Breast cancer risk prediction using Tyrer-Cuzick algorithm with an 18-SNPs polygenic risk score in a European population with below-average breast cancer incidence.

GOALS: To determine whether an 18 single nucleotide polymorphisms (SNPs) polygenic risk score (PRS18) improves breast cancer (BC) risk prediction for women at above-average risk of BC, aged 40-49, in a Central European population with BC incidence below EU average. METHODS: 502 women aged 40-49 years at the time of BC diagnosis completed a questionnaire on BC risk factors (as per Tyrer-Cuzick algorithm) with data known at age 40 and before BC diagnosis. Blood samples were collected for DNA isolation. 250 DNA samples from healthy women aged 50 served as a control cohort. 18 BC-associated SNPs were genotyped in both groups and PRS18 was calculated. The predictive power of PRS18 to detect BC was evaluated using a ROC curve. 10-year BC risk was calculated using the Tyrer-Cuzick algorithm adapted to the Slovenian incidence rate (S-IBIS): first based on questionnaire-based risk factors and, second, including PRS18. RESULTS: The AUC for PRS18 was 0.613 (95 % CI 0.570-0.657). 83.3 % of women were classified at above-average risk for BC with S-IBIS without PRS18 and 80.7 % when PRS18 was included. CONCLUSION: BC risk prediction models and SNPs panels should not be automatically used in clinical practice in different populations without prior population-based validation. In our population the addition of an 18SNPs PRS to questionnaire-based risk factors in the Tyrer-Cuzick algorithm in general did not improve BC risk stratification, however, some improvements were observed at higher BC risk scores and could be valuable in distinguishing women at intermediate and high risk of BC.

Axillary ultrasound for predicting response to neoadjuvant treatment in breast cancer patients-a single institution experience.

BACKGROUND: In node-positive breast cancer patients at diagnosis (cN +) that render node-negative after neoadjuvant systemic treatment (NAST), axillary lymph node dissection (ALND) can be avoided in selected cases. Axillary ultrasound (AUS) is most often used for re-staging after NAST. We aimed to determine sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of AUS after NAST for predicting nodal response at the Institute of Oncology, Ljubljana. METHODS: Biopsy-confirmed cN + patients consecutively diagnosed at our institution between 2008 and 2021, who received NAST, followed by surgery were identified retrospectively. Only patients that underwent AUS after NAST were included. AUS results were compared to definite nodal histopathology results. We calculated sensitivity, specificity, PPV and NPV of AUS. We also calculated the proportion of patients with false-positive AUS that results in surgical overtreatment (unnecessary ALND). RESULTS: We identified 437 cN + patients. In 244 (55.8%) AUS after NAST was performed. Among those, 42/244 (17.2%) were triple negative (TN), 78/244 (32.0%) Her-2 positive (Her-2 +), and 124/244 (50,8%) luminal Her-2 negative cancers. AUS was negative in 179/244 (73.4%), suspicious/positive in 65/244 (26.6%) (11/42 (26.2%) TN, 19/78 (24.4%) Her-2 + , and 35/124 (28.2%) luminal Her-2 negative cancers). On definite histopathology, nodal complete response (pCR) was observed in 89/244 (36.5%) (19/42 (45.2%) TN, 55/78 (70.5%) Her-2 + , and 15/124 (12.1%) luminal Her-2 negative cancers). Among patients with suspicious/positive AUS, pCR was observed in 20/65 (30.8%) (6/11 (54.5%) TN, 13/19 (68.4%) Her-2 + and 1/35 (2.9%) luminal Her-2 negative cancers). Sensitivity was 29.0%, specificity 77,5%, PPV 69.2%, NPV 38.5%. Specificity and PPV in TN was 68.4% and 45.4%, in Her-2 + 76.4% and 31.6%, in luminal Her-2 negative 93,3% and 97,1%, respectively. CONCLUSION: In approximately half of the patients, AUS falsely predicts nodal response after NAST and may lead to overtreatment in 30% of the cases (ALND). However, AUS has to be interpreted in context with tumor subtype. In luminal Her-2 negative cancers, it has a high PPV and is therefore useful.

Absence of post-treatment changes in sentinel lymph nodes does not translate into increased regional recurrence rate in initially node-positive breast cancer patients.

