscess, a percutaneous biopsy is recommended in case of mass or persistent symptoms (grade C). For mastodynia, when breast imaging is normal, no MRI neither breast biopsy is recommended (grade C). Percutaneous biopsy is recommended for BI-RADS 4-5 mass (grade B). For persistent erythematous breast nipple or atypical eczema lesion, a nipple biopsy is recommended (grade C). For distortion and asymmetry, a vacuum core needle biopsy is recommended because of the risk of underestimation by simple core needle biopsy (grade C). For BI-RADS 4-5 microcalcifications without ultrasound signal, a vacuum core needle biopsy of at least 11 gauges is recommended (grade B); in the absence of microcalcifications on radiograph carrots, additional samples are recommended (grade B). For atypical ductal hyperplasia, atypical lobular hyperplasia, lobular carcinoma in situ, flat epithelial with atypia, radial scar, mucocele with atypia, surgical excision is commonly recommended (grade C). Expectant management is feasible after multidisciplinary concertation. For these lesions, when excision is not in sano, no new excision is recommended except for pleomorphic or with necrosis CLIS (grade C). For grade 1 phyllode tumour, in sano surgical resection is recommended; for grade 2 phyllode, 10-mm margins are recommended (grade C). For breast papillary without atypia, complete disappearance of the radiologic signal is recommended (grade C). For breast papillary with atypia, complete surgical excision is recommended (grade C).

In the last few years, diagnostics of high-risk breast lesions (atypical ductal hyperplasia [ADH], flat epithelial atypia [FEA], lobular neoplasia: atypical lobular hyperplasia [ALH], lobular carcinoma in situ [LCIS], radial scar [RS], usual ductal hyperplasia [UDH], adenosis, sclerosing adenosis [SA], papillary breast lesions, mucocele-like lesion [MLL]) have increased with the growing number of breast percutaneous biopsies. The management of these lesions is highly conditioned by the enlarged risk of breast cancer combined with either an increased probability of finding cancer after surgery, either a possible malignant transformation (in situ or invasive cancer), or an increased probability of developing cancer on the long range. An overview of the literature reports grade C recommendations concerning the management and follow-up of these lesions: in case of ADH, FEA, ALH, LCIS, RS, MLL with atypia, diagnosed on percutaneous biopsies: surgical excision is recommended; in case of a diagnostic based on vacuum-assisted core biopsy with complete disappearance of radiological signal for FEA or RS without atypia: surgical abstention is a valid alternative approved by multidisciplinary meeting. In case of ALH (incidental finding) associated with benign lesion responsible of radiological signal: abstention may be proposed; in case of UDH, adenosis, MLL without atypia, diagnosed on percutaneous biopsies: the concordance of radiology and histopathology findings must be ensured. No data is available to recommend surgery; in case of non-in sano resection for ADH, FEA, ALH, LCIS (except pleomorphic type), RS, MLL: surgery does not seem to be necessary; in case of previous ADH, ALH, LCIS: a specific follow-up is recommended in accordance with HAS's recommendations. In case of FEA and RS or MLL combined with atypia, little data are yet available to differ the management from others lesions with atypia; in case of UDH, usual sclerosing adenosis, RS without atypia, fibro cystic disease: no specific follow-up is recommended in agreement with HAS's recommendations.

Type 1 auto-immune pancreatitis (type 1 AIP) is the pancreatic manifestation of IgG4-related systemic disease (IgG4-RD). This disease has recently been individualized and is characterized by elevated serum IgG4 levels and extrapancreatic lesions with common histologic characteristic: dense infiltration of lymphocytes, IgG4-positive plasma cells and storiforme fibrosis. Obliterative phlebitis is frequently detected. The pancreas is frequently involved in this disease. As approach to the pancreas for histological examination is generally difficult, AIP is diagnosed using a combination of clinical, serological, morphological and histopathological features. In pseudotumoral cases, AIP can be misdiagnosed as pancreatic cancer. Since AIP responds dramatically to steroid therapy, accurate diagnosis of AIP can avoid unnecessary laparotomy or pancreatic resection. We report here a case of a patient who underwent surgery for presumed pancreatic cancer. The final diagnosis was type 1 AIP.

