1. HEREDITARY CANCER SYNDROME REVIEW
Alix d’angelo, mgc, cgc
February 13, 2017

2. SYNDROME OVERVIEW
Breast
CRC
Gyn

3. HEREDITARY BREAST CANCER

4. SYNDROMES WITH BREAST CANCER
Hereditary Breast and Ovarian Cancer syndrome (BRCA1, BRCA2)
Li-Fraumeni syndrome (p53)
Cowden syndrome (PTEN)
Peutz-Jeghers syndrome (STK11)
Hereditary Diffuse Gastric Cancer (CDH1)

5. HBOC
Jews: 1in 40 compared to 1 in 400 in general population. Dutch and Icelanders have founder mutations too
BRCA1: 185delAG, 5382insC
BRCA2: 6174delT
Also an up to 60% lifetime risk of a second primary breast cancer
Elevated melanoma risk for BRCA2, but exact risk not known. Annual skin and eye exams by specialist may be appropriate. Screening for breast cancer- annual MRI (25) and mammography (30). Prophylactic mastectomy. Male breast cancer- no formal recs, semiannual clinical breast exam, consideration of baseline mammography followed by annual mammogram if gynecomastia is present. Ovarian- US and CA-125 semiannually at 35. Prophylactic salpingo-oophorectomy. Prostate- annual PSA and exam at 40. Pancreas- imaging in research setting

6. RECOMMENDATIONS FOR WOMEN
SCREENING
SURGERY
Prophylactic bilateral mastectomy
Reduces breast cancer risk by 90-95%
Prophylactic bilateral salpingo- oophorectomy by 35-40yo or yo
Reduces ovarian cancer risk by ~85%
Reduces breast cancer risk by ~50%
Annual Mammogram and Breast MRI
MRI beginning at 25yo; mammo at 30yo
Transvaginal ultrasound and CA-125
Every 6 months beginning at 30yo
NOT PROVEN EFFECTIVE at detecting ovarian cancer at an early stage
MRI with contrast. Can start imaging earlier if there is a breast cancer <30yo in the family. Screening is in addition to clinical breast exams every 6-12 months starting at 25yo. Considerations of just salpingectomy in premenopausal women followed by postmenopausal oophorectomy.

7. HBOC- Chemoprevention
Tamoxifen
Raloxifene
Selective estrogen receptor modulator
Originally used to prevent and treat osteoporosis in postmenopausal women
Studies show may be more effective than tamoxifen in women who have not had a hysterectomy
Partial estrogen antagonist
~50% reduction in risk of breast and contralateral breast cancers
Predicted to be more helpful in women with BRCA2 mutations
Tumors are less likely to be estrogen receptor negative than BRCA1
In the initial STAR study that compared the two drugs, tamoxifen was more effective in reducing breast cancer within a given period of time. However, tamoxifen increases the risk of uterine cancer, and in the same study, about double the number of women on tamoxifen developed uterine cancer compared to those on raloxifene. Both increase the risk of blood clots, so have to take medical history into account when deciding whether chemoprevention is appropriate. Aromatase inhibitors (i.e. anastrozole) in postmenopausal women.

8. HBOC- PARP Inhibitors Resistance Mechanisms
Platinum and PARP Inhibitor Resistance Due to Overexpression of MicroRNA-622 in BRCA1-Mutant Ovarian CancerCell Rep Jan 6. pii: S (15)
Resistance Mechanisms
Secondary mutations restoring BRCA function
microRNAs regulating NHEJ repair rescues HR deficiency
PARP senses DNA damage (SSB) and recruits HR machinery. If PARP is inhibited, this doesn’t happen and genomic instability rises, resulting in synthetic lethality. Inhibition also stimulates the error-prone NHEJ pathway, also leading to increased genomic instability.

