CDH1 Genotype Exploration in Women With Hereditary Lobular Breast Cancer Phenotype.

Importance: Pathogenic or likely pathogenic (P/LP) germline CDH1 variants are associated with risk for diffuse gastric cancer and lobular breast cancer (LBC) in the so-called hereditary diffuse gastric cancer (HDGC) syndrome. However, in some circumstances, LBC can be the first manifestation of this syndrome in the absence of diffuse gastric cancer manifestation. Objectives: To evaluate the frequency of germline CDH1 variants in women with the hereditary LBC (HLBC) phenotype, somatic CDH1 gene inactivation in germline CDH1 variant carriers' tumor samples, and the association of genetic profiles with clinical-pathological data and survival. Design, Setting, and Participants: This single-center, longitudinal, prospective cohort study was conducted from January 1, 1997, to December 31, 2021, with follow-up until January 31, 2023. Women with LBC seen at the European Institute of Oncology were included. Testing for germline CDH1, BRCA1, and BRCA2 genes was performed. Somatic profiling was assessed for germline CDH1 carriers. Main Outcomes and Measures: Accurate estimates of prevalence of germline CDH1 variants among patients with HLBC and the association of somatic sequence alteration with HLBC syndrome. The Kaplan-Meier method and a multivariable Cox proportional hazards regression model were applied for overall and disease-free survival analysis. Results: Of 5429 cases of primary LBC, familial LBC phenotype accounted for 1867 (34.4%). A total of 394 women with LBC were tested, among whom 15 germline CDH1 variants in 15 unrelated families were identified. Among these variants, 6 (40.0%) were P/LP, with an overall frequency of 1.5% (6 of 394). Of the 6 probands with P/LP CDH1 LBC, 5 (83.3%) had a positive family history of BC and only 1 (16.7%) had sporadic juvenile early-onset LBC. No germline BRCA1 and BRCA2 variants were identified in CDH1 carriers. An inactivating CDH1 mechanism (second hit) was identified in 4 of 6 explored matched tumor samples (66.7%) in P/LP germline carriers. The P/LP CDH1 LBC variant carriers had a significantly lower age at diagnosis compared with the group carrying CDH1 variants of unknown significance or likely benign (42.5 [IQR, 38.3-43.0] vs 51.0 [IQR, 45.0-53.0] years; P = .03). Conclusions and Relevance: In this cohort study, P/LP germline CDH1 variants were identified in individuals not fulfilling the classic clinical criteria for HDGC screening, suggesting that identification of these variants may provide a novel method to test women with LBC with early age at diagnosis and/or positive family history of BC.

An Unenhanced Breast MRI Protocol Based on Diffusion-Weighted Imaging: A Retrospective Single-Center Study on High-Risk Population for Breast Cancer.

PURPOSE: This study aimed to investigate the use of contrast-free magnetic resonance imaging (MRI) as an innovative screening method for detecting breast cancer in high-risk asymptomatic women. Specifically, the researchers evaluated the diagnostic performance of diffusion-weighted imaging (DWI) in this population. METHODS: MR images from asymptomatic women, carriers of a germline mutation in either the BRCA1 or BRCA2 gene, collected in a single center from January 2019 to December 2021 were retrospectively evaluated. A radiologist with experience in breast imaging (R1) and a radiology resident (R2) independently evaluated DWI/ADC maps and, in case of doubts, T2-WI. The standard of reference was the pathological diagnosis through biopsy or surgery, or ≥1 year of clinical and radiological follow-up. Diagnostic performances were calculated for both readers with a 95% confidence interval (CI). The agreement was assessed using Cohen's kappa (κ) statistics. RESULTS: Out of 313 women, 145 women were included (49.5 ± 12 years), totaling 344 breast MRIs with DWI/ADC maps. The per-exam cancer prevalence was 11/344 (3.2%). The sensitivity was 8/11 (73%; 95% CI: 46-99%) for R1 and 7/11 (64%; 95% CI: 35-92%) for R2. The specificity was 301/333 (90%; 95% CI: 87-94%) for both readers. The diagnostic accuracy was 90% for both readers. R1 recalled 40/344 exams (11.6%) and R2 recalled 39/344 exams (11.3%). Inter-reader reproducibility between readers was in moderate agreement (κ = 0.43). CONCLUSIONS: In female carriers of a BRCA1/2 mutation, breast DWI supplemented with T2-WI allowed breast cancer detection with high sensitivity and specificity by a radiologist with extensive experience in breast imaging, which is comparable to other screening tests. The findings suggest that DWI and T2-WI have the potential to serve as a stand-alone method for unenhanced breast MRI screening in a selected population, opening up new perspectives for prospective trials.

