Breast hamartoma: reassessment of an under-recognised breast lesion.

AIMS: Breast hamartomas are an under-recognised lesion because they lack a distinctive microscopic appearance. Microscopic diagnosis can often conclude 'no significant lesion' or 'normal breast tissue', leading to repeated biopsies and diagnostic delay. We describe the histological, immunohistochemical and radiological features of breast hamartomas with the aim of identifying specific signs to facilitate their diagnosis and to differentiate them from normal breast and fibroepithelial lesions. METHODS AND RESULTS: Forty-seven breast hamartomas were reassessed (histological diagnosis and imaging features). An immunohistochemical study [oestrogen receptor (ER), progesterone receptor (PR), CD34, high-mobility group A2 (HMGA2)] was performed. On breast imaging, hamartomas most often presented as probably benign solid masses with circumscribed margins and variable densities. Histologically, breast hamartomas resembled normal breast, although their stromal component was predominant, separating randomly scattered epithelial elements with areas of pure collagenous stroma. Pseudoangiomatous stromal hyperplasia (PASH) was present in 93.6% of cases and CD34 antibody highlighted intralobular, perilobular and interlobular distribution of CD34-positive fibroblasts. By comparison, CD34 was mainly expressed in the intralobular normal breast tissue stroma. Hamartoma stromal cells expressed HMGA2, ER and PR in 79%, 66% and 76.3% of our cases, respectively, compared to 7.7%, 23% and 19% in normal breast tissue, respectively (P < 0.0001; P = 0.0005; P < 0.0001). CONCLUSIONS: After ascertaining that core needle biopsy is effectively intralesional, breast hamartomas can be diagnosed with confidence by taking into account the presence of stromal changes, PASH, interlobular distribution of CD34-positive fibroblasts, HMGA2 and hormonal receptor stromal expression.

Impact of Obtaining a Digital Breast Tomosynthesis (DBT) Spot Compression View on Assessment of Equivocal DBT Findings.

BACKGROUND. A recently introduced digital breast tomosynthesis (DBT) device allows acquisition of DBT spot compression views with a small paddle during DBT acquisition. OBJECTIVE. The purpose of this study was to evaluate the impact on diagnostic performance of obtaining a DBT spot compression view for assessment of equivocal DBT findings. METHODS. This retrospective study included 102 women (mean age, 60 years) in whom a DBT spot compression view was obtained to characterize an equivocal finding on DBT at the performing radiologist's discretion. The DBT examinations were performed from December 14, 2018, to December 18, 2019. Two fellowship-trained breast radiologists and one breast imaging fellow, who were aware of the location of the equivocal lesions, independently reviewed the examinations. Readers first assigned a BI-RADS category using standard DBT views and then immediately assigned a category using the DBT spot compression view. BI-RADS categories 2 and 3 were considered negative, and categories 4A and greater were considered positive. Histology and at least 1 year of imaging follow-up served as the reference standard. Intrareader agreement for one reader and interreader agreement among all readers were evaluated with kappa coefficients. Diagnostic performance was compared between DBT with and DBT without spot compression views by use of McNemar tests. RESULTS. Intrareader agreement increased from 0.43 to 0.72, and interreader agreement increased from 0.21 to 0.45 on the basis of kappa coefficients for DBT without and with spot compression views. Eighteen cancers were present. Compared with standard DBT views, DBT spot compression views yielded significantly increased accuracy for all three readers (75% vs 90%, 74% vs 94%, 72% vs 94%); significantly increased specificity for all three readers (69% vs 90%, 75% vs 94%, 68% vs 93%); and significantly increased sensitivity for one reader (67% vs 94%) without significant change in sensitivity for the two other readers (89% vs 100%, 100% vs 89%). Radiation dose was 1.97 mGy for the DBT spot compression view versus 1.78-1.81 mGy for standard DBT craniocaudal and medio-lateral oblique views. CONCLUSION. Use of the DBT spot compression view increased intrareader agreement, interreader agreement, and diagnostic accuracy (primarily owing to improved specificity); the supplemental dose for the spot compression view was slightly higher than that for a standard DBT view. CLINICAL IMPACT. DBT spot compression may help characterize equivocal DBT findings, reducing further workup for benign findings.