9. RECOMMENDATIONS FOR MEN
Clinical breast exams every 6-12 months beginning at 35 years-old
Consider mammogram at 40 years-old (no longer explicitly in guidelines)
PSA blood test annually beginning at 45 years-old
Recommended for BRCA2; “Consider” for BRCA1

10. Li-Fraumeni syndrome (p53)
Core Cancers
Other Cancers
Sarcomas
Breast cancer
Brain tumors
Adrenocortical carcinomas
Lung
Gastrointestinal
Others
Skin
Genitourinary
Sarcomas- mostly osteosarcomas and rhabdomyosarcomas. NOT some types like Ewing sarcomas. Breast cancer typically hormone receptor positive. Brain tumors like glios, medullos and CPCs. Breast cancer screening is similar to BRCA1/2, but perhaps at an earlier age depending on family history. Increased colonoscopy screening
Neuroblastomas
Thyroid
Leukemias and lymphomas

11. Li-Fraumeni syndrome (p53)
Classic Criteria
Proband with a sarcoma <45y
First degree relative with cancer <45y
First or second degree relative with any cancer <45y or sarcoma at any age
But, can consider testing for anyone who has an LFS spectrum tumor <45y, multiple tumors <45y or ACC or CPC at any age. If they have early onset breast cancer and are BRCA1/2 negative. Tumor-specific risk estimates don’t currently exist (except breast which is up to 80%), bc of how rare it is and the diverse spectrum of tumors.

12. RECOMMENDATIONS FOR WOMEN
SCREENING
SURGERY
Breast MRI and mammogram
Annually; MRI beginning at 20yo and mammogram beginning at 30yo
Clinical breast exams
Every 6-12 months beginning at yo
Prophylactic bilateral mastectomy

13. OTHER RECOMMENDATIONS
Annual comprehensive physical exam including neurological and dermatologic exams
Consider colonoscopy every 2-5y beginning at 25yo
Annual whole body MRI (including brain MRI)
Pediatricians should be aware of childhood cancers
AVOID radiation therapy when possible

14. PTEN- Hamartoma Tumor syndrome
Cowden syndrome
Bannayan-Riley-Ruvalcaba syndrome
Proteus syndrome
Proteus-like syndrome
Need annual physical with particular attention to skin, thyroid and breasts, urinalysis, baseline thyroid US, breast screening (annual MRI and mammography) at 30y, annual thyroid US, colonoscopy at 35 every 5 yr (or more often if polyps found), renal imaging at 40 every 1-2y. Other findings:
Macrocephaly
Derm findings (Trichilemmomas, acral keratosis, papillomatous lesions)
Intestinal polyps, fibrocytic breasts, uterine fibroids, lipomas, fibromas…
Benign goiters and thyroid adenomas (75%)

15. RECOMMENDATIONS FOR WOMEN
SCREENING
SURGERY
Mammogram and breast MRI
Annually beginning at 30-35yo
Random endometrial biopsies and/or ultrasound
Prompt response to symptoms
Prophylactic bilateral mastectomy
Reduces breast cancer risk by %
Prophylactic hysterectomy
Upon completion of childbearing

16. RECOMMENDATIONS FOR MEN AND WOMEN
Annual comprehensive exam beginning at 18yo or 5y before the earliest cancer diagnosis in the family
Annual thyroid ultrasound starting at time of diagnosis
Colonoscopy beginning at 35yo performed every 5y or more frequently if polyps are found
Consider renal ultrasound beginning at 40yo (every 1-2 years)
May need dermatologic management

17. Hereditary Diffuse Gastric Cancer (CDH1)
Men: 67-80%
Women: 56-83%
Lobular breast cancer
39-52%
Colorectal?
Prophylactic gastrectomy at 18-40y
Upper endoscopy and biopsies every 6-12 months
Breast MRI and mammography similar to BRCA1/2 mutations
Different pathology from the intestinal-type gastric cancer which is more common and related to environmental risks such as H pylori infection. Efficacy of screening for gastric cancer is not high, and individuals who underwent PTG were found to have early stage cancer despite screening. Therefore, gastrectomy is preferred.

