Screening Mammography for Males With Elevated Breast Cancer Risk, Mutation Carriers, and Gynecomastia.

INTRODUCTION: The recommendations for annual mammography for male carriers with gynecomastia are controversial. This study investigated the potential link between gynecomastia and breast cancer in male carriers. PATIENTS AND METHODS: The database of a tertiary medical center was retrospectively searched for all male patients who underwent at least 1 digital mammography study from 2016 to 2023. Known carriers of a pathogenic variant in a high-risk breast-cancer gene were identified. Patients were stratified by carrier status, diagnosis of breast cancer, and diagnosis of gynecomastia. Data on demographics, hormone profile, and pathology results were compared. RESULTS: The cohort included 446 men of whom 82 were known carriers. Gynecomastia was diagnosed by mammography in 251 patients: 239/364 noncarriers (66%) and 12/82 carriers (15%) (P < .0001). Breast cancer was found in 21/364 noncarriers (6%) and 6/82 carriers (7%) (P < .6), and in 10/251 patients with gynecomastia (4%) and 17/193 (9%) without gynecomastia (P < .05). Among patients without gynecomastia, the number of breast cancer cases was similar in carriers and noncarriers (P = .3). Among patients with gynecomastia, the rate of breast cancer was higher in carriers (P < .08). On logistic regression analysis, the effect of gynecomastia on carriers was significant (P = .02). The odds ratio for a breast cancer diagnosis was 5.8 in the presence of gynecomastia (95% CI, 1.1-31, P < .04) and 0.52 in the absence of gynecomastia (95% CI, 0.2-1.7, P < .3). CONCLUSION: Gynecomastia may be associated with an increased risk of breast cancer in carriers. Larger studies are needed to determine whether and when to screen male carriers.

Postoperative Complications Following Lumpectomy With Intraoperative X-Ray Radiation Therapy: A Retrospective Comparative Study.

BACKGROUND: Lumpectomy with intraoperative radiation (IORT) is a relatively new modality for the treatment of early breast cancer. IORT delivers targeted radiation to the tumor bed and obviates the need for external beam radiation (EBRT) in 85% of the cases. IORT is being used increasingly around the world, however information regarding early and late postoperative complications associated with the procedure is limited. AIM: To describe and compare complication rates after lumpectomy and IORT with those seen after lumpectomy and EBRT or lumpectomy alone. METHODS: Clinical, demographic, and histopathological data were collected from electronic medical records and a retrospectively maintained database. Postoperative complications were compared for patients undergoing lumpectomy with IORT, lumpectomy with EBRT, and lumpectomy alone over the same period. RESULTS: A total of 445 patients were included in the study: 113 underwent lumpectomy with IORT, 253 had lumpectomy followed by EBRT, and 79 had Lumpectomy alone. Postoperative seroma was documented in 74 patients (65%) after IORT,87 (34%) after EBRT, and 9 (11%) after lumpectomy alone (P = .000). Surgical site infection requiring antibiotic treatment was diagnosed in 26 patients (23%) after IORT, 38 (15%) after EBRT, and 5 (6%) after lumpectomy alone (P = .013). Postoperative erythema was documented in 39 patients (34%) after IORT, 40 (16%) after EBRT, and 5 (6%) after lumpectomy alone (P = .000). Postoperative minor complications such as scar and breast deformity, edema, Mondor's syndrome, and chronic tenderness, were documented in 62 patients (55%) after IORT, 119 (47%) after EBRT, and 13 (17%) after lumpectomy alone (P = .000). The average follow-up was 14 months. CONCLUSIONS: IORT is associated with an increased rate of postoperative complications compared to EBRT or lumpectomy alone. Most complications are minor and transient. We hypothesize that the increased occurrence of complications may also be attributed to overreporting, which is associated with the introduction of a new technology. Educating physicians and patients about potential complications and their course may help establish expectations and improve the management of postoperative complications.

Variations in Practice and Geographic Disparities Between Dedicated Multidisciplinary Clinics for BRCA1/BRCA2 Mutation Carriers in Israel.