Expression of neurotensin receptor-1 (NTS1) in primary breast tumors, cellular distribution, and association with clinical and biological factors.

PURPOSE: Neurotensin receptor-1 (NTS1) is increasingly recognized as a potential target in diverse tumors including breast cancer, but factors associated with NTS1 expression have not been fully clarified. METHODS: We studied NTS1 expression using the Tissue MicroArray (TMA) of primary breast tumors from Institut Bergonié. We also studied association between NTS1 expression and clinical, pathological, and biological parameters, as well as patient outcomes. RESULTS: Out of 1419 primary breast tumors, moderate to strong positivity for NTS1 (≥ 10% of tumoral cells stained) was seen in 459 samples (32.4%). NTS1 staining was cytoplasmic in 304 tumors and nuclear in 155 tumors, a distribution which appeared mutually exclusive. Cytoplasmic overexpression of NTS1 was present in 21.5% of all breast tumors. In multivariate analysis, factors associated with cytoplasmic overexpression of NTS1 in breast cancer samples were higher tumor grade, Ki67 ≥ 20%, and higher pT stage. Cytoplasmic NTS1 was more frequent in tumors other than luminal A (30% versus 17.3%; p < 0.0001). Contrastingly, the main "correlates" of a nuclear location of NTS1 were estrogen receptor (ER) positivity, low E&E (Elston and Ellis) grade, Ki67 < 20%, and lower pT stage. In NTS1-positive samples, cytoplasmic expression of NTS1 was associated with shorter 10-year metastasis-free interval (p = 0.033) compared to NTS1 nuclear staining. Ancillary analysis showed NTS1 expression in 73% of invaded lymph nodes from NTS1-positive primaries. CONCLUSION: NTS1 overexpression was found in about one-third of breast tumors from patients undergoing primary surgery with two distinct patterns of distribution, cytoplasmic distribution being more frequent in aggressive subtypes. These findings encourage the development of NTS1-targeting strategy, including radiopharmaceuticals for imaging and therapy.

Diagnostic accuracy of breast MRI for patients with suspicious nipple discharge and negative mammography and ultrasound: a prospective study.

OBJECTIVES: To evaluate the diagnostic accuracy of breast MRI in identifying lesions requiring excision for patients with suspicious nipple discharge but normal mammograms and ultrasounds. METHODS: Between September 2013 and May 2019, 106 female participants (mean age 57.9 years) were consecutively included in this prospective multicenter study; 102 were retained for analysis. MRI was considered negative in the absence of suspicious enhancement and positive in cases of ipsilateral abnormal enhancement (BI-RADS 3 to 5). Final diagnoses were based on histological findings of surgical or percutaneous biopsies or at 1-year follow-up. We considered all lesions requiring excision found on pathology (papilloma, atypia, nipple adenomatosis, or cancer) as positive results. We considered spontaneous resolution of the discharge at 1 year as a negative result. RESULTS: MRI showed ipsilateral abnormal enhancement in 54 patients (53%) revealing 46 lesions requiring excision (31 benign papillomas, 5 papillomas with atypia, 2 nipple adenomatosis, and 8 cancers) and 8 benign lesions not requiring excision. No suspicious enhancement was found in the remaining 48 participants (47%). Forty-two were followed up at 1 year with spontaneous resolution of the discharge and six underwent surgery (revealing 2 benign papillomas). MRI diagnostic accuracy for the detection of a lesion requiring excision was as follows: sensitivity 96%, specificity 85%, positive predictive value 85%, and negative predictive value 96%. CONCLUSION: In patients with suspicious nipple discharge and normal mammogram and ultrasound, MRI demonstrates excellent performance to identify lesions for which excision is required. Normal MRI indicates it is safe to propose follow-up only management, thus avoiding unnecessary duct excision. TRIAL REGISTRATION: ClinicalTrials.gov NCT02819362 KEY POINTS: • Breast MRI can be useful for the management of patients with suspicious nipple discharge and negative mammogram and ultrasound. • MRI detected a lesion requiring excision in 46 participants (45%) with unexplained discharge. • If breast MRI is negative, follow-up is a safe alternative for these patients.