This retrospective study evaluates the interest of CA 15-3 measurement for early detection of breast cancer recurrences. Among 804 patients with invasive breast cancer we selected 117 patients without recurrence (WR) for 5 years or more, 33 with a local recurrence (LR) and 149 with at least one distant metastasis (DM). The sensitivity of CA 15-3 depends on the type of recurrence ([LR] or [DM]), the localization of unique DM, the presence and the number of metastatic sites, on hormonal receptor status and tumor subtypes. The number of metastatic sites and hormonal receptor status are independent predictive criteria of an elevation of CA 15-3. The analysis of ROC curve in order to separate patients with DM and patients WR shows an AUC of 0.87 (p

e12095 Background: The aim of this study was to compare the value of 18F-fluorodesoxyglucose positron emission tomography (18F-FDG PET/CT) with CGFL/Curie nomogram to predict a pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) in women with human epidermal growth factor 2 (HER2)-positive breast cancer treated by trastuzumab. Methods: Fifty-one women with HER2-positive breast cancer treated with trastuzumab plus taxane-based NAC, were retrospectively included from January 2005 to December 2015. For 18F-FDG PET/CT, the analyzed predictor was the maximum standardized uptake value of the primary tumor and axillary nodes after the first course of NAC (PET2.SUVmax). pCR was defined by no residual infiltrative tumor but in situ tumor was accepted. Accuracy of CGFL/Curie nomogram and PET2.SUVmax was evaluated measuring sensitivity (Se), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV). For each predictor, receiver operating characteristic (ROC) curve was created. To evaluate the correlation between predictors, the Spearman coefficient was calculated. Combined prediction was evaluated testing predictor’s associations. Results: For CGFL/Curie nomogram’s performances, Se, Sp, PPV and NPV were respectively: 76% (CI95%: 58-90%), 57% (CI95%: 43-66%), 55% (CI95%: 42-65), 77% (CI95%: 59-90%). For PET2.SUVmax’s performances, Se, Sp, PPV and NPV were respectively: 67% (CI95%: 48-81%), 77% (CI95%: 64-97%), 67% (CI95%: 48-82%), 77% (CI95%: 64-87%). ROC curves for these predictors were similar; the areas under the curve were 0.6 (CI95%: 0.56-0.64) for PET2.SUVmax and 0.55 (CI95%: 0.50-0.59) for CGFL/Curie nomogram. Spearman coefficient was 0.23. Combined prediction was more efficient with Se at 80%, VPN at 76%, Sp at 78% and VPP at 81 %. Conclusions: CGFL/Curie nomogram and PET2.SUVmax were two efficient predictors of pCR in patients with HER2-positive breast cancer. Combined prediction has an improved accuracy.

International audience; ObjectifsL’étude de l’infiltrat tumoral par les cellules du système immunitaire constitue un facteur pronostique favorable dans plusieurs variétés de pathologies cancéreuses. L’objectif de notre étude est de décrire l’organisation intra- et péri-tumorale de différentes populations lymphocytaires, et d’explorer leur éventuel rôle pronostique chez des patients atteints d’un cancer de l’estomac localisé.MéthodesNous avons étudié de manière rétrospective par méthode immunohistochimique l’infiltrat immunitaire de différentes sous-populations lymphocytaires T (Th17 : IL-17+, T CD8+, T régulateurs : Foxp3+ et Th1 : Tbet+) et lymphocytaires B (CD20+) en périphérie tumorale, et au sein même de la tumeur sur les pièces opératoires gastriques d’une cohorte de 82 patients atteints d’un cancer de l’estomac localisé et réséqué.RésultatsLa teneur de l’infiltrat en lymphocytes T cytotoxiques et en lymphocytes Th17 ne semble pas avoir de valeur pronostique dans notre étude. Les caractéristiques de l’infiltrat immunitaire ne sont ni influencées par l’administration d’une chimiothérapie néoadjuvante, ni par le grade histopathologique de la tumeur. En revanche, nous avons pu déceler que la présence d’infiltrats riches en cellules lymphocytaires Th1 (Tbet+) et en follicules lymphocytaires B (CD20+), associés à une faible proportion de lymphocytes T régulateurs était associée à une meilleure survie sans récidive des patients. De plus, nous mettons en évidence que ces infiltrats lymphocytes Th1/B s’organisent histologiquement en structure s’apparentant à des structures lymphoïdes tertiaires, où des lymphocytes B proliférant sont entourés de lymphocytes T eux-mêmes en contact avec des cellules présentatrices d’antigènes matures (cellules dendritiques DC-lamp+).L’analyse transcriptomique d’une série indépendante de 365 cancers de l’estomac localisés confirme le pronostic favorable conféré par une signature stromale de coopération immune lymphocytaire B et Th1.ConclusionNos résultats démontrent l’importance pronostique d’une signature immunohistochimique et génomique Th1/réponse B dans le cancer de l’estomac.