Hereditary Gastric Cancer: Single-Gene or Multigene Panel Testing? A Mono-Institutional Experience.

Gastric cancer (GC) has long been a 'Cinderella' among hereditary cancers. Until recently, single-gene testing (SGT) was the only approach to identify high-risk individuals. With the spread of multigene panel testing (MGPT), a debate arose on the involvement of other genes, particularly those pertaining to homologous recombination (HR) repair. We report our mono-institutional experience in genetic counseling and SGT for 54 GC patients, with the detection of nine pathogenic variants (PVs) (9/54:16.7%). Seven out of fifty (14%) patients who underwent SGT for unknown mutations were carriers of a PV in CDH1 (n = 3), BRCA2 (n = 2), BRCA1 (n = 1), and MSH2 (n = 1), while one patient (2%) carried two variants of unknown significance (VUSs). CDH1 and MSH2 emerged as genes involved in early-onset diffuse and later-onset intestinal GCs, respectively. We additionally conducted MGPT on 37 patients, identifying five PVs (13.5%), including three (3/5:60%) in an HR gene (BRCA2, ATM, RAD51D) and at least one VUS in 13 patients (35.1%). Comparing PV carriers and non-carriers, we observed a statistically significant difference in PVs between patients with and without family history of GC (p-value: 0.045) or Lynch-related tumors (p-value: 0.036). Genetic counseling remains central to GC risk assessment. MGPT appeared advantageous in patients with unspecific phenotypes, although it led to challenging results.

Metaplastic breast cancer: an all-round multidisciplinary consensus.

Metaplastic breast cancer (MpBC) is a rare and aggressive histologic subtype of breast cancer (BC) characterized by the presence of at least two cellular types, commonly epithelial and mesenchymal components. Despite growing evidence that MpBC is a unique entity, it has long been treated as a variant of nonspecial type (NST) BC. MpBC typically shows the phenotype of triple-negative breast cancer (TNBC), but compared to NST-TNBC, it is a relatively chemorefractory tumor associated with worse outcomes. Therefore, there is an urgent need to develop management guidelines specifically for MpBC to improve the prognosis of patients with early MpBC. This expert consensus aims to guide diagnosis and standardize clinical management of early MpBC among treating physicians. We provide guidance on the challenging radiological and pathological diagnosis of MpBC. Evidence on the involvement of genetic predisposition in the development of MpBC is also explored. We emphasize the importance of a multidisciplinary approach for the treatment of patients with early MpBC. The optimal surgery and radiotherapy approach is presented, as well as the opportunity offered by novel therapeutic approaches to increase treatment response in this chemoresistant subtype. Appropriate management of patients with MpBC is critical to reduce the high risk of local and distant recurrence that characterizes this disease.

Molecular tumour board at European Institute of Oncology: Report of the first three year activity of an Italian precision oncology experience.

BACKGROUND: Precision oncology aims to improve clinical outcomes by personalising treatment options for patients with cancer. Exploiting vulnerabilities identified in a patient's cancer genome requires reliable interpretation of a huge mole of alterations and heterogeneous biomarkers. ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) allows evidence-based evaluation of genomic findings. Molecular tumour boards (MTBs) convey the required multi-disciplinary expertise to enable ESCAT evaluation and strategical treatment choice. MATERIALS AND METHOD: We retrospectively reviewed the records of 251 consecutive patients discussed by European Institute of Oncology MTB between June 2019 and June 2022. RESULTS: One-hundred eighty-eight (74.6%) patients had at least one actionable alteration. After MTB discussion, 76 patients received molecularly matched therapies (MMTs) while 76 patients received standard of care. Patients receiving MMT displayed higher overall response rate (37.3% versus 12.9%), median progression-free survival (mPFS 5.8 months, 95% confidence interval [CI] 4.1-7.5 versus 3.6 months, 95% CI 2.5-4.8, p = 0.041; hazard ratio 0.679, 95% CI 0.467-0.987) and median overall survival (mOS 35.1 months, 95% CI not evaluable versus 8.5 months, 95% CI 3.8-13.2; hazard ratio 0.431, 95% CI 0.250-0.744, p = 0.002). Superiority in OS and PFS persisted in multivariable models. Among 61 pretreated patients receiving MMT, 37.5% of patients had PFS2/PFS1 ratio ≥1.3. Patients with higher actionable targets (ESCAT tier I) had better OS (p = 0.001) and PFS (p = 0.049), while no difference was observed in lower evidence levels. CONCLUSIONS: Our experience shows that MTBs can yield valuable clinical benefit. Higher actionability ESCAT level appears to be associated with better outcomes for patients receiving MMT.

