Role of risk scoring systems in predicting life expectancy after carotid endarterectomy in asymptomatic patients.

OBJECTIVE: The aim of this study is to compare and to test the performance of all available risk scoring systems (RSSs) designed to predict long-term survival rate in asymptomatic candidate patients for carotid endarterectomy (CEA) for significant carotid artery stenosis. METHODS: Data on asymptomatic patients who underwent CEA in three high-volume centers were prospectively recorded. Through literature research using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations, six RSSs were identified for the intent of the study. Primary endpoints were 3- and 5-year survival rates after CEA. All items used as variables to compose multiple RSSs were applied to every patient in the study population. The 3- and 5-year mortality prediction rates for each score were assessed by sensitivity, specificity, and predictive negative and positive value calculation, as well as univariable Cox proportional hazard models with the Harrell C index. RESULTS: During the study period, 825 CEAs in 825 asymptomatic patients were analyzed. All items used in RSSs were available in the dataset, with some concerns regarding their definition and application among RSSs. The 3- and 5-year survival rates of the study cohort were 94.5% and 90.3%, respectively. Among the six RSSs analyzed, no RSS demonstrated optimal results in terms of mortality rate prediction accuracy, although some scores had good diagnostic and risk of death precision. CONCLUSIONS: RSSs, when used alone, fail to optimally detect postoperative life expectancy in asymptomatic CEA patient candidates. Further prospective controlled studies are needed to compose and validate RSSs with better calibration to predict outcomes.

Interobserver variability in the evaluation of primary graft dysfunction after lung transplantation: impact of radiological training and analysis of discordant cases.

PURPOSE: Radiologic criteria for the diagnosis of primary graft dysfunction (PGD) after lung transplantation are nonspecific and can lead to misinterpretation. The primary aim of our study was to assess the interobserver agreement in the evaluation of chest X-rays (CXRs) for PGD diagnosis and to establish whether a specific training could have an impact on concordance rates. Secondary aim was to analyze causes of interobserver discordances. MATERIAL AND METHODS: We retrospectively enrolled 164 patients who received bilateral lung transplantation at our institution, between February 2013 and December 2019. Three radiologists independently reviewed postoperative CXRs and classified them as suggestive or not for PGD. Two of the Raters performed a specific training before the beginning of the study. A senior thoracic radiologist subsequently analyzed all discordant cases among the Raters with the best agreement. Statistical analysis to calculate interobserver variability was percent agreement, Cohen's kappa and intraclass correlation coefficient. RESULTS: A total of 473 CXRs were evaluated. A very high concordance among the two trained Raters, 1 and 2, was found (K = 0.90, ICC = 0.90), while a poorer agreement was found in the other two pairings (Raters 1 and 3: K = 0.34, ICC = 0.40; Raters 2 and 3: K = 0.35, ICC = 0.40). The main cause of disagreement (52.4% of discordant cases) between Raters 1 and 2 was the overestimation of peribronchial thickening in the absence of unequivocal bilateral lung opacities or the incorrect assessment of unilateral alterations. CONCLUSION: To properly identify PGD, it is recommended for radiologists to receive an adequate specific training.

BRCA mutation carriers' perception about benefits and risks associated with combined hormonal contraceptives use.

OBJECTIVE: To evaluate the actual perceptions about combined hormonal contraceptives (CHCs) use in BRCA mutation carriers in comparison to women from the general population. METHODS: This was a cross-sectional, observational study involving two Italian referral centres for hereditary cancers. An identical questionnaire investigating how CHC use could affect the risk of developing some types of cancer, specific diseases, and symptoms was administered to 85 BRCA mutation carriers and 85 healthy women without this genetic mutation (control group). Women's perceptions were evaluated using specific questions and Likert scales (-5 to +5). RESULTS: Perceptions about the effects of CHC use on developing specific diseases and symptoms did not differ between BRCA mutation carriers and controls. Conversely, the protective effects of CHC use on colorectal (p = .02), uterine body (p = .01) and ovarian (p = .01) cancers were unknown by BRCA mutation carriers. Moreover, BRCA mutation carriers recognised the association between CHC use and a higher risk of breast (p = .0008) and uterine cervix cancer (p = .007). CONCLUSIONS: Investing time and effort in transmitting the correct key messages about oncological risk related to CHC use could potentially increase their use in BRCA mutation carriers.