Residual cancer burden index and tumor-infiltrating lymphocyte subtypes in triple-negative breast cancer after neoadjuvant chemotherapy.

PURPOSE: There is a need to refine the prognosis of triple-negative breast cancer (TNBC) patients after neoadjuvant chemotherapy (NAC) and to study the influence of the tumor microenvironment. We evaluated the prognostic value of pathological and immune markers in TNBC with residual disease (RD) after NAC. METHODS: In a series of 186 TNBC patients treated by NAC, we assessed the prognostic value of the Residual Cancer Burden (RCB) index. In 109 patients with RD, we studied the impact of clinicopathological features and tumor immune response in the residual tumor on overall survival (OS) and distant recurrence-free interval (DRFI). RESULTS: In the whole group, the OS and DRFI, at 3 years, were statistically different between the different classes of RCB (P = 0.0004 and P < 0.0001, respectively). In univariate analysis of the RD group, low RCB index and high ratios of stromal tumor-infiltrating lymphocytes (TILs), CD3 + TILs, CD4 + TILs, CD8 + TILs, and IDO1-positive cells were significant favorable prognostic factors for DRFI at 3 years. In the final multivariate model, CD4 + TILs and RCB index showed a statistically independent prognostic significance for DRFI [Hazard Ratio (HR) 2.88 (95%CI 1.34-6.17), P = 0.007 and HR 12.04 (95%CI 2.78-52.23, P < 0.0001), respectively]. The CD4 + TIL levels influenced survival in the different RCB classes with a significant effect observed in RCB-II and RCB-III classes (P = 0.05 and P = 0.05, respectively). CONCLUSIONS: These results suggest that the combination of pathological (RCB index) and tumor micro-environmental features (CD4 + TILs) help refining the prognosis of TNBC patients with RD following NAC.

Soft-Tissue Sarcomas: Assessment of MRI Features Correlating with Histologic Grade and Patient Outcome.

Background Managing soft-tissue sarcoma (STS) relies on histologic grade, which is the strongest prognostic factor and a routine assessment at biopsy. However, underestimation of histologic grade may occur because of tumor heterogeneity. Purpose To identify MRI features that are associated with high-grade STS (grade III) and to determine the relationship between MRI features and patient survival. Materials and Methods In this retrospective single-center study, patients (age ≥16 years) were included if they presented with STS diagnosed between 2008 and 2015, had a baseline contrast material-enhanced MRI study, had a pathologic grade assessed on the whole surgical specimen, and had no history of neoadjuvant treatment. Visceral sarcomas, well-differentiated liposarcomas, and angiosarcomas were excluded. Images were evaluated for size, heterogeneity, architecture, margins, and surrounding tissue at T2-weighted, T1-weighted precontrast, and T1-weighted postcontrast MRI. χ2 tests, Fisher tests, and multivariable binary logistic regression were performed to identify features associated with a final grade of III. The associations between combinations of these features and overall survival and metastasis-free survival were investigated with Kaplan-Meier curves and multivariable Cox models. Results A total of 130 patients were included (53 women [mean age ± standard deviation, 60.7 years ± 19.2]); 72 of the 130 (55.4%) STSs were grade III. At multivariable analysis, three MRI features were associated with grade III STS: peritumoral enhancement (odds ratio [OR], 3.4; P = .003), presence of an area compatible with necrosis (OR, 2.4; P = .03), and heterogeneous signal intensities greater than or equal to 50% at T2-weighted imaging (OR, 2.3; P = .04). The presence of at least two of these three features was an independent predictor of metastasis-free survival (hazard ratio, 4.5; P = .01) and overall survival (hazard ratio, 4.2; P = .04). Conclusion MRI features including necrosis, heterogeneity, and peritumoral enhancement of soft-tissue sarcomas were associated with grade III tumors, metastasis-free survival, and overall survival. © RSNA, 2019 Online supplemental material is available for this article.

Renal cell carcinoma lung metastases treated by radiofrequency ablation integrated with systemic treatments: over 10 years of experience.