BACKGROUND: Population screening for the BRCA mutations in Ashkenazi Jewish women was recently implemented in Israel and is expected to lead to a 10-fold increase in the diagnosis of asymptomatic carriers. Performing the screening follow-up within multidisciplinary dedicated clinics for carriers is recommended for early detection and risk reduction. OBJECTIVES: : To determine the availability, capacity, and practices of dedicated screening clinic for BRCA carriers in Israel. METHODS: A telephone-based survey of all public hospitals in Israel was conducted October 2020 to August 2021 to determine whether they had a dedicated clinic. Dedicated clinics were defined as multidisciplinary screening clinics offering at least breast and gynecological screening and risk reducing services on site. The clinic director or nurse navigator answered a questionnaire about screening practices followed by a semi-structured interview. RESULTS: Of the ten dedicated BRCA clinics found in Israel, nine participated. Approximately 4500 BRCA carriers are currently being followed. No specialized clinics are available in the southern district or in the northernmost half of the northern district of Israel, leading to a disparity between periphery and center. Screening recommendations, although asserted as adhering to international guidelines, vary among clinics including age at initiating of clinical exam, use of adjunct imaging modalities, and follow-up during lactation and after risk reducing surgery. CONCLUSIONS: There is a suboptimal distribution of dedicated clinics for BRCA carriers in Israel. Nationally centralized attempt to create guidelines that will unify screening practices is warranted, especially considering the expected increase in demand.

Surgical site infection in reconstructive and aesthetic breast surgery: A single center retrospective analysis of the association between healthcare workers and infections.

BACKGROUND: Reconstructive and aesthetic breast surgeries are frequently performed procedures, and the consequences of a postoperative infection are devastating both for the patient and the healthcare (HC) system. Over the years, there has been heightened interest in the physical and mental well-being of physicians and HC workers. Little is known about the relationship between HC workers and surgical site infections (SSI), and whether HC workers are at an increased risk for SSI. The aim of this study was to investigate whether women working in the HC system have an increased risk for SSI following reconstructive and aesthetic breast surgery. MATERIALS AND METHODS: We conducted a retrospective analysis of all patients who underwent aesthetic and reconstructive breast surgery at our institution between the years 2013-2020. Women who were recognized as HC workers were analyzed in a separate group and compared to those who were not. RESULTS: Records of 378 patients were reviewed, of whom 53 (14%) were identified as HC workers. The overall infection rate was 17.4%. HC workers manifested a higher infection rate than the other group (32% vs. 15.1%, p<0.05) and a significantly higher relative risk for SSI (RR 2.12, p<0.01). CONCLUSIONS: Women working in the HC system may have an increased risk of developing postoperative infectious complications following aesthetic and reconstructive breast-related surgery. Further research is needed to corroborate these findings and elucidate the causes.

MRI background parenchymal enhancement in patients with invasive lobular carcinoma: Endocrine hormonal treatment effect.

OBJECTIVES: High background parenchymal enhancement (BPE) levels and asymmetric distribution could cause diagnostic uncertainty due to morphological similarity to breast cancer, especially invasive lobular carcinoma (ILC). We investigated BPE in ILC patients, its association with the tumor hormonal profile, and the effect of endocrine treatment (ET). METHODS: The analysis included all MRI examinations performed at our institution between 2010 and 2019 for ILC-diagnosed patients. Baseline study and the first follow-up study were reviewed. Digital medical records were reviewed to retrieve demographics/pathology results/treatment information. BPE and fibroglandular tissue were assessed qualitatively on the contralateral breast according to the criteria of the Breast Imaging Reporting and Data System (BI-RADS). RESULTS: The study included 129 patients. Most (91%) had pure ILC. All received ET; 12% also received chemotherapy; 90% had surgery first; 70% by breast conservation. On the baseline MRI, 70% had mild or moderate BPE; whereas, on the follow-up study, the majority (59%) had minimal BPE. Most BPE reductions were by 2 degrees. In the baseline study, additional biopsies were required in 59% of cases, and in 17%, a short-term follow-up was recommended. In the follow-up study, biopsies were recommended in 10%, and a short-term follow-up was requested in 16%. A correlation between progesterone receptor intensity index and baseline BPE level was observed (r = 0.3, p = 0.004). CONCLUSION: ILC patients usually exhibit high BPE. ET decreases BPE, and therefore may decrease false-positive interpretations. Additional research is needed to explore whether study can be performed on ET without compromising sensitivity. KEY POINTS: ∙ High background parenchymal enhancement levels reduces breast MRI sensitivity, yielding high false positive rates especially when reporting cases of invasive lobular carcinoma [ILC].∙Treatment of ILC with endocrine therapy reduces background parenchymal enhancement and thus could decrease these false-positive interpretations.