International audience; Introduction: Atypical epithelial hyperplasia (AEH) of the breast is considered benign histological lesions with breast cancer risk. This review focuses on clinical signification and management of AEH that remains controversial. Areas covered: A review of published studies was performed using medline database. In this review, we fully describe the current evidence available. In particular, we describe 1) data from immunohistochemistry and molecular studies that suggest AEH is a precursor of breast cancer; 2) epidemiological studies demonstrate low rate of breast cancer in women with AEH; 3) surgical excision is necessary after diagnosis of AEH, such as lobular carcinoma in situ or atypical ductal hyperplasia, on core needle biopsy; 4) although current recommendations are evolving to fewer (if not no) excisions for flat epithelial with atypia and classic lobular neoplasia found on percutaneous biopsy (without radiologic indications for excision). Expert commentary: HEA management steel need prospective evidences, but recent retrospective data give some clue for less invasive management for some of HEA. © 2016 Informa UK Limited, trading as Taylor & Francis Group.

International audience; Screening with breast ultrasound in combination with mammography is needed to investigate a clinical breast mass (Grade B), colored single-pore breast nipple discharge (Grade C), or mastitis (Grade C). The BI-RADS system is recommended for describing and classifying abnormal breast imaging findings. For a breast abscess, a percutaneous biopsy is recommended in the case of a mass or persistent symptoms (Grade C). For mastalgia, when breast imaging is normal, no MRI or breast biopsy is recommended (Grade C). Percutaneous biopsy is recommended for a BI-RADS category 4-5 mass (Grade B). For persistent erythematous nipple or atypical eczema lesions, a nipple biopsy is recommended (Grade C). For distortion and asymmetry, a vacuum core-needle biopsy is recommended due to the risk of underestimation by simple core-needle biopsy (Grade C). For BI-RADS category 4-5 microcalcifications without any ultrasound signal, a minimum 11-G vacuum core-needle biopsy is recommended (Grade B). In the absence of microcalcifications on radiography cores additional samples are recommended (Grade B). For atypical ductal hyperplasia, atypical lobular hyperplasia, lobular carcinoma in situ, flat epithelial atypia, radial scar and mucocele with atypia, surgical excision is commonly recommended (Grade C). Expectant management is feasible after multidisciplinary consensus. For these lesions, when excision margins are not clear, no new excision is recommended except for LCIS characterized as pleomorphic or with necrosis (Grade C). For grade 1 phyllodes tumor, surgical resection with clear margins is recommended. For grade 2 phyllodes tumor, 10 mm margins are recommended (Grade C). For papillary breast lesions without atypia, complete disappearance of the radiological signal is recommended (Grade C). For papillary breast lesions with atypia, complete surgical excision is recommended (Grade C)