PURPOSE: To determine whether the absence of post-treatment changes in the negative sentinel lymph nodes (SLN) in the neoadjuvant setting for biopsy-proven cN + disease results in an increased regional recurrence (RR) rate in patients after SLN biopsy (SLNB) only. METHODS: Breast cancer patients with biopsy-proven cN + disease who converted to node-negative disease after neoadjuvant systemic treatment (NAST) and underwent SLNB only were included. Retrospective analysis was performed for patients diagnosed between 2008 and 2021. Pathohistological specimens were reviewed for the presence of post-treatment changes in the SLNs. Patients with negative SLNs (ypN0) were divided into two groups: (i) with post-treatment changes, (ii) without post-treatment changes. Patients' characteristics were compared between groups. Crude RR rates were compared using the log-rank test. Recurrence-free (RFS) and overall survival (OS) for the entire cohort were calculated using Kaplan-Meier. RESULTS: Of 437 patients with cN + disease, 95 underwent SLNB only. 82 were ypN0, 57 with post-treatment changes (group 1), 25 without post-treatment changes (group 2). During the median follow-up of 37 months (range 6-148), 1 isolated regional recurrence occurred in group 2 (RR rate 0% for group 1 vs. 4% for group 2, p = 0.149). There were no differences in 3-year RFS and OS between groups. CONCLUSION: Absent post-treatment changes in negative SLNs for biopsy-proven cN + disease that covert to node-negative after NAST did not result in increased regional recurrence rates in our cohort. Multidisciplinary input is essential to determine whether additional treatment is needed in these patients.

Does concurrent gynaecological surgery affect infectious complications rate after mastectomy with implant-based reconstruction?

BACKGROUND: Women who undergo breast cancer surgery often have an indication for gynaecological procedure. The aim of our study was to compare infectious complications rate after mastectomy with implant-based reconstruction in patients with and without concurrent gynaecological procedure. PATIENTS AND METHODS: We retrospectively reviewed clinical records of 159 consecutively operated patients after mastectomy with implant-based reconstruction. The patients were divided in 2 groups: 102 patients without (Group1) and 57 with (Group 2) concurrent gynaecological procedure. Infectious complications rates between the groups were compared using χ2-test. Logistic regression was performed to test for association of different variables with infectious complications. RESULTS: There were 240 breast reconstructions performed. Median follow-up time was 297 days (10-1061 days). Mean patient age was 47.2 years (95% CI 32.8-65.9); 48.2 years (95% CI 46.1-50.3) in Group 1 and 45.8 years (95% CI 43.2-48.3) in Group 2; p = 0.002). Infectious complications rate was 17.6% (17.6% vs. 17.5%, p = 0.987), implant loss occurred in 5.7% (4.9% vs. 7.0%, p = 0.58). Obesity (body mass index [BMI] > 30 kg/m2), age, previous breast conserving treatment (BCT) with radiotherapy (RT) were identified as risk factors for infectious complications in univariate analysis. Obesity (adjusted odds ratio [aOR] 3.319, 95% CI 1.085-10.157, p = 0.036) and BCT with RT (aOR 7.481, 95% CI 2.230-25.101, p = 0.001) were independently associated with infectious complications in multivariate model. CONCLUSIONS: Concurrent gynaecological procedure for patients undergoing mastectomy with implant-based reconstruction did not carry an increased risk for infectious complications.

Real-World Data on Detection of Germline and Somatic Pathogenic/Likely Pathogenic Variants in BRCA1/2 and Other Susceptibility Genes in Ovarian Cancer Patients Using Next Generation Sequencing.

Detection of germline and somatic pathogenic/likely pathogenic variants (PV/LPV) in BRCA genes is at the moment a prerequisite for use of PARP inhibitors in different treatment settings of different tumors. The aim of our study was to determine the most appropriate testing workflow in epithelial ovarian cancer (EOC) patients using germline and tumor genotyping of BRCA and other hereditary breast and/or ovarian cancer (HBOC) susceptibility genes. Consecutive patients with advanced non-mucinous EOC, who responded to platinum-based chemotherapy, were included in the study. DNA extracted from blood and FFPE tumor tissue were genotyped using NGS panels TruSightCancer/Hereditary and TruSight Tumor 170. Among 170 EOC patients, 21.8% had BRCA germline or somatic PV/LPV, and additionally 6.4% had PV/LPV in other HBOC genes. Sensitivity of tumor genotyping for detection of germline PV/LPV was 96.2% for BRCA genes and 93.3% for HBOC genes. With germline genotyping-only strategy, 58.8% of HBOC PV/LPV and 68.4% of BRCA PV/LPV were detected. By tumor genotyping-only strategy, 96.1% of HBOC PV/LPV and 97.4% of BRCA PV/LPV were detected. Genotyping of tumor first, followed by germline genotyping seems to be a reasonable approach for detection of PV/LPV in breast and/or ovarian cancer susceptibility genes in non-mucinous EOC patients.

