Hereditary lobular breast cancer with an emphasis on E-cadherin genetic defect

Corso, Giovanni; Figueiredo, Joana; Vecchia, Carlo La; Veronesi, Giulia; Pravettoni, Gabriella; Macis, Debora; Karam, Rachid; Gullo, Roberto Lo; Provenzano, Elena; Toesca, Antonio; Mazzocco, Ketti; Carneiro, Fátima; Seruca, Raquel; Melo, Soraia; Schmitt, Fernando; Roviello, Franco; Scalzi, Alessandra Margherita De; Intra, Mattia; Feroce, Irene; Camilli, Elisa De; Villardita, Maria Grazia; Trentin, Chiara; Lorenzi, Francesca De; Bonanni, Bernardo; Galimberti, Viviana

doi:10.1136/jmedgenet-2018-105337

Cited by 73 publications

(85 citation statements)

References 109 publications

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“…In addition, these data support previous assertions that the 2015 IGCLC clinical testing criteria are too restrictive and should be adapted. 5,7 The penetrance estimates provided in this study will allow genetics professionals to present more accurate cancer risk estimates to patients, allowing for more informed medical management decisions.…”

Section: Discussionmentioning

confidence: 99%

Comparison of CDH1 Penetrance Estimates in Clinically Ascertained Families vs Families Ascertained for Multiple Gastric Cancers

Roberts¹,

Rañola

Marshall³

et al. 2019

JAMA Oncol

133

111

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IMPORTANCE CDH1 pathogenic variants have been estimated to confer a 40% to 70% and 56% to 83% lifetime risk for gastric cancer in men and women, respectively. These are likely to be overestimates owing to ascertainment of families with multiple cases of gastric cancer. To our knowledge, there are no penetrance estimates for CDH1 without this ascertainment bias. OBJECTIVE To estimate CDH1 penetrance in a patient cohort not exclusively ascertained based on strict hereditary diffuse gastric cancer (HDGC) criteria. DESIGN, SETTING, AND PARTICIPANTS Retrospective review of 75 families found to have pathogenic variants in CDH1 through clinical ascertainment and multigene panel testing at a large commercial diagnostic laboratory from August 5, 2013, to June 30, 2018. CDH1 pathogenic variants were identified in 238 individuals from 75 families. Pedigrees from those families included cancer status for 1679 relatives. Penetrance estimates are based on 41 families for which completed pedigrees were available. MAIN OUTCOMES AND MEASURES Gastric cancer standardized incidence ratio estimates relative to Surveillance, Epidemiology, and End Results (SEER) Program incidence for pathogenic CDH1 variants from families ascertained without regard to HDGC criteria. RESULTS Among the 238 individuals with a CDH1 pathogenic variant, mean (SD) age was 49.3 (18.1) years and 63.4% were female. Ethnicity was reported for 67 of 75 (89%) families; of these 67 families, 51 (76%) reported European ancestry, whereas Asian, African, Latino, and 2 or more ancestries were reported for 4 families (6%) each. Standardized incidence ratios for gastric and breast cancer were significantly elevated above SEER incidence. Extrapolated cumulative incidence of gastric cancer at age 80 years was 42% (95% CI, 30%-56%) for men and 33% (95% CI, 21%-43%) for women with pathogenic variants in CDH1, whereas cumulative incidence of female breast cancer was estimated at 55% (95% CI, 39%-68%). International Gastric Cancer Linkage Consortium criteria were met in 25 of the 75 (33%) families; however, dispensing with the requirement of confirmation of HDGC histologic subtype, 43 (57%) would meet criteria. CONCLUSIONS AND RELEVANCE The cumulative incidence of gastric cancer for individuals with pathogenic variants in CDH1 is significantly lower than previously described. Because prophylactic gastrectomy can have bearing upon both physical and psychological health, further discussion is warranted to assess whether this surgical recommendation is appropriate for all individuals with pathogenic variants in CDH1.