// Coureche Guillaume Kaderbhai 1,* , Romain Boidot 2,3,4,* , Francoise Beltjens 3 , Sandy Chevrier 3,4 , Laurent Arnould 3,4 , Laure Favier 1 , Aurelie Lagrange 1 , Bruno Coudert 1,* and Francois Ghiringhelli 1,2,3,4,* 1 Department of Medical Oncology, Centre Georges-Francois Leclerc, Dijon, France 2 INSERM, U866, Faculte de Medecine, Universite de Bourgogne and Centre Georges Francois Leclerc, Dijon, France 3 Department of Biology and Pathology of Tumors, Centre Georges-Francois Leclerc, Dijon, France 4 Platform of Transfer in Cancer Biology, Centre Georges-Francois Leclerc, Dijon, France * These authors have contributed equally to this work Correspondence to: Bruno Coudert, email: // Francois Ghiringhelli, email: // Keywords : precision medicine, lung cancer, NGS, clinical research Received : February 04, 2016 Accepted : March 16, 2016 Published : March 26, 2016 Abstract Advances in Next Generation Sequencing (NGS) technologies have improved the ability to detect potentially targetable mutations. However, the integration of NGS into clinical management in an individualized manner remains challenging. In this single-center observational study, we performed a dedicated NGS panel studying 41 cancer-related genes in 50 consecutive patients with metastatic non-small-cell lung cancer between May 2012 and October 2014. Molecular analysis could be performed in 48 patients with a good quality check. One hundred and thirty-three mutations, whose twenty-four unique mutations, were detected. At least one mutation was found in 46 patients. In 58% of cases, the Molecular Tumor Board (MTB) was able to recommend treatment with a targeted agent based on the evaluation of the tumor genetic profile and treatment history. Nine patients (18%) were subsequently treated with a MTB-recommended targeted therapy; four patients experienced a clinical benefit with a partial response or stabilization lasting more than 4 months. In this case series involving patients with metastatic non-small cell lung cancer, we show that including integrative clinical sequencing data into routine clinical management was feasible and could impact on patient therapeutic proposal.

Background: Determination of HER2 status in invasive breast carcinomas is now mandatory for the optimal treatment of the patient. A vast majority of initial published studies described positivity in about 20 to 25 % of breast carcinomas, but the proportion of HER2 positive gene expression in women with breast cancer varies in the literature from 9 to 74%. The population of the tumor analyzed (for example histologic types, stage, age), the type of the assays used and the lack of uniformity or quality controls in detection assays may partly explain these differences. Our study describes the evolution of HER2 positive invasive breast cancer proportions during a period of 10 years and identifies clinical and pathological characteristics of these positive tumors. Methods: Based on the regional, population-based breast cancer registry, we identify 2396 patients diagnosed with invasive breast cancer in the Côte-d'Or department and treated in a single institution between 1998 and 2008. The HER2 status was determined by immunohistochemistry and by fluorescence in situ hybridization by a single team that performed regular internal quality controls and participated to multiannual external international quality control programs. Results: During the 1998–2008 period, 12.8% of invasive breast cancers were identified as HER2 positive, with no trend to annual variations (p = 0.27). During the same period, despite an increase of 45% of the annual diagnosed cancers in the institution, the clinical and pathological characteristics such as age, tumor size, grade, hormonal receptors expression remain stable. We only noticed a slight but significant increase of lobular carcinomas (p = 0.036). In multivariate analysis, HER2 positivity was as expected associated with: hormonal receptor negative status (OR = 1.7 [IC95%: 1.2–2.4], p = 0.0035), metastatic presentation at diagnosis (OR = 2 [IC95%: 1.2–3.4], p = 0.0092), ductal subtype (OR = 1.9 [IC95%: 1.1–3.1], p = 0.0178) and high SRB grade (OR = 2.8 [IC95%: 1.7–4.5] for SBR II, OR = 5.4 [IC95%: 3.2–9.1] for SBR III, p = 0.0035). Conversely, patients older than 75 years presented mostly HER2 negative tumors (OR = 0.5 [IC95%: 0.3–0.8], p < 0.0001). Conclusions: This population based study on HER2 breast cancer status emphasizes that in a population with stable clinical and tumoral characteristics, when standardized and controlled assays are used, the proportion of HER positive tumors remains stable over a large period and is lower than usually reported (12.8%). Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-08-07.