BACKGROUND: To determine safety and efficacy of radiofrequency ablation (RFA) for local treatment of lung metastases of renal cell carcinoma (RCC), sequenced or combined with systemic treatments. METHODS: Retrospectively, we studied 53 patients treated by RFA for a maximum of six lung metastases of RCC. The endpoints were local efficacy, overall (OS), disease-free (DFS), pulmonary progression-free (PPFS) and systemic treatment-free (STFS) survivals, complications graded by the CTCAE classification and factors associated with survivals. Potential factors analysed were: clinical and pathological data, tumoral staging of TNM classification, primary tumor histology, Fuhrman's grade, age, number and size of lung metastases and extra-pulmonary metastases pre-RFA. RESULTS: One hundred metastases were treated by RFA. Median follow-up time was 61 months (interquartile range 90-34). Five-year OS was 62% (95% confidence interval (CI): 44-75). Median DFS was 9.9 months (95% CI: 6-16). PPFS at 1 and 3 years was 58.9% (95%CI: 44.1-70.9) and 35.2% (95%CI: 21.6-49.1), respectively. We observed 3% major complications (grade 3 and 4 of CTCAE classification). Local efficacy was 91%. Median STFS was 28.3 months. Thirteen patients (25%) with lung recurrence could be treated by another RFA. T3/T4 tumors had significantly worse OS, PPFS and STFS. Having two or more lung metastases increased the risk of pulmonary progression more than threefold. CONCLUSION: Integrated to systemic treatment strategy, RFA is safe and effective for the treatment strategy of lung metastasis from RCC with good OS and long systemic treatment-free survival. RFA offers the possibility of repeat procedures, with low morbidity.

Distal extremities soft tissue sarcomas: Are they so different from other limb localizations?

BACKGROUND AND OBJECTIVES: Soft tissue sarcoma localization in distal extremities (DESTS) of the limbs (hand/fingers, and foot/toes) is unusual. The literature is scarce about their behavior and this study was designed to assess their epidemiological characteristics, outcomes, and prognosis compared to other limb localizations (OLSTS). METHODS: From 1980 to 2010, adult DESTS and OLSTS in 22 centers were included. Demographics, tumor type, treatment modalities, and latest follow-up status were collected. Primary endpoints were overall survival and local/metastatic recurrence incidences. RESULTS: Two hundred five DESTS and 3001 OLSTS were included. The patients were younger, with more female and smaller tumors in DESTS. There were more clear cell/epithelioid sarcomas, synovial sarcomas, and myxoid liposarcomas vs more dedifferentiated liposarcomas in OLSTS. DESTS tumors were less irradiated and more often amputated (24.3% vs 3.4%). The five-year survival rate was 78.2% compared to 68.6% in OLSTS and after multivariate analysis, STS localization did not impact survival or local/metastatic recurrence. CONCLUSION: Though rare and smaller than other limb localizations, DESTS are to be considered as aggressive. Despite a higher amputation rate, the prognosis remains the same as in OLSTS. Limb sparing vs amputation should be carefully assessed in DESTS, especially if grade 3 or of a poor prognosis histological subtype.

Time-varying coefficients in a multivariate frailty model: Application to breast cancer recurrences of several types and death.

During their follow-up, patients with cancer can experience several types of recurrent events and can also die. Over the last decades, several joint models have been proposed to deal with recurrent events with dependent terminal event. Most of them require the proportional hazard assumption. In the case of long follow-up, this assumption could be violated. We propose a joint frailty model for two types of recurrent events and a dependent terminal event to account for potential dependencies between events with potentially time-varying coefficients. For that, regression splines are used to model the time-varying coefficients. Baseline hazard functions (BHF) are estimated with piecewise constant functions or with cubic M-Splines functions. The maximum likelihood estimation method provides parameter estimates. Likelihood ratio tests are performed to test the time dependency and the statistical association of the covariates. This model was driven by breast cancer data where the maximum follow-up was close to 20 years.

Early objective response may not be a prognostic factor of survival for patients with metastatic urothelial carcinoma: from a retrospective analysis of a cohort of 113 patients.

