HBOCS, PTEN, TP53, AR Conditions

ductal hyperplasia

(non-cancerous)

• “too many cells in the duct”

• does not cause lumps b/c it takes place inside the duct

• reversible through hormones

hyperplasia with atypia

(non-cancerous)

• ductal or lobular

• atypical ductal hyperplasia is thought to be reversible, consider “pre-precancer” (increases risk by 15%), and is used in the Gail model 

  • tamoxifen can be used for treatment 

lobular carcinoma in situ

(LCIS)

• pre-cancerous conditions

• does not develop into cancer (not a true pre-cancer)

• 15% lifetime risk to develop invasive breast cancer (in either breast) 

• treatment an include prophylactic mastectomy (extreme), close monitoring, tamoxifen (lowers risk by 56%)

ductal carcinoma in situ

(DCIS)

• non-invasive breast cancer 

  • stage 0

• 20-25% of women with untreated DCIS will develop invasive cancer within 25 years (majority of women w/ DCIS do not develop invasive disease) 

• treatment can include lumpectomy, lumpectomy & radiation, lumpectomy & radiation & tamoxifen (if hormone positive), mastectomy w/ or w/out tamoxifen (extensive disease) 

common sites of breast cancer metastases

• bone

• lung

• liver

• brain

HBOC red flags

• breast cancer at or < 50 

• ovarian cancer at any age

• male breast cancer at any age

• two primary breast cancers in an individual at any age 

• triple negative breast cancer (ER/PR/HER2-neu)

• pancreatic cancer

• metastatic prostate cancer

• AJ heritage

• previously identified BRCA mutation in the family

BRCA1 pathology associations

• increased medullary carcinomas

• decreased associated DCIS

• high grade (2/3 of BRCA1-cancers are grade III)

• hormone receptor negative

• HER2 negative 

In women with hormone receptor-positive breast cancer, hormones can spur the ______ of breast tumors. 

• growth 

• ~2/3 of sporadic breast cancers are hormone receptor-positive

• hormone blockers may be used in cases with receptor-positive breast cancers 

HER2-neu

(human epidermal growth factor receptor 2)

• proto-oncogene located on 17q

• protein exists on the surface of epithelial cells and functions in the normal cells as a receptor for a cellular growth factor

• too many copies of HER2 can result in HER2 overexpression 

  • causes cells to grow and divide more quickly

  • HER2+ breast cancer is often more aggressive

• herceptin is an antibody that stops the growth of HER2 positive cells

• 25-30% of women with breast cancer have amplification of HER2

prophylactic mastectomy

• greater than 90% breast cancer risk reduction in BRCA carrier

• total (simple) mastectomy is more effective than a subcutaneous mastectomy (one that leaves nipple and areola intact)

prophylactic oophorectomy

• ~96% ovarian cancer risk reduction in BRCA carriers

• in premenopausal women, can reduce breast cancer risk by up to 50% for both BRCA1 and BRCA2 carriers 

common sites of ovarian cancer metastases

• liver

• lungs

BRCA1/2 ovarian cancer

• very low frequency of borderline and mucinous tumors

• higher than average frequency of serous tumors

Lynch ovarian cancer

• more frequently non-serous ovarian histologies

  • clear cell, endometroid type, and mucinous 

BRCA1

• primary breast: 60-72%

• male breast: 0.2-1.2%

• epithelial ovarian: 39-58%

• pancreatic: at or <5%

• prostate: 7-26%

BRCA2

• primary breast: 55-69%

• male breast: 1.8-7.1%

• epithelial ovarian: 13-29%

• pancreatic: 5-10%

• prostate: 19-61%

• melanoma

PALB2

• primary breast: 32-53%

• male breast: 0.9%

• epithelial ovarian: 3-5%

• pancreatic: 2-5%

• prostate: emerging evidence 

Cowden syndrome

(PTEN)

• primary breast: 40-60%

• colorectal

• endometrial

• kidney

• neurological: behavioral differences like ASD

• skin/melanoma

• thyroid: particularly follicular

• penile freckling (pt. of diagnostic criteria)

• mucocutaneous lesions (pt. of diagnostic criteria)

• molecular testing is appropriate for minors given the possible early disease presentation

Li-Fraumeni syndrome

(TP53)

• primary breast: >60% 

• pancreatic: ~5%

• prostate: 25-50%

• others: soft tissue sarcoma, osteosarcoma, CNS tumor, ACC, melanoma, colorectal, and gastric 

• molecular testing is appropriate for minors given the possible early disease presentation

ataxia-telangiectasia

(ATM; autosomal recessive)

• characterized by progressive cerebellar ataxia, telangiectasias, immune defects, and a predisposition to malignancy 

• cells with AT are abnormally sensitive to ionizing radiation 

Fanconi anemia

(BRCA1, BRCA2, BRIP1, PALB2, RAD51C)

• characterized by developmental abnormalities in major organ systems, early-onset bone marrow failure, and a high predisposition to cancer

• bone marrow failure with pancytopenia often presents in the 1st decade of life

• BRCA1: characterized by developmental delay apparent from infancy, short stature, microcephaly, and coarse dysmorphic facial features

• BRCA2: associated with early-onset acute leukemia and solid tumors

• PALB2: associated with solid tumors (like medulloblastomas and Wilms tumors)

constitutional mismatch repair deficiency

(MLH1, MSH2, MSH6, PMS2, EPCAM)

• childhood cancer predisposition syndrome characterized by hematologic malignancies, brain/CNS tumors, colorectal tumors and multiple intestinal polyps, and other malignancies including embryonic tumors and rhabdomyosarcoma