Quality assured implementation of the Slovenian breast cancer screening programme.

SETTING: The organised, population-based breast cancer screening programme in Slovenia began providing biennial mammography screening for women aged 50-69 in 2008. The programme has taken a comprehensive approach to quality assurance as recommended by the European guidelines for quality assurance in breast cancer screening and diagnosis (4th edition), including centralized assessment, training and supervision, and proactive monitoring of performance indicators. This report describes the progress of implementation and rollout from 2003 through 2019. METHODS: The screening protocol and key quality assurance procedures initiated during the planning from 2003 and rollout from 2008 of the screening programme, including training of the professional staff, are described. The organisational structure, gradual geographical rollout, and coverage by invitation and examination are presented. RESULTS: The nationwide programme was up and running in all screening regions by the end of 2017, at which time the nationwide coverage by invitation and examination had reached 70% and 50%, respectively. Nationwide rollout of the population-based programme was complete by the end of 2019. By this time, coverage by invitation and examination had reached 98% and 76%, respectively. The participation rates consistently exceeded 70% from 2014 to 2019. CONCLUSIONS: The successful implementation of the screening programme can be attributed to an independent central management, external guidance, and strict adherence to quality assurance procedures, all of which contributed to increasing governmental and popular support. The benefits of quality assurance have influenced all aspects of breast care and have provided a successful model for multidisciplinary management of other diseases.

Trends and timing of risk-reducing mastectomy uptake in unaffected BRCA1 and BRCA2 carriers in Slovenia.

OBJECTIVES: Risk-reducing mastectomy (RRM) is one of key prevention strategies in female carriers of germline BRCA pathogenic/likely pathogenic variants (PV/LPV). We retrospectively investigated the rate, timing and longitudinal trends of bilateral RRM uptake and the incidence and types of cancers among unaffected BRCA carriers who underwent genetic counseling at the Institute of Oncology Ljubljana in Slovenia. MATERIALS AND METHODS: Female BRCA carriers without personal history of cancer were included in the study. Clinical data on PV/LPV type, date of RRM, type of reconstructive procedure, occult carcinoma and histopathology results was collected and analyzed. RESULTS: Of the 346 unaffected BRCA carriers (median age 43 years, 70% BRCA1, 30% BRCA2, median follow-up 46 months) who underwent genetic testing between October 1999 and December 2019, 25.1% had a RRM (range 35-50 years, median age at surgery 38 years). A significant difference in time to prophylactic surgery between women undergoing RRM only vs. women undergoing RRM combined with risk-reducing salpingo-oophorectomy was observed (22.6 vs 8.7 months, p = 0.0009). We observed an upward trend in the annual uptake in line with the previously observed Angelina Jolie effect. In 5.7% of cases, occult breast cancer was detected. No women developed breast cancer after RRM. Women who did not opt for surgical prevention developed BRCA1/2-related cancers (9.3%). CONCLUSION: The uptake of RRM among unaffected BRCA carriers is 25.1% and is similar to our neighboring countries. No women developed breast cancer after RRM while women who did not opt for surgical prevention developed BRCA1/2 related cancers in 9.3% of cases. The reported data may provide meaningful aid for carriers when deciding on an optimal prevention strategy.

Screening Strategy Modification Based on Personalized Breast Cancer Risk Stratification and its Implementation in the National Guidelines - Pilot Study.

BACKGROUND: One of the most consistent models for estimating personalized breast cancer (BC) risk is the Tyrer-Cuzick algorithm that is incorporated into the International Breast Cancer Intervention Study (IBIS) software. Our main objective was to provide criteria for the classification of the Slovenian population, which has BC incidence below the European average, into risk groups, and to evaluate the integration of the criteria in Slovenian guidelines. Our main focus was on women age <50 with higher BC risk, since no organized BC screening is available for these women. METHODS: Slovenian age-specific BC risks were incorporated into IBIS software and threshold values of risk categories were determined. Risk categories were assigned according to the individual's ten-year risk for women aged 40 and older, and lifetime risk for women between 20 and 39. To test the software, we compared screening strategies with the use vs. no use of IBIS. RESULTS: Of the 197 women included in the study IBIS assigned 75.1% to the BC risk group, and the rest to the moderately increased risk. Without IBIS 80 women were offered mammographic and 33 ultrasound screening. In contrast, 28 instead of 80 would have been offered mammographic screening and there would have been no referrals for ultrasound if IBIS had been used. CONCLUSIONS: The Slovenian IBIS has been developed, tested and suggested for personalized breast cancer risk assessment. The implementation of the software with the consideration of Slovenian risk thresholds enables a more accurate and nationally unified assessment.