Fulvestrant and trastuzumab in patients with luminal HER2-positive advanced breast cancer (ABC): an Italian real-world experience (HERMIONE 9).

PURPOSE: The most appropriate therapy for HR + /HER2-positive (HER2 +) advanced breast cancer (ABC) is a matter of debate. Co-targeting of both receptors represents an attractive strategy to overcome the cross-talk between them. METHODS: The HERMIONE 9 is an observational retrospective multicentric study which aimed to describe the clinical outcome of patients with HR + /HER2 + ABC who received the combination of Fulvestrant (F) and Trastuzumab (T) as part of their routine treatment at 10 Italian Institutions. RESULTS: Eighty-seven patients were included. Median age was 63 (range, 35-87) years. The median number of previous treatments was 3 (range, 0-10) and F and T were administered as ≥ 3rd line in 67 patients. Among the 86 evaluable patients, 6 (6.9%) achieved CR, 18 (20.7%) PR, and 44 (50.6%) had SD ≥ 24 weeks with an overall CBR of 78.2%. At a median follow-up of 33.6 months, mPFS of the entire cohort was 12.9 months (range, 2.47-128.67). No difference was observed in mPFS between patients treated after progression or as maintenance therapy (mPFS 12.9 and 13.9 months in 64 and 23 patients, respectively), neither considering the number of previous treatment lines (≤ 3 or < 3). CONCLUSION: The combination of F and T was active in this cohort at poor prognosis and deserves further investigations possibly in combination with pertuzumab in patients with high ER expression.

BRCA mutation carriers' perceptions on postmenopausal hormone therapy: An Italian study.

OBJECTIVE: To evaluate the actual perceptions of postmenopausal hormone therapy (HT) in BRCA mutation carriers (BRCAmc) in comparison with women from the general population. METHODS: Questionnaire-based study of 83 BRCAmc and a control group of 89 women without a genetic mutation. Perceptions were evaluated by specific questions and Likert scales (-5-+5). RESULTS: Present and past users of HT were more frequent in the control group (p = 0.01), with a longer time of use (p = 0.03). The preferred route of administration of HT was 'oral' (54.6%). The most frequently reported adverse effect of HT was venous thrombosis (0.8), while a protective effect on bone health was reported. No noticeable beneficial effects of HT have been recognised for hot flushes (0.2) and vaginal dryness (0.1). The most frequently perceived beneficial and adverse effects of HT were not significantly different between BRCA mutation carriers and controls. The greatest oncological fear was breast cancer (1.0). The protective role of HT on colorectal cancer was not known (0.1). These oncological impacts were mostly overestimated in BRCAmc, however this was not significant. Few BRCAmc would think of taking HT after risk-reducing surgeries. CONCLUSIONS: Knowledge of the effects of HT on BRCAmc is relatively poor and they are likely to overstate its negative effects and underestimate its health benefits; however, this is not significant in comparison to the general population. More and better information should be given to BRCAmc to allow them to make informed decisions about the use of HT, especially before undergoing risk-reducing surgeries.

The multifaceted spectrum of liver cirrhosis in older hospitalised patients: analysis of the REPOSI registry.