Oncoplastic breast consortium recommendations for mastectomy and whole breast reconstruction in the setting of post-mastectomy radiation therapy.

AIM: Demand for nipple- and skin- sparing mastectomy (NSM/SSM) with immediate breast reconstruction (BR) has increased at the same time as indications for post-mastectomy radiation therapy (PMRT) have broadened. The aim of the Oncoplastic Breast Consortium initiative was to address relevant questions arising with this clinically challenging scenario. METHODS: A large global panel of oncologic, oncoplastic and reconstructive breast surgeons, patient advocates and radiation oncologists developed recommendations for clinical practice in an iterative process based on the principles of Delphi methodology. RESULTS: The panel agreed that surgical technique for NSM/SSM should not be formally modified when PMRT is planned with preference for autologous over implant-based BR due to lower risk of long-term complications and support for immediate and delayed-immediate reconstructive approaches. Nevertheless, it was strongly believed that PMRT is not an absolute contraindication for implant-based or other types of BR, but no specific recommendations regarding implant positioning, use of mesh or timing were made due to absence of high-quality evidence. The panel endorsed use of patient-reported outcomes in clinical practice. It was acknowledged that the shape and size of reconstructed breasts can hinder radiotherapy planning and attention to details of PMRT techniques is important in determining aesthetic outcomes after immediate BR. CONCLUSIONS: The panel endorsed the need for prospective, ideally randomised phase III studies and for surgical and radiation oncology teams to work together for determination of optimal sequencing and techniques for PMRT for each patient in the context of BR.

Potential Refinement of Recurrence Score by pSTAT3 Status.

The likelihood of recurrence in breast cancer patients with hormone receptor-positive (HR-positive) tumors is influenced by clinical, histopathological, and molecular features. Recent studies suggested that activated STAT3 (pSTAT3) might serve as a biomarker of outcome in breast cancer patients. In the present work, we have analyzed the added value of pSTAT3 to OncotypeDx Recurrence Score (RS) in patient prognostication. We have found that patients with low RS (<26) and low pSTAT3 might represent a population at a higher risk for cancer recurrence. Furthermore, we have observed that a positive pSTAT3 score alone can be a favorable marker for patients with HR-positive breast cancer under the age of 50. In an era of personalized medicine, these findings warrant further appraisal of chemotherapy benefit in this population.

Thyroid Hormones and Morphological Features of Primary Breast Cancer.

BACKGROUND/AIM: Many experimental studies have suggested the importance of thyroid hormones in breast cancer (BC) morphogenesis. The aim of this study was to evaluate the association of thyroid hormone levels in serum of patients with primary BC with morphological presentations of the disease in pathological specimens and prognosis. PATIENTS AND METHODS: We measured the serum levels of thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine (FT4), along with serum thymidine kinase 1 activity and examined their relation to pathological features and prognosis of 158 patients with primary BC. RESULTS: We found a significant positive association of serum FT3 level with the presence of carcinoma in situ component (CIS) (p=0.032) and its size (p=0.047), with the presence (p=0.022) and the number of multifocal/multicentric tumors (MMTs) (p=0.002), as well as with increased proliferative activity in terms of serum thymidine kinase 1 (p=0.002). Moreover, we report that each 1.0 unit rise of FT3/FT4 ratio×10 was associated with an odds ratio of 1.77 (95% confidence interval=1.17-3.30, p=0.007), 1.97 (95% confidence interval=1.17-2.67, p=0.010) and 1.56 (95% confidence interval=1.02-2.37, p=0.039) for the detection of patients with CIS, MMTs and lymphovascular invasion, respectively, after adjusting for age. We did not find statistically significant associations of serum TSH level with breast cancer`s parameters. A Cox regression survival analysis identified serum FT3 level >5.95 pmol/l as a risk factor for BC recurrence (relative risk=2.65, p=0.017), a finding that retained significance in a multivariate model (relative risk=2.52, p=0.027). CONCLUSION: The FT3/FT4 ratio is a valuable parameter predicting the presence of CIS, MMTs and lymphovascular invasion in pathological specimens. An elevated serum FT3 level is associated with the presence of CIS, MMTs, increased proliferative activity and poor prognosis.

Personalized Screening for Breast Cancer: Rationale, Present Practices, and Future Directions.