Breast cancer risk based on adapted IBIS prediction model in Slovenian women aged 40-49 years - could it be better?

Background The aim of the study was to assess the proportion of women that would be classified as at above-average risk of breast cancer based on the 10 year-risk prediction of the Slovenian breast cancer incidence rate (S-IBIS) program in two presumably above-average breast cancer risk populations in age group 40-49 years: (i) women referred for any reason to diagnostic breast centres and (ii) women who were diagnosed with breast cancer aged 40-49 years. Breast cancer is the commonest female cancer in Slovenia, with an incidence rate below European average. The Tyrer-Cuzick breast cancer risk assessment algorithm was recently adapted to S-IBIS. In Slovenia a tailored mammographic screening for women at above average risk in age group 40-49 years is considered in the future. S-IBIS is a possible tool to select population at above-average risk of breast cancer for tailored screening. Patients and methods In 357 healthy women aged 40-49 years referred for any reason to diagnostic breast centres and in 367 female breast cancer patients aged 40-49 years at time of diagnosis 10-years breast cancer risk was calculated using the S-IBIS software. The proportion of women classified as above-average risk of breast cancer was calculated for each subgroup of the study population. Results 48.7% of women in the Breast centre group and 39.2% of patients in the breast cancer group had above-average 10-year breast cancer risk. Positive family history of breast cancer was more prevalent in the Breast centre group (p < 0.05). Conclusions Inclusion of additional risk factors into the S-IBIS is warranted in the populations with breast cancer incidence below European average to reliably stratify women into breast cancer risk groups.

Does regular quality control improve the quality of surgery in Slovenian breast cancer screening program?

Background The aim of our study was to evaluate the quality of surgery of Slovenian breast cancer screening program (DORA) using the requested EU standards. Furthermore, we investigated whether regular quality control over the 3-year period improved the quality of surgical management. Patients and methods Patients who required surgical management within DORA between January 1st, 2016 and December 31st, 2018 were included in the retrospective study. Quality indicators (QIs) were adjusted mainly according to European Society of Breast Cancer Specialists (EUSOMA) and European Breast Cancer Network (EBCN) recommendations. Five QIs for therapeutic and two for diagnostic surgeries were selected. Additionally, variability in achieving the requested QIs among surgeons was analysed. Results Between 2016 and 2018, 14 surgeons performed 1421 breast procedures in 1398 women. There were 1197 therapeutical (for proven breast cancer) and 224 diagnostic surgical interventions respectively. Overall, the minimal standard was met in two QIs for therapeutic and none for diagnostic procedures. A statistically significant improvement in three QIs for therapeutic and in one QI for diagnostic procedures was observed however, indicating that regular quality control improves the quality of surgery. A high variability in achieving the requested QIs was observed among surgeons, which remained high throughout the study period. Conclusions Adherence to all selected surgical QIs in patients from screening program is difficult to achieve, especially to those specifically defined for screen-detected lesions. Regular quality control may improve results over time. Reducing the number of surgeons dedicated to breast pathology may reduce variability of management inside the institution.

Reducing indications for radial scar surgical excision in Slovenian breast cancer screening program.

PURPOSE: Management of the radial scar (RS)/complex sclerosing lesion (CSL) diagnosed by core needle biopsy (CNB) in breast cancer screening population (BCSP) is controversial due to its intrinsic malignant potential. We aimed to determine (i) the rate of upgrade of the RS/CSL to malignant lesions and (ii) radiological characteristics and CNB histopathological findings of the lesions related to the upgrade of the RS/CSL to malignant lesions after surgical excision in our BCSP. PATIENTS AND METHODS: Database of Slovenian National Breast Cancer Screening Program was checked for terms RS/CSL in all patients who underwent CNB in the period 2008-2018. The ratios of upgrade from CNB RS/SCL to malignant lesions after surgical excision were calculated with specific interest to the radiological characteristics and the CNB patohistologically findings of the lesions. RESULTS: Of 162 patients with diagnosis of RS/CSL on the CNB, 121/156 (78%) cases underwent surgical excision. 6 of 121 (5%) cases were upgraded to a malignant diagnosis in surgical specimen, 3 cases of invasive carcinoma and 3 cases of DCIS, respectively. Five of the upgraded cases (5/6, 83.3%) showed atypical epithelial proliferative lesions (AEPL) on CNB. In one upgraded case without AEPL the lesion presented as 33 mm architectural distortion with microcalcifications on the mammogram. CONCLUSIONS: In BCSP setting RS/CSL without AEPL/papilloma and those measuring less than 2 cm in the largest diameter can be followed radiologically. Increasing the number of cores and adequate sampling of the periphery and the centre of the RS/CSL improves the pick-up rate of associated atypia/malignancy.