BACKGROUND: Knowledge on the main clinical and prognostic characteristics of older multimorbid subjects with liver cirrhosis (LC) admitted to acute medical wards is scarce. OBJECTIVES: To estimate the prevalence of LC among older patients admitted to acute medical wards and to assess the main clinical characteristics of LC along with its association with major clinical outcomes and to explore the possibility that well-distinguished phenotypic profiles of LC have classificatory and prognostic properties. METHODS: A cohort of 6,193 older subjects hospitalised between 2010 and 2018 and included in the REPOSI registry was analysed. RESULTS: LC was diagnosed in 315 patients (5%). LC was associated with rehospitalisation (age-sex adjusted hazard ratio, [aHR] 1.44; 95% CI, 1.10-1.88) and with mortality after discharge, independently of all confounders (multiple aHR, 2.1; 95% CI, 1.37-3.22), but not with in-hospital mortality and incident disability. Three main clinical phenotypes of LC patients were recognised: relatively fit subjects (FIT, N = 150), subjects characterised by poor social support (PSS, N = 89) and, finally, subjects with disability and multimorbidity (D&M, N = 76). PSS subjects had an increased incident disability (35% vs 13%, P < 0.05) compared to FIT. D&M patients had a higher mortality (in-hospital: 12% vs 3%/1%, P < 0.01; post-discharge: 41% vs 12%/15%, P < 0.01) and less rehospitalisation (10% vs 32%/34%, P < 0.01) compared to PSS and FIT. CONCLUSIONS: LC has a relatively low prevalence in older hospitalised subjects but, when present, accounts for worse post-discharge outcomes. Phenotypic analysis unravelled the heterogeneity of LC older population and the association of selected phenotypes with different clinical and prognostic features.

Inappropriate prescribing in intermediate care facilities.

Inappropriate prescribing for older people is a global healthcare problem. This study aimed to determine the prevalence of older patients receiving potentially inappropriate medications (PIMs) at admission and discharge at the intermediate care facility of ASP Pio Albergo Trivulzio. We consecutively enrolled 100 patients aged ≥ 65 from December 2017 to May 2018 and evaluated PIMs with the 2015 version of the Beers criteria. We found a significant reduction in the prescription of drugs to avoid and proton pump inhibitors (PPIs), while patients with at least one psychotropic drug to avoid or to use with caution significantly increased. The inappropriate prescription of PPIs was mainly associated with the use of heparin. Optimizing PPI and psychotropic drug prescriptions should be considered for deprescribing inappropriate polypharmacy in intermediate care facilities.

Detecting Variants in the NBN Gene While Testing for Hereditary Breast Cancer: What to Do Next?

The NBN gene has been included in breast cancer (BC) multigene panels based on early studies suggesting an increased BC risk for carriers, though not confirmed by recent research. To evaluate the impact of NBN analysis, we assessed the results of NBN sequencing in 116 BRCA-negative BC patients and reviewed the literature. Three patients (2.6%) carried potentially relevant variants: two, apparently unrelated, carried the frameshift variant c.156_157delTT and another one the c.628G>T variant. The latter was subsequently found in 4/1390 (0.3%) BC cases and 8/1580 (0.5%) controls in an independent sample, which, together with in silico predictions, provided evidence against its pathogenicity. Conversely, the rare c.156_157delTT variant was absent in the case-control set; moreover, a 50% reduction of NBN expression was demonstrated in one carrier. However, in one family it failed to co-segregate with BC, while the other carrier was found to harbor also a probably pathogenic TP53 variant that may explain her phenotype. Therefore, the c.156_157delTT, although functionally deleterious, was not supported as a cancer-predisposing defect. Pathogenic/likely pathogenic NBN variants were detected by multigene panels in 31/12314 (0.25%) patients included in 15 studies. The risk of misinterpretation of such findings is substantial and supports the exclusion of NBN from multigene panels.

Detection of Germline Variants in 450 Breast/Ovarian Cancer Families with a Multi-Gene Panel Including Coding and Regulatory Regions.

