Hereditary lobular breast cancer is a rare inherited cancer predisposition associated with pathogenicCDH1 (gene)germline mutations, and without apparent correlation with thehereditary diffuse gastric cancer syndrome. Research studies identified novel CDH1 germline variants in women with diagnosed lobularbreast cancer (in invasive and/orin situ histotype) and without any family history of gastric carcinoma. Firstly, in 2018Giovanni Corso et al. defined this syndrome as a new cancer predisposition and the Authors suggested additional clinical criteria to testing CDH1 in lobularbreast cancer patients.[1]In 2020, the International Gastric Cancer Linkage Consortium recognized officially that the hereditary lobularbreast cancer is a possible independent syndrome.[2] To date, there are reported about 40 families clustering for lobularbreast cancer and associated with CDH1 germline mutations but without association with diffusegastric cancer. Other recent studies demonstrated a possible correlation between hereditary lobular breast cancer and gastric cancer risk.[3][4]
In aCDH1 (gene) wild-type situation, lobules are well-organized structures characterized by the cell-cell adhesion mediated through the homophilic binding ofE-cadherin molecules on adjacent cells. In case of aCDH1 (gene) mutation theE-cadherin function can be deregulated, with a decreased cell-cell adhesion and increased cell proliferation, so-called lobular hyperplasia. Subsequently, in case of a second-hitCDH1 (gene) inactivation,E-cadherin protein expression is undetectable and, consequently, it disrupts the organization of the lobule. During this pathway, abnormal cells emerge and accumulate in the lobules giving rise to lobular intraepithelial neoplasia. Finally,cancer cells disrupt the basement membrane and invade surrounding breast tissues, a stage that is classified as invasive lobular carcinoma.[5]
Clinical criteria forgenetic testing were suggested as following: (a) bilateral lobularbreast cancer with or without family history ofbreast cancer, with age at onset <50 years; and (b) unilateral lobularbreast cancer with family history ofbreast cancer, with age at onset <45 years. In this context, it has been estimated that the frequency of E-cadherin germline mutation is a rare event, affecting about 3% of the screened population. However, there are ongoing studies to assess the penetrance and the cancer risk in the hereditary lobular breast cancer syndrome.[6]
Actions to minimize the risk are prophylactic bilateral mastectomy, flat closure without reconstruction or six-month breast surveillance. In case of important family history forbreast cancer withCDH1 (gene) germline mutations, prophylactic bilateral mastectomy with or without breast reconstruction is recommended after a careful genetic counseling. In general, as well in hereditary lobularbreast cancer associated withCDH1 (gene) mutations, in absence of family history forgastric cancer, prophylactic gastrectomy is not indicated; therefore, yearly endoscopic surveillance should be purposed. In case of breast surveillance only, annual breastmagnetic resonance imaging followed bymammography andultrasound at six months interval, are recommended.Chemoprevention with low-doseTamoxifen is also considered.[7]