BRCA1 inactivation is a frequent event in basal-like breast carcinomas (BLC). However, BRCA1 can be inactivated by multiple mechanisms and determining its status is not a trivial issue. As an alternate approach, we profiled 65 BLC cases using single-nucleotide polymorphism arrays to define a signature of BRCA1-associated genomic instability. Large-scale state transitions (LST), defined as chromosomal break between adjacent regions of at least 10 Mb, were found to be a robust indicator of BRCA1 status in this setting. Two major ploidy-specific cutoffs in LST distributions were sufficient to distinguish highly rearranged BLCs with 85% of proven BRCA1-inactivated cases from less rearranged BLCs devoid of proven BRCA1-inactivated cases. The genomic signature we defined was validated in a second independent series of 55 primary BLC cases and 17 BLC-derived tumor cell lines. High numbers of LSTs resembling BRCA1-inactivated BLC were observed in 4 primary BLC cases and 2 BLC cell lines that harbored BRCA2 mutations. Overall, the genomic signature we defined predicted BRCA1/2 inactivation in BLCs with 100% sensitivity and 90% specificity (97% accuracy). This assay may ease the challenge of selecting patients for genetic testing or recruitment to clinical trials of novel emerging therapies that target DNA repair deficiencies in cancer. Cancer Res; 72(21); 5454-62. Ó2012 AACR.

Phyllodes tumors are a rare distinctive fibroepithelial tumors of the breast and their management continues to be questioned. The aim of our study was to examine the treatment and outcome of 165 patients with phyllodes tumors and to review the options for surgical management. This is a retrospective study of 165 patients who presented to the Institut Curie between January 1994 and November 2008 for benign, borderline or malignant phyllodes tumors. The median follow-up was 12.65 months [range 0-149.8]. The median age at diagnosis was 44 years [range 17-79]. One hundred and sixty patients (97%) had breast-conserving treatment, of whom 3 patients (1.8%) had oncoplastic breast surgery. Younger women had a significantly higher chance of having a benign phyllodes tumor (p = 0.0001) or a tumor of small size (p < 0.0001). Histologic examination showed 114 benign (69%), 37 borderline (22%) and 14 malignant tumors (9%). The median tumor size was 30 mm [range 5-150]. The tumor margins were considered incomplete (< 10 mm) in 46 out of 165 cases (28%) with 52% revision surgery. Only the tumor grade was a significant risk factor for incomplete tumor margins (p = 0.005). Fifteen patients developed local recurrence (10%) and two, metastases. In univariate analysis, the histologic grade (p = 0.008), and tumor size (p = 0.02) were significative risk factors for local recurrence with an accentuated risk for "borderline" tumors and tumors of large size.).Similar results were obtained using multivariate analysis (p = 0.07). The mainstay of treatment for phyllodes tumors remains excision with a safe surgical margin, taking advantage breast conserving surgery where amenable. For borderline or malignant phyllodes tumors or in cases of local tumor recurrence, mastectomy, and immediate breast reconstruction may become the preferred option. Genetic analysis will potentially supplement classical histologic examination in order to improve our management of these tumors. The role of adjuvant treatments is unproven and must be considered on a case-by-case basis.

IntroductionSeveral authors have underscored a strong relation between the molecular subtypes and the axillary status of breast cancer patients. The aim of our work was to decipher the interaction between this classification and the probability of a positive sentinel node biopsy.Materials and MethodsOur dataset consisted of a total number of 2654 early-stage breast cancer patients. Patients treated at first by conservative breast surgery plus sentinel node biopsies were selected. A multivariate logistic regression model was trained and validated. Interaction covariate between ER and HER2 markers was a forced input of this model. The performance of the multivariate model in the training and the two validation sets was analyzed in terms of discrimination and calibration. Probability of axillary metastasis was detailed for each molecular subtype.ResultsThe interaction covariate between ER and HER2 status was a stronger predictor (p = 0.0031) of positive sentinel node biopsy than the ER status by itself (p = 0.016). A multivariate model to determine the probability of sentinel node positivity was defined with the following variables; tumour size, lympho-vascular invasion, molecular subtypes and age at diagnosis. This model showed similar results in terms of discrimination (AUC = 0.72/0.73/0.72) and calibration (HL p = 0.28/0.05/0.11) in the training and validation sets. The interaction between molecular subtypes, tumour size and sentinel nodes status was approximated.DiscussionWe showed that biologically-driven analyses are able to build new models with higher performance in terms of breast cancer axillary status prediction. The molecular subtype classification strongly interacts with the axillary and distant metastasis process.

