Ackerman breast carcinoma general features and genes with Hereditary breast cancer

Carcinoma

General Features

Age

The large majority of breast cancers are detected during the postmenopausal years.

However, breast cancer can develop at any age, from childhood to old age.

Incidence

Breast carcinoma is the most common malignant tumor and the second most common cause of carcinoma death in women, with more than 1.7 million cases occurring worldwide annually.

In the United States, there has been a sharp increase in the detection of breast carcinoma, largely due to the widespread use of mammography.

Risk Factors

Several risk factors for the development of breast carcinoma have been established, whereas many others remain questionable. It has been hypothesized that the common denominator for most of these factors is strong and/or prolonged estrogen stimulation operating on a genetically susceptible background.

1. Country of birth.

high in North America and Northern Europe (92 new cases per 100,000 women/year),
intermediate in southern European and Latin American countries,
low in most Asian and African countries

2. Family history.

first-degree relative with breast carcinoma have a risk 2 or 3 times that of the general population,
risk further increased if the

relative was affected at an early age and/or
had bilateral disease.

3. Menstrual and reproductive history.

Increased risk is with

carcinoma is rare in women

early menarche,
nulliparity,
late age at first birth, and
late menopause.
postmenopausal women with a hyperandrogenic plasma hormone profile

undergone bilateral oophorectomy;
risk-reducing salpingooophorectomy <35 years of age reduces the risk by about one half.
Younger age at first pregnancy
breastfed for at least 4 month

there is a dual effect associated with pregnancy:

an early transient increase in breast cancer risk
followed by a prolonged protective effect

4. Intraductal proliferative lesions.

The relationship between intraductal proliferative lesions without atypia and breast carcinoma has been discussed in earlier sections.

5. Exogenous estrogens.

risk appears greater with

longer duration of use/current use and
use of estrogen combined with progestins compared with use of estrogen alone.

6. Contraceptive agents.

no increased risk, or at
most a very low increase among young long-term users.271

7. Ionizing radiation. if this exposure occurred at the time of breast development, such as in

young women receiving mantle irradiation for Hodgkin disease
atomic bomb survivors who were <10 years of age at exposure.272–274

8. Breast augmentation.

Breast implants do not result in an increase in breast cancer risk.

9. Others.

association between breast carcinoma and meningioma has been repeatedly noted, with the even more peculiar observation that sometimes the breast carcinoma is found to metastasize to the meningioma.

Genetic Predisposition

5%–10% of all breast cancers are familial.

BRCA

discovery of two high-penetrance susceptibility genes which, when affected by germline mutations, are associated with a high lifetime risk for development of breast cancer, as well as some other cancers, in particular ovarian cancer.

16% of familial cancers are due to

BRCA1, located on 17q21, and
BRCA2, located on 13q12.3 (Table 36.3).

Mutations in 2% of the Ashkenazi Jewish population;

Br CA risk among carriers is up to 70%–80% by age of 70yrs

positive test for the mutation close follow-up or bilateral prophylactic mastectomy.

functions of BRCA1-encoded protein	BRCA2
repair of DNA damage through homologous recombination, cell cycle checkpoint control, ubiquitylation, chromatin remodeling, and DNA decatenation.	DNA repair, cytokinesis, and meiosis.
both BRCA1 and BRCA2 are essential for accurate repair of DNA double-strand breaks through homologous recombination
basal-like gene expression	heterogeneous group
high grade, mitotically very active, with a syncytial growth pattern, pushing margins, confluent necrosis	without specific morphology
triple negative	positive for hormone receptors

novel therapies

synthetic lethality

poly-adenosine diphosphate (ADP)-ribose polymerase (PARP) inhibitors which block repair of DNA damage via alternate pathways in tumor cells deficient in DNA repair through homologous recombination—

several other genes

(e.g., CHEK2 (Checkpoint kinase 2) is a tumor suppressor gene that encodes the protein CHK2, a serine-threonine kinase. CHK2 is involved in DNA repair,

CDH1 E-cadherin

RAD50, protein involved in DNA double-strand break repair

PALB2 Partner and localizer of BRCA2, also known as PALB2 or FANCN)

confer a low to moderate increased risk for the development of breast cancer.