Ever since screening for early breast cancer (BC) diagnosis was shown to decrease mortality from the disease, screening programs have been widely implemented throughout the world. Targeted age groups and schedules vary between countries but the majority use a population-based approach, regardless of personal BC risk. The purpose of this review was to describe current population-based screening practices, point out some of the shortcomings of these practices, describe BC risk factors and risk assessment models, and present ongoing clinical trials of personalized risk-adapted BC screening. Three ongoing, large-scale, randomized controlled clinical trials (WISDOM in the US, MyPEBS in Europe, and TBST in Italy) were identified through a search of the MEDLINE and US National Library of Medicine (ClinicalTrials.gov) databases. In these trials, women either undergo standard or personalized screening. The trials vary in methods of risk stratification and screening modalities, but all aim to examine whether personalized risk-adapted screening can safely replace the current population-based approach and lead to rates of advanced-stage BC at diagnosis comparable with those of current screening regimens. The results of these trials may change current population-based screening practices.

Elevated Free Triiodothyronine Is Associated With Increased Proliferative Activity in Triple-negative Breast Cancer.

BACKGROUND/AIM: Thyroid hormones (THs) stimulate breast cancer (BC) cell proliferation. We hypothesized that these hormones and the proliferative marker thymidine kinase 1 (TK1) represent the initial and final steps of the proliferative pathway, respectively. PATIENTS AND METHODS: We measured the serum levels of thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine (FT4), along with serum TK1 activity, in 144 newly diagnosed BC patients, and examined the associations between THs and proliferation in different BC receptor profiles. RESULTS: TK1 activity did not correlate with TSH (r=0.06, p=0.473) or FT4 levels (r=0.04, p=0.665), but did correlate with FT3 levels (r=0.28, p=0.001). Elevated FT3 (>6.0 pmol/l) predicted increased TK1 activity (>140 Du/l) after adjusting for age (odds ratio 4.1, p=0.014). We also found a significant association of the combined elevation of FT3 and TK1, assumed as a surrogate marker of accomplished proliferative signal, with triple-negative (TN) profile (p=0.003). The rates of combined FT3 and TK1 elevation in TN and ER-positive profiles were 20.0% and 1.8%, respectively (p=0.005). CONCLUSION: FT3 may be involved in proliferative signaling, as measured by TK1 activity, predominately in TN breast cancer.

Innovative Standards in Surgery of the Breast after Neoadjuvant Systemic Therapy.

BACKGROUND: The goal of neoadjuvant systemic therapy (NST) in breast cancer is to downstage tumors and downgrade treatment. Indications are constantly evolving. These changes raise practical questions for planning of surgery after NST. SUMMARY: In this review we discuss current evolving aspects of surgery of the breast after NST. Breast-conserving surgery (BCS) eligibility increases after NST - both neoadjuvant chemotherapy (NAC) and neoadjuvant endocrine therapy. Adequate margin width in NST and upfront surgery are similar - "no tumor on ink" for invasive cancer. Oncoplastic breast surgery after NST is feasible - both for BCS and mastectomy with reconstruction. There is increasing interest in the possibility of omitting surgery in patients with a complete response to NAC. Several trials are being conducted in aim of achieving acceptable prediction of pathological complete response, by combination of imaging and percutaneous biopsy of the tumor bed, as well as assessing the safety of such an approach. KEY MESSAGES: Surgery of the breast after NST should be determined not only according to biologic and anatomic parameters at diagnosis, but is dynamic, and must be tailored according to the response to therapy. The omission of surgery in exceptional responders after NAC is being explored.

Diffusivity in breast malignancies analyzed for b > 1000 s/mm2 at 1 mm in-plane resolutions: Insight from Gaussian and non-Gaussian behaviors.