Completely resected stage III melanoma controversy - 15 years of national tertiary centre experience.

BACKGROUND: Two prospective randomized studies analysing cutaneous melanoma (CM) patients with sentinel lymph node (SLN) metastases and rapid development of systemic adjuvant therapy have changed our approach to stage III CM treatment. The aim of this study was to compare results of retrospective survival analysis of stage III CM patients' treatment from Slovenian national CM register to leading international clinical guidelines. PATIENTS AND METHODS: Since 2000, all Slovenian CM patients with primary tumour ≥ TIb are treated at the Institute of Oncology Ljubljana and data are prospectively collected into a national CM registry. A retrospective analysis of 2426 sentinel lymph node (SLN) biopsies and 789 lymphadenectomies performed until 2015 was conducted using Kaplan-Meier survival curves and log-rank tests. RESULTS: Positive SLN was found in 519/2426 (21.4%) of patients and completion dissection (CLND) was performed in 455 patients. The 5-year overall survival (OS) of CLND group was 58% vs. 47% of metachronous metastases group (MLNM) (p = 0.003). The 5-year OS of patients with lymph node (LN) metastases and unknown primary site (UPM) was 45% vs. 21% of patients with synchronous LN metastasis. Patients with SLN tumour burden < 0.3 mm had 5-year OS similar to SLN negative patients (86% vs. 85%; p = 0.926). The 5-year OS of patients with burden > 1.0 mm was similar to the MLNM group (49% vs. 47%; p = 0.280). CONCLUSIONS: Stage III melanoma patients is a heterogeneous group with significant OS differences. CLND after positive SLNB might still remain a method of treatment for selected patients with stage III.

Is preoperative ultrasound of the axilla necessary in screen-detected breast cancer?

BACKGROUND: Axillary ultrasound (US) with fine needle aspiration biopsy (FNAB) of suspicious lymph nodes helps identify patients with axillary metastases preoperatively avoiding a 2-step axillary procedure. However, it does not accurately differentiate between low and high axillary tumour burden. Our aim was to determine the rationale of preoperative axillary US in screen-detected breast cancer. METHODS: We retrospectively analysed patients, aged between 50 and 69 years, which had an invasive breast cancer diagnosed in the Slovenian National Breast Cancer Screening program between January 2012 and June 2017. Proportion of patients that proceeded directly to ALND and the proportion of patients with unnecessary ALND as a result of positive US-FNAB were calculated. RESULTS: Altogether 892 patients were eligible for analysis. Preoperative US of the axilla was performed in 856/892 (96%) patients, while 36/892 patients (4%) did not undergo US of the axilla. We have found out that upfront ALND due to positive US-FNAB was performed in 91/856 (10.6%) patients. 116/856 patients (13.6%) had tumours in inner quadrants and maximal mammographic tumour size ≤ 2 cm. Among them only 1/116 (0.9%) proceeded directly to ALND due to positive US-FNAB.The final pathology of those who underwent upfront ALND due to positive US-FNAB showed low axillary tumour burden not meeting the indications for ALND in 13/91 (14.3%) patients.Among patients without preoperative axillary US, only 1/36 (2.8%) met the indications for ALND. CONCLUSION: Our results showed that performing US of the axilla is not justified in screen detected breast cancer patients.

Axillary dissection versus no axillary dissection in patients with breast cancer and sentinel-node micrometastases (IBCSG 23-01): 10-year follow-up of a randomised, controlled phase 3 trial.