With the progress of sequencing technologies, an ever-increasing number of variants of unknown functional and clinical significance (VUS) have been identified in both coding and non-coding regions of the main Breast Cancer (BC) predisposition genes. The aim of this study is to identify a mutational profile of coding and intron-exon junction regions of 12 moderate penetrance genes (ATM, BRIP1, CDH1, CHEK2, NBN, PALB2, PTEN, RAD50, RAD51C, RAD51D, STK11, TP53) in a cohort of 450 Italian patients with Hereditary Breast/Ovarian Cancer Syndrome, wild type for germline mutation in BRCA1/2 genes. The analysis was extended to 5'UTR and 3'UTR of all the genes listed above and to the BRCA1 and BRCA2 known regulatory regions in a subset of 120 patients. The screening was performed through NGS target resequencing on the Illumina platform MiSeq. 8.7% of the patients analyzed is carriers of class 5/4 coding variants in the ATM (3.6%), BRIP1 (1.6%), CHEK2 (1.8%), PALB2 (0.7%), RAD51C (0.4%), RAD51D (0.4%), and TP53 (0.2%) genes, while variants of uncertain pathological significance (VUSs)/class 3 were identified in 9.1% of the samples. In intron-exon junctions and in regulatory regions, variants were detected respectively in 5.1% and in 32.5% of the cases analyzed. The average age of disease onset of 44.4 in non-coding variant carriers is absolutely similar to the average age of disease onset in coding variant carriers for each proband's group with the same cancer type. Furthermore, there is not a statistically significant difference in the proportion of cases with a tumor onset under age of 40 between the two groups, but the presence of multiple non-coding variants in the same patient may affect the aggressiveness of the tumor and it is worth underlining that 25% of patients with an aggressive tumor are carriers of a PTEN 3'UTR-variant. This data provides initial information on how important it might be to extend mutational screening to the regulatory regions in clinical practice.

Combined endocrine approaches vs endocrine therapy alone as first line treatment in elderly patients with hormone receptor-positive, HER2 negative, advanced breast cancer: to prescribe for the patient or the physician? A meta-analysis of phase II and III randomized clinical trials.

BACKGROUND: Elderly patients are underrepresented in clinical study where combined endocrine strategies were compared to endocrine therapy (ET) in hormone receptors positive, HER2 negative, metastatic breast cancer. The role of the new endocrine approaches in elderly women is still unclear. METHODS: We performed a meta-analysis of first line phase II/III randomized trials on ET versus combined strategies considering clinical benefit and safety profile. Trials with hazard ratio (HR) for PFS in elderly patients were included. RESULTS: Overall, the meta-analysis showed a PFS advantage for the experimental arms [HR 0.77, p 0.016] with a significant high/moderate heterogeneity [I2 65.46%, p 0.005]. For patients on CDK 4/6 inhibitors and ET, HR was 0.57 (p < 0.0001), with low heterogeneity [I2 0.0001%, p 0.96]. Hematological adverse events, as well as diarrhea with Abemaciclib, were significantly higher in elderly population. CONCLUSIONS: The magnitude of PFS benefit due to the combined strategies in elderly patients is similar to those reported in the overall clinical trial population. Adding CDK4/6 inhibitors to ET significantly prolongs PFS, even if toxicity profile have to be carefully considered. Future trials should be designed taking into account patients' age, geriatric assessment and comorbidity.

Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification.

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification.

Breast ultrasonography (BU) in the screening protocol for women at hereditary-familial risk of breast cancer: has the time come to rethink the role of BU according to different risk categories?

This article evaluates the breast cancer (BC) screening efficacy of biannual ultrasound (US) in three different risk categories. In a single-center, prospective, nonrandomized comparison study, BRCA mutation carriers and women with high risk (HR) or intermediate risk (IR) received mammography (MMG), ultrasound, (US) and Magnetic Resonance Imaging (MRI), scheduled according to the risk categories. Single and combined sensitivity were evaluated in specific groups of risk and the US performance at six-monthly interval was notably considered. Among 2,313 asymptomatic women at different risk (136 mutation carriers, 1,749 at HR and 428 at IR) 211 developed a BC, of which 193 (91.5%) were screen detected BC (SDBC) and 18 (8.5%) were interval BC (IBC). The SDBC detection rate (DR) was 11.2 per 1.000 person-years (37.9, 8.5 and 16.1 for BRCA, HR and IR, respectively); 116 BC were detected by MMG (DR = 6.6 × 1,000 persons-years), 62 by US (DR = 3.6 × 1,000 persons-years) and 15 by MRI, that was applied only in 60 BRCA women (DR = 37 × 1,000 persons-years). At the six-monthly US, 52 BC were detected (DR = 3.0 × 1,000 persons/years), of which 8 were BRCA-related. The most sensitive technique was MRI (93.7%) followed by MMG (55%) and US (29.4%). Combined sensitivity for MMG plus US was 100% in HR and 80.4% for IR women (p < 0.01). In BRCA mutated patients, MRI alone with annual US performed after six months, could be offered. In HR patients, MMG plus biannual US provide the most sensitive diagnosis and for IR group an annual MMG could be sufficient.