Diffusion-weighted imaging (DWI) can improve breast cancer characterizations, but often suffers from low image quality -particularly at informative b > 1000 s/mm2 values. The aim of this study was to evaluate multishot approaches characterizing Gaussian and non-Gaussian diffusivities in breast cancer. This was a prospective study, in which 15 subjects, including 13 patients with biopsy-confirmed breast cancers, were enrolled. DWI was acquired at 3 T using echo planar imaging (EPI) with and without zoomed excitations, readout-segmented EPI (RESOLVE), and spatiotemporal encoding (SPEN); dynamic contrast-enhanced (DCE) data were collected using three-dimensional gradient-echo T1 weighting; anatomies were evaluated with T2 -weighted two-dimensional turbo spin-echo. Congruence between malignancies delineated by DCE was assessed against high-resolution DWI scans with b-values in the 0-1800 s/mm2 range, as well as against apparent diffusion coefficient (ADC) and kurtosis maps. Data were evaluated by independent magnetic resonance scientists with 3-20 years of experience, and radiologists with 6 and 20 years of experience in breast MRI. Malignancies were assessed from ADC and kurtosis maps, using paired t tests after confirming that these values had a Gaussian distribution. Agreements between DWI and DCE datasets were also evaluated using Sorensen-Dice similarity coefficients. Cancerous and normal tissues were clearly separable by ADCs: by SPEN their average values were (1.03 ± 0.17) × 10-3 and (1.69 ± 0.19) × 10-3  mm2 /s (p < 0.0001); by RESOLVE these values were (1.16 ± 0.16) × 10-3 and (1.52 ± 0.14) × 10-3 (p = 0.00026). Kurtosis also distinguished lesions (K = 0.64 ± 0.15) from normal tissues (K = 0.45 ± 0.05), but only when measured by SPEN (p = 0.0008). The best statistical agreement with DCE-highlighted regions arose for SPEN-based DWIs recorded with b = 1800 s/mm2 (Sorensen-Dice coefficient = 0.67); DWI data recorded with b = 850 and 1200 s/mm2 , led to lower coefficients. Both ADC and kurtosis maps highlighted the breast malignancies, with ADCs providing a more significant separation. The most promising alternative for contrast-free delineations of the cancerous lesions arose from b = 1800 s/mm2 DWI. LEVEL OF EVIDENCE: 2. TECHNICAL EFFICACY STAGE: 3.

Meshed Acellular Dermal Matrix in Immediate Prepectoral Implant-based Breast Reconstruction.

Prepectoral implant placement has many potential advantages in immediate breast reconstruction. Acellular dermal matrices (ADMs) are commonly used in these surgeries. ADM meshing may enhance integration, decrease seroma and infection rates, and reduce surgical costs. METHODS: This was a retrospective, single-center study of 49 women (71 breasts) undergoing immediate, prepectoral, implant-based breast reconstruction with 2:1 meshed, bovine-derived ADM (SurgiMend). Outcomes were compared against those of 77 patients (105 breasts) undergoing a similar procedure but with partial subpectoral implant placement. RESULTS: In the prepectoral group, the mean age was 49.1 years and mean body mass index was 24.7 kg/m2. There were no significant differences in baseline characteristics versus the partial subpectoral control group. Mean follow-up was 18.6 months (prepectoral) and 21.3 months (partial subpectoral). Mean time to drain removal was reduced in the prepectoral group (6.5 versus 8.5 days; P < 0.001). Rates of minor and major complications with prepectoral implant placement were 15.5% and 11.3%, respectively - similar to partial subpectoral placement (15.2% and 14.3%) (overall P = 0.690). Capsular contracture and explantation were associated with radiation therapy, and rates were similar between groups. CONCLUSIONS: Prepectoral implant placement with meshed ADM is a safe and reproducible alternative to partial muscle coverage with meshed ADM. Recovery may be easier and animation deformity avoided. It could therefore become the standard of care for implant-based breast reconstruction.

Thyroid Hormones, Silencing Mediator for Retinoid and Thyroid Receptors and Prognosis in Primary Breast Cancer.

BACKGROUND/AIM: Silencing mediator of retinoid and thyroid receptors (SMRT) is a nuclear corepressor in thyroid and estrogen hormones pathways. The aim was to evaluate SMRT expression in relation to thyroid hormone levels and prognostic markers in breast cancer (BC). PATIENTS AND METHODS: Serum and tumor tissues were obtained from 36 patients with benign breast disease (BBD) and 79 BC patients. SMRT expression was determined by immunohistochemistry. Free-triiodothyronine (FT3), free thyroxine (FT4) and thyroid-stimulating hormone (TSH) were measured in serum. RESULTS: Higher FT4, lower FT3/FT4 ratio and higher expression of SMRT were found in BC compared to BBD (for all p<0.001). In BC, increased SMRT expression was associated with lower FT3 (p=0.028), higher tumor grade (p=0.031), increased KI67 proliferation index (p=0.015), higher risk of recurrence (p=0.014) and shorter disease-free survival (p=0.006). In multivariate analysis, SMRT overexpression and below-median levels of TSH were independent prognostic factors in BC. CONCLUSION: Elevated FT4 and decreased FT3/FT4 in BC patients suggest a role for thyroid hormones in malignant transformation. SMRT tumor overexpression is associated with lower FT3 levels, tumor proliferative activity and an aggressive clinical course.