Association of Vitamin D Receptor and Vitamin D-Binding Protein Polymorphisms with Familial Breast Cancer Prognosis in a Mono-Institutional Cohort.

Low 25-hydroxyvitamin D (25OHD) has been associated with an increased cancer incidence and poorer prognosis. Single nucleotide polymorphisms (SNPs) of vitamin D receptor (VDR) and vitamin D binding protein (GC gene) may interfere with vitamin D activity. This study assesses the role of VDR and GC SNPs on breast cancer (BC) recurrence and survival in a cohort of patients with a family history of breast cancer, without the pathogenic variant for BRCA1 and BRCA2. A consecutive series of patients who underwent genetic testing were genotyped for VDR and GC genes. Specifically, ApaI, FokI, TaqI, BsmI and rs2282679, rs4588, rs7041 SNPs were determined. A total of 368 wild type (WT) patients with BC were analyzed for VDR and GC SNPs. The GC rs2282679 minor allele was significantly associated with luminal subtype of the primary tumor compared to Her2+/TN breast cancer (p = 0.007). Multivariate Cox models showed that BmsI and TaqI are significantly associated with BC outcome. Patients with the major alleles showed more than 30% lower hazard of relapse (BsmI p = 0.02 and TaqI p = 0.03). Our study supports the evidence for a pivotal role of 25OHD metabolism in BC. GC SNPs may influence the hormone tumor responsiveness and VDR may affect tumor prognosis.

ZC4H2 deletions can cause severe phenotype in female carriers.

ZC4H2 is involved in human brain development, and, if mutated, can be responsible for a rare X-linked disorder, originally presented in literature as Wieacker-Wolff syndrome and Miles-Carpenter syndrome. In males, severe intellectual disability is associated with variable symptoms of central and peripheral nervous system involvement, such as spasticity, hyperreflexia, muscle weakness, and arthrogryposis. Female carriers are usually described as asymptomatic or only mildly affected. Here, we report on a girl carrying a de novo deletion of ZC4H2 detected by array-CGH analysis. She showed a complex neurodevelopmental disorder resembling the clinical picture commonly observed in male patients. X-inactivation was found to be random. Additionally, she had an unusual appearance of fingers and hand creases, and electromyography showed a peculiar pattern of both neurogenic and myopathic anomalies. The present patient confirms that female carriers can also be severely affected. Systematic clinical investigations of both males and females are needed to define the variety in nature and severity of phenotypes related to ZC4H2 variants.

Gas-phase reactions of XH3(+) (X = C, Si, Ge) with NF3: a comparative investigation on the detailed mechanistic aspects.

The gas-phase reaction of CH(3)(+) with NF(3) was investigated by ion trap mass spectrometry (ITMS). The observed products include NF(2)(+) and CH(2)F(+). Under the same experimental conditions, SiH(3)(+) reacts with NF(3) and forms up to six ionic products, namely (in order of decreasing efficiency) NF(2)(+), SiH(2)F(+), SiHF(2)(+), SiF(+), SiHF(+), and NHF(+). The GeH(3)(+) cation is instead totally unreactive toward NF(3). The different reactivity of XH(3)(+) (X = C, Si, Ge) toward NF(3) has been rationalized by ab initio calculations performed at the MP2 and coupled cluster level of theory. In the reaction of both CH(3)(+) and SiH(3)(+), the kinetically relevant intermediate is the fluorine-coordinated isomer H(3)X-F-NF(2)(+) (X = C, Si). This species forms from the exoergic attack of XH(3)(+) to one of the F atoms of NF(3) and undergoes dissociation and isomerization processes which eventually result in the experimentally observed products. The nitrogen-coordinated isomers H(3)X-NF(3)(+) (X = C, Si) were located as minimum-energy structures but do not play an active role in the reaction mechanism. The inertness of GeH(3)(+) toward NF(3) is also explained by the endoergic character of the dissociation processes involving the H(3)Ge-F-NF(2)(+) isomer.