BACKGROUND: We previously reported the 5-year results of the phase 3 IBCSG 23-01 trial comparing disease-free survival in patients with breast cancer with one or more micrometastatic (≤2 mm) sentinel nodes randomly assigned to either axillary dissection or no axillary dissection. The results showed no difference in disease-free survival between the groups and showed non-inferiority of no axillary dissection relative to axillary dissection. The current analysis presents the results of the study after a median follow-up of 9·7 years (IQR 7·8-12·7). METHODS: In this multicentre, randomised, controlled, open-label, non-inferiority, phase 3 trial, participants were recruited from 27 hospitals and cancer centres in nine countries. Eligible women could be of any age with clinical, mammographic, ultrasonographic, or pathological diagnosis of breast cancer with largest lesion diameter of 5 cm or smaller, and one or more metastatic sentinel nodes, all of which were 2 mm or smaller and with no extracapsular extension. Patients were randomly assigned (1:1) before surgery (mastectomy or breast-conserving surgery) to no axillary dissection or axillary dissection using permuted blocks generated by a web-based congruence algorithm, with stratification by centre and menopausal status. The protocol-specified primary endpoint was disease-free survival, analysed in the intention-to-treat population (as randomly assigned). Safety was assessed in all randomly assigned patients who received their allocated treatment (as treated). We did a one-sided test for non-inferiority of no axillary dissection by comparing the observed hazard ratios (HRs) for disease-free survival with a margin of 1·25. This 10-year follow-up analysis was not prespecified in the trial's protocol and thus was not adjusted for multiple, sequential testing. This trial is registered with ClinicalTrials.gov, number NCT00072293. FINDINGS: Between April 1, 2001, and Feb 8, 2010, 6681 patients were screened and 934 randomly assigned to no axillary dissection (n=469) or axillary dissection (n=465). Three patients were ineligible and were excluded from the trial after randomisation. Disease-free survival at 10 years was 76·8% (95% CI 72·5-81·0) in the no axillary dissection group, compared with 74·9% (70·5-79·3) in the axillary dissection group (HR 0·85, 95% CI 0·65-1·11; log-rank p=0·24; p=0·0024 for non-inferiority). Long-term surgical complications included lymphoedema of any grade in 16 (4%) of 453 patients in the no axillary dissection group and 60 (13%) of 447 in the axillary dissection group, sensory neuropathy of any grade in 57 (13%) in the no axillary dissection group versus 85 (19%) in the axillary dissection group, and motor neuropathy of any grade (14 [3%] in the no axillary dissection group vs 40 [9%] in the axillary dissection group). One serious adverse event (postoperative infection and inflamed axilla requiring hospital admission) was attributed to axillary dissection; the event resolved without sequelae. INTERPRETATION: The findings of the IBCSG 23-01 trial after a median follow-up of 9·7 years (IQR 7·8-12·7) corroborate those obtained at 5 years and are consistent with those of the 10-year follow-up analysis of the Z0011 trial. Together, these findings support the current practice of not doing an axillary dissection when the tumour burden in the sentinel nodes is minimal or moderate in patients with early breast cancer. FUNDING: International Breast Cancer Study Group.

Textural analysis of early-phase spatiotemporal changes in contrast enhancement of breast lesions imaged with an ultrafast DCE-MRI protocol.

PURPOSE: New ultrafast view-sharing sequences have enabled breast dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to be performed at high spatial and temporal resolution. The aim of this study is to evaluate the diagnostic potential of textural features that quantify the spatiotemporal changes of the contrast-agent uptake in computer-aided diagnosis of malignant and benign breast lesions imaged with high spatial and temporal resolution DCE-MRI. METHOD: The proposed approach is based on the textural analysis quantifying the spatial variation of six dynamic features of the early-phase contrast-agent uptake of a lesion's largest cross-sectional area. The textural analysis is performed by means of the second-order gray-level co-occurrence matrix, gray-level run-length matrix and gray-level difference matrix. This yields 35 textural features to quantify the spatial variation of each of the six dynamic features, providing a feature set of 210 features in total. The proposed feature set is evaluated based on receiver operating characteristic (ROC) curve analysis in a cross-validation scheme for random forests (RF) and two support vector machine classifiers, with linear and radial basis function (RBF) kernel. Evaluation is done on a dataset with 154 breast lesions (83 malignant and 71 benign) and compared to a previous approach based on 3D morphological features and the average and standard deviation of the same dynamic features over the entire lesion volume as well as their average for the smaller region of the strongest uptake rate. RESULT: The area under the ROC curve (AUC) obtained by the proposed approach with the RF classifier was 0.8997, which was significantly higher (P = 0.0198) than the performance achieved by the previous approach (AUC = 0.8704) on the same dataset. Similarly, the proposed approach obtained a significantly higher result for both SVM classifiers with RBF (P = 0.0096) and linear kernel (P = 0.0417) obtaining AUC of 0.8876 and 0.8548, respectively, compared to AUC values of previous approach of 0.8562 and 0.8311, respectively. CONCLUSION: The proposed approach based on 2D textural features quantifying spatiotemporal changes of the contrast-agent uptake significantly outperforms the previous approach based on 3D morphology and dynamic analysis in differentiating the malignant and benign breast lesions, showing its potential to aid clinical decision making.