Insight into genetic susceptibility to male breast cancer by multigene panel testing: Results from a multicenter study in Italy.

Breast cancer (BC) in men is rare and genetic predisposition is likely to play a relevant role in its etiology. Inherited mutations in BRCA1/2 account for about 13% of all cases and additional genes that may contribute to the missing heritability need to be investigated. In our study, a well-characterized series of 523 male BC (MBC) patients from the Italian multicenter study on MBC, enriched for non-BRCA1/2 MBC cases, was screened by a multigene custom panel of 50 cancer-associated genes. The main clinical-pathologic characteristics of MBC in pathogenic variant carriers and non-carriers were also compared. BRCA1/2 pathogenic variants were detected in twenty patients, thus, a total of 503 non-BRCA1/2 MBC patients were examined in our study. Twenty-seven of the non-BRCA1/2 MBC patients were carriers of germline pathogenic variants in other genes, including two APC p.Ile1307Lys variant carriers and one MUTYH biallelic variant carrier. PALB2 was the most frequently altered gene (1.2%) and PALB2 pathogenic variants were significantly associated with high risk of MBC. Non-BRCA1/2 pathogenic variant carriers were more likely to have personal (p = 0.0005) and family (p = 0.007) history of cancer. Results of our study support a central role of PALB2 in MBC susceptibility and show a low impact of CHEK2 on MBC predisposition in the Italian population. Overall, our data indicate that a multigene testing approach may benefit from appropriately selected patients with implications for clinical management and counseling of MBC patients and their family members.

Generation and validation of algorithms to identify subjects with dementia using administrative data.

OBJECTIVES: To generate and validate algorithms for the identification of individuals with dementia in the community setting, by the interrogation of administrative records, an inexpensive and already available source of data. METHODS: We collected and anonymized information on demented individuals 65 years of age or older from ten general practitioners (GPs) in the district of Brianza (Northern Italy) and compared this with the administrative data of the local health protection agency (Agenzia per la Tutela della Salute). Indicators of the disease in the administrative database (diagnosis of dementia in the hospital discharge records; use of cholinesterase inhibitors/memantine; neuropsychological tests; brain CT/MRI; outpatient neurological visits) were used separately and in different combinations to generate algorithms for the detection of patients with dementia. RESULTS: When used individually, indicators of dementia showed good specificity, but low sensitivity. By their combination, we generated different algorithms: I-therapy with ChEI/memantine or diagnosis of dementia at discharge or neuropsychological tests (specificity 97.9%, sensitivity 52.5%); II-therapy with ChEI/memantine or diagnosis of dementia at discharge or neuropsychological tests or brain CT/MRI or neurological visit (sensitivity 90.8%, specificity 70.6%); III-therapy with ChEI/memantine or diagnosis of dementia at discharge or neuropsychological tests or brain CT/MRIMRI and neurological visit (specificity 89.3%, sensitivity 73.3%). CONCLUSIONS: These results show that algorithms obtained from administrative data are not sufficiently accurate in classifying patients with dementia, whichever combination of variables is used for the identification of the disease. Studies in large patient cohorts are needed to develop further strategies for identifying patients with dementia in the community setting.

