Hereditary lobular breast cancer is a rare inherited cancer predisposition associated with pathogenic CDH1 (gene)

germline mutation A germline mutation, or germinal mutation, is any detectable variation within germ cells (cells that, when fully developed, become sperm and Egg cell, ova). Mutations in these cells are the only mutations that can be passed on to offspring, when e ...

s, and without apparent correlation with the hereditary diffuse gastric cancer syndrome. Research studies identified novel CDH1 germline variants in women with diagnosed lobular

breast cancer Breast cancer is a cancer that develops from breast tissue. Signs of breast cancer may include a Breast lump, lump in the breast, a change in breast shape, dimpling of the skin, Milk-rejection sign, milk rejection, fluid coming from the nipp ...

(in invasive and/or ''in situ'' histotype) and without any family history of gastric carcinoma. Firstly, in 2018 Giovanni Corso et al. defined this syndrome as a new cancer predisposition and the Authors suggested additional clinical criteria to testing CDH1 in lobular

patients. In 2020, the International Gastric Cancer Linkage Consortium recognized officially that the hereditary lobular

is a possible independent syndrome. To date, there are reported about 40 families clustering for lobular

and associated with CDH1 germline mutations but without association with diffuse gastric cancer. Other recent studies demonstrated a possible correlation between hereditary lobular breast cancer and gastric cancer risk.

CDH1 inactivation in lobular breast cancer

In a CDH1 (gene) wild-type situation, lobules are well-organized structures characterized by the cell-cell adhesion mediated through the homophilic binding of

E-cadherin Cadherin-1 or Epithelial cadherin (E-cadherin), is a protein that in humans is encoded by the ''CDH1'' gene (not to be confused with the APC/C activator protein CDH1). Mutations are correlated with Hereditary diffuse gastric cancer, gastric, Here ...

molecules on adjacent cells. In case of a CDH1 (gene) mutation the

function can be deregulated, with a decreased cell-cell adhesion and increased cell proliferation, so-called lobular hyperplasia. Subsequently, in case of a second-hit CDH1 (gene) inactivation,

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 Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...

cells disrupt the basement membrane and invade surrounding breast tissues, a stage that is classified as invasive lobular carcinoma.

Criteria for genetic screening

Clinical criteria for

genetic testing Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, or ...

were suggested as following: (a) bilateral lobular

with or without family history of

, with age at onset <50 years; and (b) unilateral lobular

with family history of

, 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.

Measures for risk management

Actions to minimize the risk are prophylactic bilateral mastectomy, flat closure without reconstruction or six-month breast surveillance. In case of important family history for

with CDH1 (gene) germline mutations, prophylactic bilateral mastectomy with or without breast reconstruction is recommended after a careful genetic counseling. In general, as well in hereditary lobular

associated with CDH1 (gene) mutations, in absence of family history for gastric cancer, prophylactic gastrectomy is not indicated; therefore, yearly endoscopic surveillance should be purposed. In case of breast surveillance only, annual breast

magnetic resonance imaging Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to generate pictures of the anatomy and the physiological processes inside the body. MRI scanners use strong magnetic fields, magnetic field gradients, and ...

followed by mammography and

ultrasound Ultrasound is sound with frequency, frequencies greater than 20 Hertz, kilohertz. This frequency is the approximate upper audible hearing range, limit of human hearing in healthy young adults. The physical principles of acoustic waves apply ...

at six months interval, are recommended. Chemoprevention with low-dose

Tamoxifen Tamoxifen, sold under the brand name Nolvadex among others, is a selective estrogen receptor modulator used to prevent breast cancer in women and men. It is also being studied for other types of cancer. It has been used for Albright syndrome ...

is also considered.

References

{{Breast cancer types Breast cancer