Axillary dissection versus no axillary dissection in patients with sentinel-node micrometastases (IBCSG 23-01): a phase 3 randomised controlled trial.

BACKGROUND: For patients with breast cancer and metastases in the sentinel nodes, axillary dissection has been standard treatment. However, for patients with limited sentinel-node involvement, axillary dissection might be overtreatment. We designed IBCSG trial 23-01 to determine whether no axillary dissection was non-inferior to axillary dissection in patients with one or more micrometastatic (≤2 mm) sentinel nodes and tumour of maximum 5 cm. METHODS: In this multicentre, randomised, non-inferiority, phase 3 trial, patients were eligible if they had clinically non-palpable axillary lymph node(s) and a primary tumour of 5 cm or less and who, after sentinel-node biopsy, had one or more micrometastatic (≤2 mm) sentinel lymph nodes with no extracapsular extension. Patients were randomly assigned (in a 1:1 ratio) to either undergo axillary dissection or not to undergo axillary dissection. Randomisation was stratified by centre and menopausal status. Treatment assignment was not masked. The primary endpoint was disease-free survival. Non-inferiority was defined as a hazard ratio (HR) of less than 1·25 for no axillary dissection versus axillary dissection. The analysis was by intention to treat. Per protocol, disease and survival information continues to be collected yearly. This trial is registered with ClinicalTrials.gov, NCT00072293. FINDINGS: Between April 1, 2001, and Feb 28, 2010, 465 patients were randomly assigned to axillary dissection and 469 to no axillary dissection. After the exclusion of three patients, 464 patients were in the axillary dissection group and 467 patients were in the no axillary dissection group. After a median follow-up of 5·0 (IQR 3·6-7·3) years, we recorded 69 disease-free survival events in the axillary dissection group and 55 events in the no axillary dissection group. Breast-cancer-related events were recorded in 48 patients in the axillary dissection group and 47 in the no axillary dissection group (ten local recurrences in the axillary dissection group and eight in the no axillary dissection group; three and nine contralateral breast cancers; one and five [corrected] regional recurrences; and 34 and 25 distant relapses). Other non-breast cancer events were recorded in 21 patients in the axillary dissection group and eight in the no axillary dissection group (20 and six second non-breast malignancies; and one and two deaths not due to a cancer event). 5-year disease-free survival was 87·8% (95% CI 84·4-91·2) in the group without axillary dissection and 84·4% (80·7-88·1) in the group with axillary dissection (log-rank p=0·16; HR for no axillary dissection vs axillary dissection was 0·78, 95% CI 0·55-1·11, non-inferiority p=0·0042). Patients with reported long-term surgical events (grade 3-4) included one sensory neuropathy (grade 3), three lymphoedema (two grade 3 and one grade 4), and three motor neuropathy (grade 3), all in the group that underwent axillary dissection, and one grade 3 motor neuropathy in the group without axillary dissection. One serious adverse event was reported, a postoperative infection in the axilla in the group with axillary dissection. INTERPRETATION: Axillary dissection could be avoided in patients with early breast cancer and limited sentinel-node involvement, thus eliminating complications of axillary surgery with no adverse effect on survival. FUNDING: None.

Multi-institutional comparison of non-sentinel lymph node predictive tools in breast cancer patients with high predicted risk of further axillary metastasis.

Although axillary lymph node dissection (ALND) has been the standard intervention in breast cancer patients with sentinel lymph node (SLN) metastasis, only a small proportion of patients benefit from this operation, because most do not harbor additional metastases in the axilla. Several predictive tools have been constructed to identify patients with low risk of non-SLN metastasis who could be candidates for the omission of ALND. In the present work, predictive nomograms were used to predict a high (>50 %) risk of non-SLN metastasis in order to identify patients who would most probably benefit from further axillary treatment. Data of 1000 breast cancer patients with SLN metastasis and completion ALND from 5 institutions were tested in 4 nomograms. A subset of 313 patients with micrometastatic SLNs were also tested in 3 different nomograms devised for the micrometastatic population (the high risk cut-off being 20 %). Patients with a high predicted risk of non-SLN metastasis had higher rates of metastasis in the non-SLNs than patients with low predicted risk. The positive predictive values of the nomograms ranged from 44 % to 64 % with relevant inter-institutional variability. The nomograms for micrometastatic SLNs performed much better in identifying patients with low risk of non-SLN involvement than in high-risk-patients; for the latter, the positive predictive values ranged from 13 % to 20 %. The nomograms show inter-institutional differences in their predictive values and behave differently in different settings. They are worse in identifying high risk patients than low-risk ones, creating a need for new predictive models to identify high-risk patients.