BACKGROUND: This study aims to better define prognostic factors for patients with metastatic urothelial carcinoma (mUC), and to identify patients who will benefit from first-line cisplatin-based chemotherapy. We test the hypothesis that early objective response (EOR), defined as the occurrence of an objective response following 2 or 3 courses of chemotherapy, could be a prognostic factor for overall survival (OS) and thus be used to guide treatment decisions. Data from 113 patients with evaluable mUC receiving first-line cisplatin-based treatment between January 2004 and December 2006 was collected retrospectively from prospectively-maintained databases across seven French cancer centers. Clinical factors potentially associated with survival and EOR were analyzed in univariate and multivariate analysis. RESULTS: One hundred three patient records were complete and available for inclusion in the multivariate model. Four factors were independently associated with OS: Performance status 1 and 2 (HR 2.3 [95 % CI 1.3-3.9], p = 0.002; HR 3.4 [95 % CI 1.6-7.2], p = 0.001 respectively); presence of visceral metastases (HR 2.2 [95 % CI 1.3-3.9], p = 0.004); abnormal hemoglobin levels (HR 1.7 [95 % CI 1.01-2.8], p = 0.045); disease progression (HR 10.1 [95 % CI 4.2-24.1], p < 0.001). CONCLUSIONS: This study confirms the prognostic factors previously reported in first-line chemotherapy for mUC. However, we failed to demonstrate that EOR was an independent predictive factor of OS. Nevertheless, an early response evaluation is recommended since early progression is an important parameter that can be used to decide whether treatment should be interrupted and changed for alternative strategies integrating the concept of personalized medicine or new immune therapies.

Smooth muscle differentiation identifies two classes of poorly differentiated pleomorphic sarcomas with distinct outcome.

The clinical relevance of accurately diagnosing pleomorphic sarcomas has been shown, especially in cases of undifferentiated pleomorphic sarcomas with myogenic differentiation, which appear significantly more aggressive. To establish a new smooth muscle differentiation classification and to test its prognostic value, 412 sarcomas with complex genetics were examined by immunohistochemistry using four smooth muscle markers (calponin, h-caldesmon, transgelin and smooth muscle actin). Two tumor categories were first defined: tumors with positivity for all four markers and tumors with no or incomplete phenotypes. Multivariate analysis demonstrated that this classification method exhibited the strongest prognostic value compared with other prognostic factors, including histological classification. Secondly, incomplete or absent smooth muscle phenotype tumor group was then divided into subgroups by summing for each tumor the labeling intensities of all four markers for each tumors. A subgroup of tumors with an incomplete but strong smooth muscle differentiation phenotype presenting an intermediate metastatic risk was thus identified. Collectively, our results show that the smooth muscle differentiation classification method may be a useful diagnostic tool as well as a relevant prognostic tool for undifferentiated pleomorphic sarcomas.

Progress in survival outcomes in patients with advanced ovarian cancer treated by neo-adjuvant platinum/taxane-based chemotherapy and late interval debulking surgery.

BACKGROUND: Steady progress in outcomes has been observed after standard treatment by surgery and chemotherapy in patients with advanced ovarian cancer (AOC), but little is known about outcomes after alternative neoadjuvant chemotherapy (NAC) proposed to primary inoperable patients. We assessed whether NAC offers comparable survival to standard treatment, whether survival rates have progressed over time, and what the optimal extent of surgery at late interval debulking surgery (IDS) should be. METHODS: This was a retrospective data analysis of prospectively recorded patients with poor prognosis AOC treated by platinum/taxane NAC and late IDS (after six cycles). Independent prognostic factors for surgical morbidity and overall survival (OS) are determined and survival outcomes are compared to survival rates for a similar group of patients treated with platinum protocols. RESULTS: A total of 118 patients with stages IIIC-IV AOC (median age: 64 years, stage IV: 31%) received IDS (46% standard surgery and 54% radical, with 68% obtaining complete resection). Major morbidity was 18%. OS was 42 months across all patients (95% confidence interval 35.3-49.1) and 80 months in stage IIIC. This is higher by 15 months than after platinum-based treatment. Higher morbidity was associated with bowel resection. Longer OS was associated with ASA class I, stage IIIC, no bowel surgery, and no residual disease. CONCLUSIONS: The neoadjuvant approach with late IDS offers survival similar to that reported by standard treatment, with progress in outcomes compared with rates after platinum treatment. The goal of IDS surgery is complete resection, while sparing surrounding organs.