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Section: Discussionmentioning

confidence: 99%

Comparison of CDH1 Penetrance Estimates in Clinically Ascertained Families vs Families Ascertained for Multiple Gastric Cancers

Roberts¹,

Rañola

Marshall³

et al. 2019

JAMA Oncol

133

111

View full text Add to dashboard Cite

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“…We propose to differentially diagnose ILC based on phenotype, AJ dysfunction and the activation of downstream effectors. Prime candidates to serve as biomarkers are established hallmarks, such as E-cadherin loss 46 and cytosolic p120-catenin 47 , or markers that correspond to E-cadherin inactivation, such as nuclear localisation of phosphorylated cofilin 3 or YAP 48 .…”

Section: Discussionmentioning

confidence: 99%

E-cadherin loss induces targetable autocrine activation of growth factor signalling in lobular breast cancer

Teo

Gómez-Cuadrado

Tenhagen

et al. 2018

Sci Rep

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Despite the fact that loss of E-cadherin is causal to the development and progression of invasive lobular carcinoma (ILC), options to treat this major breast cancer subtype are limited if tumours develop resistance to anti-oestrogen treatment regimens. This study aimed to identify clinically targetable pathways that are aberrantly active downstream of E-cadherin loss in ILC. Using a combination of reverse-phase protein array (RPPA) analyses, mRNA sequencing, conditioned medium growth assays and CRISPR/Cas9-based knock-out experiments, we demonstrate that E-cadherin loss causes increased responsiveness to autocrine growth factor receptor (GFR)-dependent activation of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/Akt signalling. Autocrine activation of GFR signalling and its downstream PI3K/Akt hub was independent of oncogenic mutations in PIK3CA, AKT1 or PTEN. Analyses of human ILC samples confirmed growth factor production and pathway activity. Pharmacological inhibition of Akt using AZD5363 or MK2206 resulted in robust inhibition of cell growth and survival of ILC cells, and impeded tumour growth in a mouse ILC model. Because E-cadherin loss evokes hypersensitisation of PI3K/Akt activation independent of oncogenic mutations in this pathway, we propose clinical intervention of PI3K/Akt in ILC based on functional E-cadherin inactivation, irrespective of activating pathway mutations.

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“…11 Conversely, surveillance recommendations for LBC endorse annual mammogram starting at age 30 years with consideration of both breast MRI with contrast and tomosynthesis. 12 There is currently insufficient evidence for the role of mastectomy in CDH1 pathogenic variant carriers, 12 but some experts suggest that prophylactic breast surgery can be offered in selected cases. 13 An important limitation is that gastric and breast cancer risks have been described, for the most part, analysing a limited number of families highly enriched with gastric cancers, as they were pre-selected according to clinical criteria of HDGC.…”

Section: Introductionmentioning

confidence: 99%

Clinical features and cancer risk in families with pathogenicCDH1variants irrespective of clinical criteria

et al. 2019

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BackgroundThe clinical phenotype of CDH1 pathogenic variant carriers has mostly been studied in families that fulfil criteria of hereditary diffuse gastric cancer (HDGC). We aimed at determining cancer phenotype and cancer risk estimation among families with CDH1 pathogenic variants not selected by HDGC clinical criteria.MethodsPatients were all consecutively identified CDH1 pathogenic variant carriers from a clinical laboratory tested with multigene panel testing and from an academic cancer genetics programme. Clinical and demographic features, cancer phenotypes and genotype–phenotype correlations were determined among CDH1 families. Age-specific cumulative cancer risks (penetrance) were calculated based on 38 families with available pedigrees.ResultsWithin the 113 CDH1 pathogenic variant probands and 476 relatives, 113 had gastric cancer, 177 breast cancer and 196 other cancers. Mean age at diagnosis was 47 for gastric and 54 for breast cancer. Forty-six per cent fulfilled criteria of HDGC. While 36% of families had both gastric and breast cancers, 36% had breast but no gastric cancers and 16% had gastric but not breast cancers. Cumulative risk of cancer by age 80 was 37.2% for gastric and 42.9% for breast cancer.ConclusionIn unselected CDH1 pathogenic variant carrier families, gastric cancer risks were lower and age at diagnosis higher than previously reported in families pre-selected for HDGC criteria. A substantial proportion of families did not present with any gastric cancers and their cancers were limited to breast. Thus, clinical criteria for CDH1 testing should be widened, including breast cancer families only, and a consideration for delayed prophylactic gastrectomy/surveillance should be evaluated.

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Hereditary lobular breast cancer with an emphasis on E-cadherin genetic defect

Cited by 73 publications

References 109 publications

Comparison of CDH1 Penetrance Estimates in Clinically Ascertained Families vs Families Ascertained for Multiple Gastric Cancers

Comparison of CDH1 Penetrance Estimates in Clinically Ascertained Families vs Families Ascertained for Multiple Gastric Cancers

E-cadherin loss induces targetable autocrine activation of growth factor signalling in lobular breast cancer

Clinical features and cancer risk in families with pathogenicCDH1variants irrespective of clinical criteria

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