Tumor-to-Nipple Distance in Selecting Patients for Nipple-sparing Mastectomy.

Nipple-sparing mastectomy (NSM) is a valid option for carefully selected cases. Oncologic guidelines have not been established, but proximity of the tumor to the nipple, tumor size, lymph node involvement, and neoadjuvant chemotherapy have been suggested as contraindications to nipple preservation. This study describes our experience with NSM in relation to these factors, in particular distance of tumor from the nipple, to help establish evidence-based guidelines for NSM. METHOD: All NSM procedures performed at our institution between 2014 and 2018 were reviewed. The tumor-to-nipple distance was measured for each patient using mammography, ultrasound, or magnetic resonance imaging. All patients underwent a frozen section (FS) biopsy of the base of the nipple during surgery, and if cancer was detected, the procedure was converted to a skin-sparing mastectomy. Patients were followed for postoperative complications and cancer recurrence. RESULTS: Sixty-eight patients (98 breasts) underwent NSM with immediate reconstruction. Fifty-three patients (78%) underwent the procedure for breast cancer. Nipple involvement was detected on FS in 1 patient and on permanent pathology after a negative FS in 1 patient. Forty-three percent of our patients had a tumor-to-nipple distance of ≤2 cm. During a mean follow-up of 32.5 months (±19.4 months), no locoregional recurrences were observed; however, distant metastasis occurred in 3 patients. CONCLUSIONS: When histologic examination from the base of the nipple is negative (either by FS or permanent pathology), NSM can be considered oncologically safe. Lack of nipple involvement by preoperative clinical and imaging assessment and intraoperative FS is sufficient to classify patients as suitable for NSM.

Breast-Specific Epigenetic Regulation of DeltaNp73 and Its Role in DNA-Damage-Response of BRCA1-Mutated Human Mammary Epithelial Cells.

The function of BRCA1/2 proteins is essential for maintaining genomic integrity in all cell types. However, why women who carry deleterious germline mutations in BRCA face an extremely high risk of developing breast and ovarian cancers specifically has remained an enigma. We propose that breast-specific epigenetic modifications, which regulate tissue differentiation, could team up with BRCA deficiency and affect tissue susceptibility to cancer. In earlier work, we compared genome-wide methylation profiles of various normal epithelial tissues and identified breast-specific methylated gene promoter regions. Here, we focused on deltaNp73, the truncated isoform of p73, which possesses antiapoptotic and pro-oncogenic functions. We showed that the promoter of deltaNp73 is unmethylated in normal human breast epithelium and methylated in various other normal epithelial tissues and cell types. Accordingly, deltaNp73 was markedly induced by DNA damage in human mammary epithelial cells (HMECs) but not in other epithelial cell types. Moreover, the induction of deltaNp73 protected HMECs from DNA damage-induced cell death, and this effect was more substantial in HMECs from BRCA1 mutation carriers. Notably, when BRCA1 was knocked down in MCF10A, a non-malignant breast epithelial cell line, both deltaNp73 induction and its protective effect from cell death were augmented upon DNA damage. Interestingly, deltaNp73 induction also resulted in inhibition of BRCA1 and BRCA2 expression following DNA damage. In conclusion, breast-specific induction of deltaNp73 promotes survival of BRCA1-deficient mammary epithelial cells upon DNA damage. This might result in the accumulation of genomic alterations and allow the outgrowth of breast cancers. These findings indicate deltaNp73 as a potential modifier of breast cancer susceptibility in BRCA1 mutation carriers and may stimulate novel strategies of prevention and treatment for these high-risk women.

Diagnostic yield of multigene panel testing in an Israeli cohort: enrichment of low-penetrance variants.