18. MODERATE RISK GENES
Other genes with elevated but not yet defined risks:
BLM
FANCC
MRE11A
MUTYH
NF1
RAD50
RAD51C
RAD51D
XRCC2
These have known moderate risks with clinical guidelines. CHEK2 also warrants male breast screening. New literature says BRIP1 probably just ovarian cancer risk gene.

19. RECOMMENDATIONS
Anecdotally, I’ve seen testing done on families with breast and ovarian cancer come back positive for PMS2 mutation

20. RECOMMENDATIONS

21. RECOMMENDATIONS

22. SYNDROME OVERVIEW

23. Lynch syndrome/HNPCC Amsterdam II Criteria
3 or more family members with HNPCC-related cancers
1 must be a 1st degree relative of the other 2
2 successive affected generations
1 or more HNPCC-related cancer diagnosed before 50y
Exclusion of FAP

24. Lynch syndrome (HNPCC)
+ means the combined risk is 6% to age 70y. EPCAM is a regulator of PMS2 expression, so risks are similar. Different studies actually quote MSH6’s endometrial risk as higher (more like 60%). Colonoscopy 1-2yr (may be less if no polyps are found) at for MLH1/MSH2, got MSH6/PMS2/EPCAM, pancreas surveillance and, prophylactic hysterectomy and BSO or screening

25. RECOMMENDATIONS FOR MEN AND WOMEN
Colorectal cancer
Colonoscopy every 1-2y beginning at 20-25yo
Gastric and small bowel cancer
Consider EGD with extended duodenoscopy every 3-5y beginning at age 30-35yo
Only in selected individuals/families or those of Asian descent
Urothelial cancer
Consider annual urinalysis beginning at 30-35yo
CNS cancers
Consider annual neurologic exam beginning at 25-30yo
Aspirin use may decrease CRC risk. No guidelines for pancreatic cancer risk, but can consider research protocols with EUS and MRCP.

26. RECOMMENDATIONS FOR WOMEN
SCREENING
SURGERY
Endometrial biopsies and transvaginal ultrasound
Not proven effective
Transvaginal ultrasound and CA- 125
Prophylactic hysterectomy
Consider upon completion of childbearing
Prophylactic bilateral salpingo- oophorectomy

27. CHEMOTHERAPY and MSI Microsatellite instability (MSI-H)
90% of Lynch syndrome related tumors (data on colon and endometrial cancers)
10-15% of sporadic colorectal tumors
Data shows stage II MSI-H tumors have better prognosis
5-FU use is contraindicated in stage II MSI-H tumors
5-10% false negative rate for Lynch with MSI and IHC testing.

28. Familial Adenomatous Polyposis (FAP)
Mutations in APC
100s-1000s of colon polyps
10-99 for attenuated form (AFAP)
Nearly 100% risk of CRC in classic form
~70% risk in AFAP
Elevated risk for thyroid (1-12%), gastric, small bowel (4-12%)and other GI cancers
Osteomas, supernumerary teeth, desmoid tumors, CHRPE
CHRPE= congenital hypertrophy of the retinal pigment epithelium. Mean age of cancer diagnosis is 39y. Certain variants called Gardner (epidermoid cysts, desmoid tumors) and Turcot that also have an increased risk of CNS tumors like Medulloblastoma. Genotype-phenotype correlations exist. Colonoscopy at 10-15y, colectomy and upper endoscopy, thyroid exam

29. COLORECTAL RECOMMENDATIONS
SCREENING
SURGERY
Annual flex sigmoidoscopy or colonoscopy beginning at yo
Can continue until polyp burden becomes unmanageable
Colectomy or proctocolectomy (dependent on several factors)
Still need screening after surgery
Colectomy  endoscopic eval of rectum every 6-12 mos

30. EXTRACOLONIC RECOMMENDATIONS

31. MUTYH- associated polyposis
Autosomal recessive inheritance
Similar presentation to AFAP
10-99 polyps
43-99% lifetime risk of CRC
Similar extracolonic features as FAP but not completely defined
Carriers may have increased risk for late-onset CRC
Also, a new gene called NTHL1 that is autosomal recessive and similar presentations