High cumulative risks of cancer in patients with PTEN hamartoma tumour syndrome.

BACKGROUND: PTEN hamartoma tumour syndrome (PHTS) encompasses several clinical syndromes with germline mutations in the PTEN tumour suppressor gene, including Cowden syndrome which is characterised by an increased risk of breast and thyroid cancers. Because PHTS is rare, data regarding cancer risks and genotype-phenotype correlations are limited. The objective of this study was to better define cancer risks in this syndrome with respect to the type and location of PTEN mutations. METHODS: 154 PHTS individuals with a deleterious germline PTEN mutation were recruited from the activity of the Institut Bergonié genetic laboratory. Detailed phenotypic information was obtained for 146 of them. Age and sex adjusted standardised incidence ratio (SIR) calculations, cumulative cancer risk estimations, and genotype-phenotype analyses were performed. RESULTS: Elevated SIRs were found mainly for female breast cancer (39.1, 95% CI 24.8 to 58.6), thyroid cancer in women (43.2, 95% CI 19.7 to 82.1) and in men (199.5, 95% CI 106.39 to 342.03), melanoma in women (28.3, 95% CI 7.6 to 35.4) and in men (39.4, 95% CI 10.6 to 100.9), and endometrial cancer (48.7, 95% CI 9.8 to 142.3). Cumulative cancer risks at age 70 were 85% (95% CI 70% to 95%) for any cancer, 77% (95% CI 59% to 91%) for female breast cancer, and 38% (95% CI 25% to 56%) for thyroid cancer. The risk of cancer was two times greater in women with PHTS than in men with PHTS (p<0.05). CONCLUSIONS: This study shows a considerably high cumulative risk of cancer for patients with PHTS, mainly in women without clear genotype-phenotype correlation for this cancer risk. New recommendations for the management of PHTS patients are proposed.

Patterns of complications following intraoperative radiofrequency ablation for liver metastases.

BACKGROUND: Intraoperative radiofrequency ablation (IRFA) is added to surgery to obtain hepatic clearance of liver metastases. Complications occurring in IRFA should differ from those associated with wedge or anatomic liver resection. METHODS: Patients with liver metastases treated with IRFA from 2000 to 2010 were retrospectively analysed. Postoperative outcomes are reported according to the Clavien-Dindo system of classification. RESULTS: A total of 151 patients underwent 173 procedures for 430 metastases. Of these, 97 procedures involved IRFA plus liver resection and 76 involved IRFA only. The median number of lesions treated by IRFA was two (range: 1-11). A total of 123 (71.1%) procedures were carried out in patients who had received preoperative chemotherapy. The mortality rate was 1.2%. Thirty (39.5%) IRFA-only patients and 45 (46.4%) IRFA-plus-resection patients presented complications. Immediate complications (n = 4) were associated with IRFA plus resection. American Society of Anesthesiologists (ASA) class, previous abdominal surgery or hepatic resection, body mass index, number of IRFA procedures, portal pedicle clamping, total vascular exclusion and preoperative chemotherapy were not associated with a greater number of complications of Grade III or higher severity. Length of surgery >4 h [odds ratio (OR) 2.67, 95% confidence interval (CI) 1.1-6.3; P < 0.05] and an associated contaminating procedure (OR 3.72, 95% CI 1.53-9.06; P < 0.005) led to a greater frequency of complications of Grade III or higher. CONCLUSIONS: Mortality and morbidity after IRFA, with or without resection, are low. Nevertheless, long interventions and concurrent bowel operations increase the risk for septic complications.

Impact on survival without chemotherapy of local treatments of lung metastasis of colorectal cancers: Analysis on REPULCO cohort.