BACKGROUND: Carriers of pathogenic variants (PVs) in moderate-high-penetrance cancer susceptibility genes are offered tailored surveillance schemes for early cancer diagnosis. The clinical implications of low-penetrance variant carriers are less clear. METHODS: Clinical and demographic data were retrieved for a cohort of Israeli individuals who underwent oncogenetic testing by the 30-gene cancer panel at Color Genomics laboratory, between 04/2013 and 12/2018. RESULTS: Of 758 genotyped individuals, 504 had been diagnosed with cancer prior to testing: 283 (56%) had breast cancer and 106 (21%) colorectal cancer. Pathogenic or likely pathogenic (P/LP) variants were detected in 123 (16%) individuals. Overall, 44 different P/LP variants were detected in 18/30 cancer susceptibility genes; 20 of them were founder/recurrent mutations. Of the carriers, 39 (32%), 10 (8%), and 74 (60%) carried high-, moderate-, or low-penetrance variants, respectively. After excluding low-penetrance variants, 7% (33/504) of all cancer patients, 6% of breast or ovarian cancer patients were found to be carriers, as well as 7% (14/203) of individuals with colonic polyps, and 4% (11/254) of cancer-free individuals. CONCLUSIONS: The diagnostic yield of moderate- and high-penetrance PVs using multigene panel testing was 6%, with 3.7% carriers of non-recurrent PVs. This yield should be discussed during pre-test counseling, and emphasizes the need for harmonized recommendations regarding clinical implications of low-penetrance variants.

Breast density does not affect breast cancer tumor size assessment: A comparison of radiologic versus pathologic measurement by different imaging modalities across breast densities.

BACKGROUND: Tumor size is an important parameter in breast cancer staging. Definitive tumor size is determined by measurement of the pathologic specimen. However, prior to surgery, size must be assessed by imaging with mammography (MMG), ultrasound (US), or magnetic resonance imaging (MRI). Discrepancies between imaging-assessed and pathologic size are not uncommon. Breast density decreases the sensitivity of MMG, and may affect image-based tumor size assessment. AIM: To compare tumor size assessed by the different imaging modalities to pathologic size across breast densities. MATERIAL & METHODS: This was a retrospective analysis of 183 female patients (197 breast cancers) diagnosed and operated for primary breast cancer at a single center. Tumor size measurements were collated for each available imaging modality and compared with measurements from pathologic specimens. Breast density was assessed on MMG using the Breast Imaging Reporting and Data System. RESULTS: Mean pathologic tumor size was 23.0 ± 19.3 mm. Mean tumor size did not differ significantly with MMG (22.3 ± 16.6 mm; P = 0.165) or MRI (23.4 ± 19.2 mm; P = 0.620). However, US significantly underestimated mean tumor size (15.2 ± 8.6 mm; P = 0.0001 vs pathology). Breast density did not affect the accuracy of tumor size assessment by any imaging modality. CONCLUSIONS: US may underestimate breast tumor size. Treatment decisions that take into account tumor size can be made equally reliably in patients with high or low breast density.

Ultrasound guided tattooing of axillary lymph nodes in breast cancer patients prior to neoadjuvant therapy, and identification of tattooed nodes at the time of surgery.

BACKGROUND: Breast cancer patients with lymph node (LN) metastases at diagnosis often undergo neoadjuvant therapy (NAT). Identification of a LN which regressed after NAT remains a challenge. OBJECTIVE: To evaluate marking of involved nodes by tattooing with carbon suspension, and identifying these nodes during surgery. METHODS: A small amount (0.2-0.5 ml) of carbon suspension was injected into one or two axillary LNs under ultrasound guidance at the time of LN biopsy or before or shortly after starting NAT for LN positive breast cancer. During surgery an attempt was made to identify and remove the tattooed LN as a separate specimen. All patients underwent sentinel LN mapping and biopsy and/or axillary LN dissection as mandated by their clinical status. RESULTS: Sixty three patients underwent tattooing of axillary LNs with no complications or adverse events. At surgery a tattooed node was identified in 60 patients (95%; 95% CI 87, 98). Of 56 patients who underwent sentinel mapping with Tc99, in 51 (91%; 95% CI 81, 96) at least one radioactive LN was identified. Of 50 patients in whom both radioactivity and tattoo were identified in axillary LNs, in 40 (80%; 95% CI 67, 89) LNs were radioactive and tattooed, however in 10 patients (20%; 95% CI 11, 33), the tattooed LN was not radioactive. CONCLUSIONS: Tattooing of axillary LNs is safe and easily performed. Tattooing was helpful in identifying the marked LN in the majority of cases. This technique helps to ensure that metastatic LNs are identified and removed at surgery after NAT.