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Purpose/Objective Recently, we developed RSI, a clinically-validated molecular signature that estimates tumor radiosensitivity. Here, we test whether integrating RSI with molecular subtype refines the classification of local recurrence risk in breast cancer Methods and Materials RSI and molecular subtype were evaluated in 343 patients treated with breast-conserving therapy including whole-breast RT plus/minus tumor bed boost (dose range, 45 – 72 Gy). The follow up for patients without recurrence was 10 years. Clinical endpoint was local recurrence-free survival (LRFS). Results While RSI did not uniformly predict for local recurrence across the entire cohort, combining RSI and molecular subtype identifies a subpopulation with an increased risk of local recurrence: triple negative (TN) and radioresistant (TN-R) (Ref –TN-R, HR=0.37 (0.15, 0.92) p=0.02). TN patients that were RSI-Sensitive/Intermediate (RSI-S/Int) had similar LR rates as LUM patients (HR=0.86 (0.47, 1.57) p=0.63). On multivariate analysis (MVA) combined RSI-Molecular Subtype (p=0.004), along with age (p=0.001) were the most significant predictors of LR. In contrast, integrating RSI into the LUM subtype did not identify additional risk groups. We hypothesized that RT dose escalation was impacting radioresistance in the LUM subtype and serving as a confounder. Indeed, increased RT dose decreased LR only in the LUM-R subset (HR = 0.23 (0.05, 0.98), p=0.03). On MVA, RT dose was an independent variable only in the LUMA/B-RR subset (HR=0.025 (0.001, 0.946), p=0.046), along with age (p=0.008), T stage (p=0.004) and chemotherapy (p=0.008). Conclusions Combined molecular subtype-RSI identifies a novel molecular sub-population (Triple Negative and Radioresistant) with an increased risk of local recurrence after BCT. We propose RSI-molecular subtype may be useful in guiding RT-based decisions in breast cancer.

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BRCA1 and BRCA2 gene pathogenic variants account for most hereditary breast cancer and are increasingly used to determine eligibility for PARP inhibitor (PARPi) therapy of BRCA-related cancer. Because issues of BRCA testing in clinical practice now overlap with both preventive and therapeutic management, updated and comprehensive practice guidelines for BRCA genotyping are needed. The integrative recommendations for BRCA testing presented here aim to (1) identify individuals who may benefit from genetic counselling and risk-reducing strategies; (2) update germline and tumour-testing indications for PARPi-approved therapies; (3) provide testing recommendations for personalised management of early and metastatic breast cancer; and (4) address the issues of rapid process and tumour analysis. An international group of experts, including geneticists, medical and surgical oncologists, pathologists, ethicists and patient representatives, was commissioned by the French Society of Predictive and Personalised Medicine (SFMPP). The group followed a methodology based on specific formal guidelines development, including (1) evaluating the likelihood of BRCAm from a combined systematic review of the literature, risk assessment models and expert quotations, and (2) therapeutic values of BRCAm status for PARPi therapy in BRCA-related cancer and for management of early and advanced breast cancer. These international guidelines may help clinicians comprehensively update and standardise BRCA testing practices.

DNA breakpoint information more often agreed with the clinical determination than CNAs in this population. The partial identity score, which was calculated based on DNA breakpoints, allows statistical discrimination between new primary tumors and true recurrences that could outperform the clinical determination in terms of prognosis.