BACKGROUND: The impact of local management of pulmonary metastases on the disease course of patients with metastatic colorectal cancer is poorly assessed. METHODS: REPULCO database was a retrospective cohort on 18 years that included all patients treated for lung metastases from colorectal cancer who received local and/or systemic treatments. AIMS: Primary objective was overall survival, secondary were progression-free survival and survival without chemotherapy. RESULTS: Three hundred and fifteen patients were analyzed, 157 with only systemic treatments, 78 with only local treatments, and 80 with local and systemic treatments. Overall survival at 5 years was 26.9% (IC95%: [17.7-36.9]) for systemic treatments only, 61.0% (IC95%: [40.8-76.1]) for local treatments only, and 77.8% (IC95%: [60.1-88.3]) for local and systemic treatments. Progression-free survival at 2 years was 4.8% (IC95%: [2.1-9.2]) for systemic treatment only, 28.3% (IC95%: [17.7-39.9]) for local treatments only, and 21.8% (IC95%: [13.1-31.9]) for local and systemic treatments. Median survival without chemotherapy was 2.99 months (IC95%: [2.33-3.68]) for systemic treatments, 33.97 months (IC95%: [19.06-NA]) for local treatments, and 12.85 months (IC95%: [8.18-21.06]) for local and systemic treatments. CONCLUSION: Local treatments of lung metastasis led to prolonged survival and allowed long periods of time without chemotherapy in this cohort.

Comprehensive analysis of PTEN status in breast carcinomas.

PTEN plays a well-established role in the negative regulation of the PI3K pathway, which is frequently activated in several cancer types, including breast cancer. A nuclear function in the maintenance of chromosomal stability has been proposed for PTEN but is yet to be clearly defined. In order to improve understanding of the role of PTEN in mammary tumorigenesis in terms of a possible gene dosage effect, its PI3K pathway function and its association with p53, we undertook comprehensive analysis of PTEN status in 135 sporadic invasive ductal carcinomas. Four PTEN status groups were defined; complete loss (19/135, 14%), reduced copy number (19/135, 14%), normal (86/135, 64%) and complex (11/135, 8%). Whereas the PTEN complete loss status was significantly associated with estrogen receptor (ER) negativity (p=0.006) and in particular the basal-like phenotype (p<0.0001), a reduced PTEN copy number was not associated with hormone receptor status or a particular breast cancer subtype. Overall, PI3K pathway alteration was suggested to be involved in 59% (79/134) of tumors as assessed by human epidermal growth factor receptor 2 overexpression, PIK3CA mutation or a complete loss of PTEN. A complex PTEN status was identified in a tumor subgroup which displayed a specific, complex DNA profile at the PTEN locus with a strikingly similar highly rearranged pan-genomic profile. All of these tumors had relapsed and were associated with a poorer prognosis in the context of node negative disease (p=1.4 × 10(-13) ) thus may represent a tumor subgroup with a common molecular alteration which could be targeted to improve clinical outcome.

Triple-negative breast cancers: associations between imaging and pathological findings for triple-negative tumors compared with hormone receptor-positive/human epidermal growth factor receptor-2-negative breast cancers.

BACKGROUND: Triple-negative (TN) breast cancers have high malignancy potential and are often characterized by early systemic relapse. Early detection is vital, but there are few comprehensive imaging reports. Here we describe mammography, ultrasound, and magnetic resonance imaging (MRI) findings of TN breast cancers, investigate the specific features of this subtype, and compare the characteristics of TN breast cancers with those of hormone receptor (HR)-positive/human epidermal growth factor receptor (HER)-2-negative breast cancers. MATERIALS AND METHODS: From July 2009 to June 2011, mammography and ultrasound findings of 210 patients with pathologically confirmed TN (n = 105) and HR-positive/HER-2-negative breast cancers (n = 105) were retrospectively reviewed from our institutional database. Ultrasound vascularity was notified in 88 cases and elasticity scores were notified in 49 cases overall. Thirty-five patients underwent MRI (22 TN and 13 HR-positive/HER-2-negative). Mammograms, ultrasound, and MRI were reviewed according to the Breast Imaging-Reporting and Data System (BI-RADS) lexicon and classification. RESULTS: TN breast cancers were more likely to show round, oval, or lobulated masses with indistinct margins on mammography than HR-positive/HER-2-negative breast cancers. On ultrasound, TN tumors were more likely than HR-positive/HER-2-negative breast cancers to show circumscribed or microlobulated margins and no posterior acoustic features or posterior enhancement-positive. On MRI, TN cancers exhibited suspicious aspects more often than HR-positive/HER-2-negative cancers, often with rim enhancement-positiveHER-2 (84.6% of masses were classified BI-RADS 5). CONCLUSION: This study is the first to describe findings on mammography, ultrasound, and MRI for TN breast cancers with a matched HR-positive/HER-2-negative control group. Several distinctive morphological features of these aggressive tumors are identified that can be used for earlier diagnosis and treatment, and ultimately to improve outcomes.