International audience; Tumor-infiltrating T and B lymphocytes could have the potential to affect cancer prognosis. The objective of this study was to investigate the prognostic significance of tumor infiltration by CD8 and CD4 T cells, and B lymphocytes in patients with localized gastric cancer. In a retrospective cohort of 82 patients with localized gastric cancer and treated by surgery we quantitatively assessed by immunohistochemistry on surgical specimen, immune infiltrates of IL-17(+), CD8(+), Foxp3(+), Tbet(+) T cells and CD20(+) B cells both in the tumor core and at the invasive margin via immunohistochemical analyses of surgical specimens. We observed that CD8(+) and IL17(+) T-cell densities were not significantly associated with gastric cancer prognosis. In contrast, high infiltration of Tbet(+) T cells, high numbers of CD20(+) B-cell follicles, and low infiltration of Foxp3(+) T cells, were associated with better relapse-free survival. Interestingly, treatment with neoadjuvant chemotherapy or histological tumor type (diffuse versus intestinal) did not influence type and density of immune infiltrates or their prognostic value. Immunohistochemical analysis of the gastric cancer stromal microenvironment revealed organized T and B cell aggregates, with strong structural analogies to normal secondary lymphoid organs and which could be considered as tertiary lymphoid structures. Using transcriptomic data from an independent cohort of 365 localized gastric cancer, we confirmed that a coordinated Th1, and B cell stromal gene signature is associated with better outcome. Altogether, these data suggest that tumor infiltration by B and Th1 T cells could affect gastric cancer prognosis and may be used to better define the outcome of patients with localized gastric cancer.

This retrospective study evaluates the interest of CEA measurement for early detection of breast cancer recurrences. Among 804 patients with invasive breast cancer, we selected 97 patients without recurrence (WR) for 5 years or more, 32 with a local recurrence (LR) and 131 with at least one distant metastasis (DM). Elevated CEA and CA 15-3 levels (3.1 μg/L and26 kU/L respectively) were found in 6 % and 22 % of patients with RL respectively and in 49 % and 69 % of patients with DM. Both CEA and CA 15-3 retained a significant value in predicting DM by univariate and multivariate analysis. Higher sensitivity of CEA and CA 15-3 were found in tumors with positive hormonal receptor status. CEA and CA 15-3 levels at DM were raised respectively in 23 and 65 % of the triple negative group, 58 and 75 % of the luminal, 56 and 78 % of the luminal-HER2 and 50 and 30 % of HER2-enriched group (P=0.0094 and 0.0252 respectively). The combination of CEA and CA 15-3 increased CA 15-3 sensitivity in especially luminal and HER2-enriched groups. In conclusion, elevated CA 15-3 and CEA levels at initial diagnosis of recurrence were found to be associated with hormonal receptor status and breast cancer subtypes. The combination of CEA and CA 15-3 appeared useful especially luminal and HER2-enriched groups.

Aflibercept is a recombinant fusion protein that acts as a soluble decoy receptor for vascular endothelial growth factor (VEGF). This molecule binds to all isoforms of VEGF-A as well as VEGF-B and placental growth factor, preventing them from activating their respective receptors. Aflibercept is used for the treatment of metastatic colorectal cancer (mCRC) in association with irinotecan. For reasons that remain to be elucidated, the addition of aflibercept to irinotecan-based chemotherapy increases the incidence of grade 3-4 diarrhea. We performed systematic colonic biopsies in three patients with grade 3 diarrhea after introduction of fluorouracil, leucovorin, irinotecan and aflibercept treatment for mCRC. For each patient, the diarrhea necessitated treatment discontinuation. Colonoscopy showed normal colonic mucosa. However, histopathological examination of the biopsies performed in these three patients revealed typical features of microscopic colitis. All three patients were treated with budesonide and mesalazine, leading to rapid regression of clinical symptoms. Chemotherapy was reintroduced in all patients, with only mild, grade 1 diarrhea under mesalazine and budesonide treatment. These are the first observations of aflibercept-induced microscopic colitis, and support the use of specific treatment on top of anti-diarrheal treatment in case of important digestive adverse events.