Need for Deprescribing in Hospital Elderly Patients Discharged with a Limited Life Expectancy: The REPOSI Study.

OBJECTIVE: Older people approaching the end of life are at a high risk for adverse drug reactions. Approaching the end of life should change the therapeutic aims, triggering a reduction in the number of drugs.The main aim of this study is to describe the preventive and symptomatic drug treatments prescribed to patients discharged with a limited life expectancy from internal medicine and geriatric wards. The secondary aim was to describe the potentially severe drug-drug interactions (DDI). MATERIALS AND METHODS: We analyzed Registry of Polytherapies Societa Italiana di Medicina Interna (REPOSI), a network of internal medicine and geriatric wards, to describe the drug therapy of patients discharged with a limited life expectancy. RESULTS: The study sample comprised 55 patients discharged with a limited life expectancy. Patients with at least 1 preventive medication that could be considered for deprescription at the end of life were significantly fewer from admission to discharge (n = 30; 54.5% vs. n = 21; 38.2%; p = 0.02). Angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers, lipid-lowering drugs, and clonidine were the most frequent potentially avoidable medications prescribed at discharge, followed by xanthine oxidase inhibitors and drugs to prevent fractures. Thirty-seven (67.3%) patients were also exposed to at least 1 potentially severe DDI at discharge. CONCLUSION: Hospital discharge is associated with a small reduction in the use of commonly prescribed preventive medications in patients discharged with a limited life expectancy. Cardiovascular drugs are the most frequent potentially avoidable preventive medications. A consensus framework or shared criteria for potentially inappropriate medication in elderly patients with limited life expectancy could be useful to further improve drug prescription.

Rate and appropriateness of polypharmacy in older patients with hemophilia compared with age-matched controls.

BACKGROUND: In older people, multiple chronic ailments lead to the intake of multiple medications (polypharmacy) that carry a number of negative consequences (adverse events, prescription and intake errors, poor adherence, higher mortality). Because ageing patients with haemophilia (PWHs) may be particularly at risk due to their pre-existing multiple comorbidities (arthropathy, liver disease), we chose to analyse the pattern of chronic drug intake in a cohort of PWHs aged 60 years or more. PATIENTS AND METHODS: S + PHERA is a multicentre observational study, with the broad goal to evaluate prospectively the health status and medication intake in 102 older patients with severe haemophilia A or B compared with 204 age- and residence-matched controls chosen randomly from the same general practices of PWHs. The rate of potential drug-drug interactions (PDDI) was evaluated as a proxy of prescription appropriateness. RESULTS: After excluding replacement therapies and antiviral drugs, PWHs took in average less daily drugs than controls (2.4 ± 2.5 vs 3.0 ± 2.4) and had a lower rate of polypharmacy. Moreover, their prevalence of PDDI was lower (16.7% vs 27%). CONCLUSIONS: The rate of polypharmacy and the appropriateness of medications other than those for haemophilia and related comorbidities are acceptable in Italian PWHs, and better than those in their age peers without haemophilia, perhaps owing to drug tailoring and deprescribing by the specialized haemophilia centres at the time of regular visits. However, the PWHs investigated herewith were relatively young and the rate of polypharmacy and related PDDIs may become more prominent and crucial when older ages are reached, suggesting the need of continuous surveillance on prescribed drugs and the risk of drug-drug interactions.

Whole-exome sequencing and targeted gene sequencing provide insights into the role of PALB2 as a male breast cancer susceptibility gene.