Imaging features of sporadic breast cancer in women under 40 years old: 97 cases.

OBJECTIVES: To evaluate characteristic features of mammography, ultrasound and magnetic resonance imaging (MRI) of sporadic breast cancer in women <40 years and to determine correlations with pathological and biological factors. METHODS: A retrospective review of radiological, clinicopathological and biological features of sporadic breast cancers for women under 40 years at our institution between 2007-2012 covering 91 patients. Mammography was available for 97 lesions, ultrasound for 94 and MRI for 38. RESULTS: The most common imaging features were masses, nearly all classified BI-RADS 4 or 5. On mammography microcalcifications alone accounted for 31 %, all suspicious. There were 42.6 % luminal B, 24.5 % luminal A, 19.1 % HER2-enriched and 10.6 % triple-negative (TN) tumours by immunohistochemistry. HER2 overexpression was correlated with the presence of calcifications at mammography (P = 0.03). TN cancers more often had an oval shape and abrupt interface at ultrasound and rim enhancement on MRI. MRI features were suspicious for all cancers and rim enhancement of a mass was a significant predictor of triple-negative tumours (P = 0.01). CONCLUSIONS: The imaging characteristics of cancers in patients under 40 years without proven gene mutations do not differ from their older counterparts, but appear correlated to phenotypic profiles, which have a different distribution in young women compared to the general population.

Multivariate frailty models for two types of recurrent events with a dependent terminal event: application to breast cancer data.

Individuals may experience more than one type of recurrent event and a terminal event during the life course of a disease. Follow-up may be interrupted for several reasons, including the end of a study, or patients lost to follow-up, which are non informative censoring events. Death could also stop the follow-up, hence, it is considered as a dependent terminal event. We propose a multivariate frailty model that jointly analyzes two types of recurrent events with a dependent terminal event. Two estimation methods are proposed: a semiparametrical approach using penalized likelihood estimation where baseline hazard functions are approximated by M-s plines, and another one with piecewise constant baseline hazard functions. Finally, we derived martingale residuals to check the goodness-of-fit. We illustrate our proposals with a real dataset on breast cancer. The main objective was to model the dependency between the two types of recurrent events (locoregional and metastatic) and the terminal event (death) after a breast cancer.

Idylla EGFR assay on extracted DNA: advantages, limits and place in molecular screening according to the latest guidelines for non-small-cell lung cancer (NSCLC) patients.

AIMS: Idylla epidermal growth factor receptor (EGFR) is a fast and fully automated mutation assay that is easy to implement. However, under the Biocartis-recommended technical conditions, tissue sections are directly introduced into the cartridge, at the risk of exhausting the tumour sample. In this study, we evaluate the performance of Idylla EGFR on extracted DNA and discuss its place within the global non-small-cell lung cancer (NSCLC) screening strategy. METHODS: 577 comparative tests between Idylla EGFR on extracted DNA and next-generation sequencing (NGS) were performed across two centres. RESULTS: Preanalytical thresholds were established (20% tumour cell content, 50 ng DNA input) and challenged prospectively in routine practice. 16.8% of samples referred for screening were considered non eligible for Idylla EGFR testing. Due to discordant by design cases, Idylla EGFR sensitivity was 86.9% for currently actionable EGFR mutations. Idylla EGFR specificity was 100% in first-line screening. NGS was always feasible on the same DNA. CONCLUSION: Idylla EGFR on extracted DNA is feasible and enables tumour material to be saved compared with tissue section use. It is not necessary to replace the analytical thresholds of the Biocartis algorithm. Due to both the limits of the mutational repertoire and the high increase of targetable genes in NSCLC, the use of Idylla EGFR should be restricted to clinical emergency situations accompanied by NGS.