This retrospective study evaluates the interest of CA 15-3 measurement for early detection of breast cancer recurrences. Among 804 patients with invasive breast cancer we selected 117 patients without recurrence (WR) for 5 years or more, 33 with a local recurrence (LR) and 149 with at least one distant metastasis (DM). The sensitivity of CA 15-3 depends on the type of recurrence ([LR] or [DM]), the localization of unique DM, the presence and the number of metastatic sites, on hormonal receptor status and tumor subtypes. The number of metastatic sites and hormonal receptor status are independent predictive criteria of an elevation of CA 15-3. The analysis of ROC curve in order to separate patients with DM and patients WR shows an AUC of 0.87 (p0.0001). The optimal discriminative threshold is 26 kU/L. In conclusion, these data confirm that CA 15-3 increase depends on the kind of evolution and on initial tumor's hormonal status.

Type 1 auto-immune pancreatitis (type 1 AIP) is the pancreatic manifestation of IgG4-related systemic disease (IgG4-RD). This disease has recently been individualized and is characterized by elevated serum IgG4 levels and extrapancreatic lesions with common histologic characteristic: dense infiltration of lymphocytes, IgG4-positive plasma cells and storiforme fibrosis. Obliterative phlebitis is frequently detected. The pancreas is frequently involved in this disease. As approach to the pancreas for histological examination is generally difficult, AIP is diagnosed using a combination of clinical, serological, morphological and histopathological features. In pseudotumoral cases, AIP can be misdiagnosed as pancreatic cancer. Since AIP responds dramatically to steroid therapy, accurate diagnosis of AIP can avoid unnecessary laparotomy or pancreatic resection. We report here a case of a patient who underwent surgery for presumed pancreatic cancer. The final diagnosis was type 1 AIP.

Background: Breast tumors with negative estrogen receptor (ER-) and positive progesterone receptor (PR+) are rare (from 0 to 3.4 % according to the studies), and their existence is contested. These markers determine cancer molecular subtypes which play a determinant role for both the management and the prognosis of breast cancers. It is then essential to document the real existence of ER-/PR+ tumors. The present study aimed at determining if ER-/PR+ tumors share more basal or luminal characteristics. Methods: Between 2000 and 2015, 50 patients with ER-/PR+ breast tumors, representing 0.6 % of all breast cancers diagnosed in our institution, were included in this study. Their clinical (age, node status), morphological (size, histological type, Elston and Ellis (EE) grade, necrosis, inflammation, pushing margins, central scar, mitotic index) and immunohistochemical characteristics (ER, PR, HER2, CK5/6 and EGFR status) were compared with those of 50 luminal and 50 triple negative (TN) tumors randomly selected in our lab database. At the time this abstract is written, the Ki67 index determination is still in progress. Five of these ER-/PR+ tumors were also given a molecular test (Nanostring). Qualitative variables were compared using Chi2 or Fisher test, quantitative variables were compared using Student or Mann & Whitney tests. To take into account for multiple comparisons, p-values less than 0.025 were considered as significant. Results: The results are summarized in table 1. For almost all the analyzed criteria, ER-/PR+ tumors present statistical difference with luminal ones. On the contrary, they share most of TN tumors characteristics. The 5 molecular analyzes performed on ER-/PR+ samples showed the following phenotypes: 3 basal, 1 HER2 enriched and 1 luminal. For this last one, new immunohistological analyzes reveal in fact an ER+ staining. Table 1: Study results ER-/PR+ tumorsER+ tumorsTN tumorsp ER-/PR+ vs ER+p ER-/PR+ vs TNSize (mm)23.12525.20.00440.4822Histological type0.00120.2424 ductal9480.4100 lobular219.60 neuro-endocrine40 Differentiation Conclusion: This study tends to support that ER-/PR+ tumors may not exist and are likely to be TN cancers or less frequently false negative ER+ tumors. In a practical point of view, we think that 1) when a tumor shows ER-/PR+ and TN characteristics, it is probably a false positive PR staining, and the tumor has to be considered as a TN one, 2) when an ER-/PR+ tumor don't fit the triple negative tumors characteristics, ER must be retested in order to exclude a true luminal tumor. Citation Format: Molly D, Bertaut A, Blanchet C, Beltjens F, Charon-Barra C, Loustalot C, Desmoulins I, Arnould L. Do estrogen receptor negative and progesterone receptor positive breast tumors really exist? Attitude for not making them real. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-01-14.