International multicenter tool to predict the risk of nonsentinel node metastases in breast cancer.

BACKGROUND: Axillary treatment of breast cancer patients is undergoing a paradigm shift, as completion axillary lymph node dissections (ALNDs) are being questioned in the treatment of patients with tumor-positive sentinel nodes. This study aims to develop a novel multi-institutional predictive tool to calculate patient-specific risk of residual axillary disease after tumor-positive sentinel node biopsy. METHODS: Breast cancer patients with a tumor-positive sentinel node and a completion ALND from five European centers formed the original patient series (N = 1000). Statistically significant variables predicting nonsentinel node involvement were identified in logistic regression analysis. A multivariable predictive model was developed and validated by area under the receiver operating characteristics curve (AUC), first internally in 500 additional patients and then externally in 1068 patients from other centers. All statistical tests were two-sided. RESULTS: Nine tumor- and sentinel node-specific variables were identified as statistically significant factors predicting nonsentinel node involvement in logistic regression analysis. A resulting predictive model applied to the internal validation series resulted in an AUC of 0.714 (95% confidence interval [CI] = 0.665 to 0.763). For the external validation series, the AUC was 0.719 (95% CI = 0.689 to 0.750). The model was well calibrated in the external validation series. CONCLUSIONS: We present a novel, international, multicenter, predictive tool to assess the risk of additional axillary metastases after tumor-positive sentinel node biopsy in breast cancer. The predictive model performed well in internal and external validation but needs to be further studied in each center before application to clinical use.

Lower tumour burden and better overall survival in melanoma patients with regional lymph node metastases and negative preoperative ultrasound.

BACKGROUND: The purpose of the study was to evaluate the ability of ultrasound (US) and fine needle aspiration biopsy (FNAB) in reducing the number of melanoma patients requiring a sentinel node biopsy (SNB); to compare the amount of metastatic disease in regional lymph nodes in SNB candidates with clinically uninvolved lymph nodes and of those with US uninvolved lymph nodes; and to compare the overall survival (OS) of both groups. METHODS: Between 2000 and 2007, a SNB was successfully performed in 707 patients with melanoma. The preoperative US of the regional lymph node basins was performed in 405 SNB candidates. In 14 of these patients, the US-guided FNAB was positive and they proceeded directly to lymph node dissection. In 391 patients, the preoperative US was either negative (343 patients) or suspicious (48 patients) (US group). In the remaining 316 patients the preoperative US was not performed (non-US group). RESULTS: The proportion of macrometastatic sentinel lymph nodes (SN), number of metastatic lymph nodes per patient and proportion of nonsentinel lymph node metastases were found to be lower in the US group compared to the non-US group. The smaller tumour burden of the US group was reflected in a significantly better OS of patients with SN metastases. CONCLUSIONS: The preoperative US of regional lymph nodes spares some patients with melanoma from undergoing a SNB. Patients with regional metastases and a negative preoperative US have a significantly lower tumour burden in comparison to those with clinically negative lymph nodes, which is also reflected in a better OS.

Novel BRCA1 and BRCA2 pathogenic mutations in Slovene hereditary breast and ovarian cancer families.

The estimated proportion of hereditary breast and ovarian cancers among all breast and ovarian cancer cases is 5-10%. According to the literature, inherited mutations in the BRCA1 and BRCA2 tumour-suppressor genes, account for the majority of hereditary breast and ovarian cancer cases. The aim of this report is to present novel mutations that have not yet been described in the literature and pathogenic BRCA1 and BRCA2 mutations which have been detected in HBOC families for the first time in the last three years. In the period between January 2009 and December 2011, 559 individuals from 379 families affected with breast and/or ovarian cancer were screened for mutations in the BRCA1 and BRCA2 genes. Three novel mutations were detected: one in BRCA1 - c.1193C>A (p.Ser398*) and two in BRCA2 - c.5101C>T (p.Gln1701*) and c.5433_5436delGGAA (p.Glu1811Aspfs*3). These novel mutations are located in the exons 11 of BRCA1 or BRCA2 and encode truncated proteins. Two of them are nonsense while one is a frameshift mutation. Also, 11 previously known pathogenic mutations were detected for the first time in the HBOC families studied here (three in BRCA1 and eight in BRCA2). All, except one cause premature formation of stop codons leading to truncation of the respective BRCA1 or BRCA2 proteins.