BACKGROUND: Male breast cancer (MBC) is a rare disease whose etiology appears to be largely associated with genetic factors. BRCA1 and BRCA2 mutations account for about 10% of all MBC cases. Thus, a fraction of MBC cases are expected to be due to genetic factors not yet identified. To further explain the genetic susceptibility for MBC, whole-exome sequencing (WES) and targeted gene sequencing were applied to high-risk, BRCA1/2 mutation-negative MBC cases. METHODS: Germ-line DNA of 1 male and 2 female BRCA1/2 mutation-negative breast cancer (BC) cases from a pedigree showing a first-degree family history of MBC was analyzed with WES. Targeted gene sequencing for the validation of WES results was performed for 48 high-risk, BRCA1/2 mutation-negative MBC cases from an Italian multicenter study of MBC. A case-control series of 433 BRCA1/2 mutation-negative MBC and female breast cancer (FBC) cases and 849 male and female controls was included in the study. RESULTS: WES in the family identified the partner and localizer of BRCA2 (PALB2) c.419delA truncating mutation carried by the proband, her father, and her paternal uncle (all affected with BC) and the N-acetyltransferase 1 (NAT1) c.97C>T nonsense mutation carried by the proband's maternal aunt. Targeted PALB2 sequencing detected the c.1984A>T nonsense mutation in 1 of the 48 BRCA1/2 mutation-negative MBC cases. NAT1 c.97C>T was not found in the case-control series. CONCLUSIONS: These results add strength to the evidence showing that PALB2 is involved in BC risk for both sexes and indicate that consideration should be given to clinical testing of PALB2 for BRCA1/2 mutation-negative families with multiple MBC and FBC cases. Cancer 2017;123:210-218. © 2016 American Cancer Society.

Evaluation of Transvaginal Ultrasound plus CA-125 Measurement and Prophylactic Salpingo-Oophorectomy in Women at Different Risk Levels of Ovarian Cancer: The Modena Study Group Cohort Study.

OBJECTIVE: To evaluate the effectiveness of transvaginal ultrasound (TVU) and serum CA-125 measurement in women at different risk of developing ovarian cancer/fallopian tube cancer (OC/FTC) and the incidence of primary peritoneal cancer (PPC) after risk-reducing salpingo-oophorectomy (RRSO). METHODS: Between 2002 and 2014, 661 women at different risk of OC/FTC/PPC due to a family history or BRCA1/2 gene mutation were offered TVU and CA-125 measurement or RRSO as prevention strategies. The detection rate of OC/FTC/PPC was evaluated, and the sensitivity and specificity for CA-125 measurement and TVU were calculated. Survival and event analysis was performed for diagnosed patients. RESULTS: After a median follow-up of 112 months, 12 OC/FTC/PPC cases were detected (2.6/1,000 persons/year). The screening sensitivity was 70%, with 73% for BRCA carriers. Six (50%) of 12 cancers were stage I or II. Among 41 women who underwent RRSO, 2 BRCA1 carriers developed a PPC (4.9%). At 61-month follow-up, overall and event-free survival were 75 and 64%, respectively. CONCLUSIONS: The cancer detection rate in women with BRCA mutation or a strong family history supports the effectiveness of our surveillance program for early diagnosis. Screening for women at lower risk of OC/FTC is not recommended. A residual risk of PPC after RRSO remains for BRCA1 carriers.

Molecular Biomarkers for Prediction of Targeted Therapy Response in Metastatic Breast Cancer: Trick or Treat?

In recent years, the study of genomic alterations and protein expression involved in the pathways of breast cancer carcinogenesis has provided an increasing number of targets for drugs development in the setting of metastatic breast cancer (i.e., trastuzumab, everolimus, palbociclib, etc.) significantly improving the prognosis of this disease. These drugs target specific molecular abnormalities that confer a survival advantage to cancer cells. On these bases, emerging evidence from clinical trials provided increasing proof that the genetic landscape of any tumor may dictate its sensitivity or resistance profile to specific agents and some studies have already showed that tumors treated with therapies matched with their molecular alterations obtain higher objective response rates and longer survival. Predictive molecular biomarkers may optimize the selection of effective therapies, thus reducing treatment costs and side effects. This review offers an overview of the main molecular pathways involved in breast carcinogenesis, the targeted therapies developed to inhibit these pathways, the principal mechanisms of resistance and, finally, the molecular biomarkers that, to date, are demonstrated in clinical trials to predict response/resistance to targeted treatments in metastatic breast cancer.