Recombinational repair of DNA double-strand damage - some key steps.

ATM (ATM) is a protein kinase that is recruited and activated by DNA double-strand breaks.

DNA double-strand damages also activate the Fanconi anemia core complex (FANCA/B/C/E/F/G/L/M).

ATM activates (phosphorylates) CHEK2 and FANCD2

CHEK2 phosphorylates BRCA1

The FA core complex monoubiquitinates the downstream targets FANCD2 and FANCI.

Ubiquinated FANCD2 complexes with BRCA1 and RAD51

The PALB2 protein acts as a hub,[13] bringing together BRCA1, BRCA2 and RAD51 at the site of a DNA double-strand break, and also binds to RAD51C, a member of the RAD51 paralog complex BCDX2 (RAD51B-RAD51C-RAD51D-XRCC2)
The BCDX2 complex is responsible for RAD51 recruitment or stabilization at damage sites.
RAD51 plays a major role in homologous recombinational repair of DNA during double strand break repair.
In this process, an ATP dependent DNA strand exchange takes place in which a single strand invades base-paired strands of homologous DNA molecules. RAD51 is involved in the search for homology and strand pairing stages of the process.

Hereditary breast cancer in of multiple cancer syndromes,

such as

Lynch syndrome (e.g., MLH1),
Li–Fraumeni syndrome (TP53),
ataxia–telangiectasia syndrome (ATM), and
Cowden syndrome (PTEN),

Location

33% in the ✅upper outer quadrant,
9% in the upper inner quadrant,
6% in the lower outer quadrant,
5% in the lower inner quadrant,
7% in the central region (within 1 cm of the areola), and
40% occur in overlapping quadrants (or location not specified).296

more frequent in the ✅left breast than in the right (“laterality ratio”).

mouse models indicate that there may be baseline differences in gene expression that are left-right independently regulated during pubertal development, which may play a role in this observation.

Multicentricity and Multifocality

higher incidence of multicentricity and multifocality is reported in patients undergoing preoperative MRI and mastectomy
✅single largest tumor diameter, as is recommended by the AJCC TNM staging system, even in patients with multiple tumor foci, is an accurate method for staging patients

Theoretically, ✅multiple breast carcinomas can (Clonal studies support both)

result from either intramammary spread of a single lesion or
from independent events.

❇️Multicentricity	Multifocality
carcinoma in a breast quadrant other than the one containing the dominant mass, was described as early as 1920 and later reported by others.	additional foci of carcinoma in the same quadrant as the index carcinoma.
common in lobular than in ductal	ductal carcinomas that had an extensive intraductal component
younger with larger tumors, to have LVI lymphovascular space invasion and positive lymph nodes.	ER, PR, and HER2 positive.

The chance of contralateral breast carcinoma is:

about 1% per year and is even
higher if there is a family history of breast carcinoma and
in cases of invasive lobular carcinoma.

The use of ❇️adjuvant estrogen blockade with or without chemotherapy significantly decreases the risk of metachronous contralateral breast carcinoma.

Annual screening mammography is the current surveillance

if lifetime risk is > 20%–25%, in which case adjunctive screening with MRI is recommended.

Synchronous bilateral invasive breast carcinomas are being detected more frequently because of the use of MRI in the work-up for surgical planning purposes.

An unfortunate corollary of this practice is the rising number of contralateral mastectomies being performed in patients found to have benign or atypical (nonmalignant) pathology on core needle biopsies of areas of radiologic concern in the contralateral breast.308,309

No significant difference in overall survival has been reported for patients with bilateral breast carcinoma when appropriately matched to women with unilateral breast cancer.310