32. RECOMMENDATIONS

33. Peutz-Jeghers syndrome (STK11)
Clinical Diagnostic Criteria
≥2 PJS-type hamartomatous polyps
Characteristic mucocutaneous pigmentation and a family history of PJS
Any number of PJS polyps and a family history of PJS
Any number of PJS polyps and characteristic mucocutaeous pigmentation
Pigmentation on mouth, lips, nose, eyes, genitalia or fingers

34. Peutz-Jeghers syndrome

35. Juvenile Polyposis syndrome
Specific histology
polyps in lifetime
Lifetime CRC risk: 68%
Lifetime gastric cancer risk: 21%
Pancreas cancer?
Hamartomatous mucus-filled cystic glands among other features and are missing the muscle fibers and proliferative characteristics of adenomas. JPS can be clinically diagnosed if 5+ polyps are in the colon, many are anywhere in the GI tract, or if there are any number of polyps and a family history. Need colonoscopies and upper endoscopies annually at 15y, and CBC to monitor for bleeding and anemia.

36. JPS/Hereditary Hemorrhagic Telangectasia
Only with SMAD4 mutations, NOT BMPR1A
Mucocutaneous telangectasias
Vascular malformations
Pulmonary, GI, hepatic and cerebral AVMs
Need pulse oximetry every 1-2 yrs in first decade,
contrast echocardiogram every 5 yrs thereafter;
brain MRI after puberty
Arteriovenous malformations

37. RECOMMENDATIONS

38. RECOMMENDATIONS

39. GENETIC TESTING Single Gene Phenotype Panel Pan-Cancer Panel
Still important when clinical diagnosis can be made
Decreases risk of VUS in unrelated gene
Will NOT pick up unusual results
Only include genes related to specific cancer
Different sizes
Will pick up some unexpected results
Increases risk of VUS
Includes all genes related to hereditary cancer
# depends on lab
Will pick up unexpected results
Increases risk of VUS

40. CHEK2 deletion 2 d. 62y 73y 53y dx. triple neg. breast ca @ 53y 30s
dx. “ovarian 20s
34y
dx. triple neg. breast 34y
31y

41. BRCA2 + hx of colon cancer hx of pancreas cancer 60s + tob
hx of colon polyps and thyroid cancer
uterine fibroids
breast cancer 40s
hx of thyroid disease
breast cancer 30s
hx of thyroid disease

42. MSH2 + 3 d. 82y dx. Ovarian ca @ 45y dx. Bladder and stomach ca @ 77y
MVA
85y
d. 65 heart disease
d. 67y
dx. ovarian 35y
dx. breast ca 45y
hx of colon polyps and 38y
hx of colon polyps
TAH-BSO?
d. 47y surgical complications
d. 23y
MVA
Mother originally had negative BRCA1/2 sequencing and BART. Several years later, the daughter presented for hx of breast cancer. My colleague recommended that the mother have updated panel testing. 3
34y
32y
20s
42y

43. BRCA1+ and ATM+ 5 1 maternal cousin with breast ca @ 55y (d. 57y)
dx. breast 51y
70y
dx. breast
50y
75y
dx. prostate 65y
1 maternal cousin with breast 55y (d. 57y)
1 maternal cousin with “breast 20y (now 40y)
30s
40y
18y
14y

44. Genetic Counseling Process
Review family and medical history
Use models for risk assessment when appropriate (i.e. Tyrer-Cusick)
Decide on appropriate testing
Discuss benefits and risks with patient
Follow-up appointment to discuss results and management recommendations

45. REFERRAL CRITERIA- breast cancer dx
A known mutation in a cancer susceptibility gene within the family
Early-onset breast cancer
Triple negative breast cancer ≤60y
Two breast cancer primaries in a single individual
Breast cancer at any age AND
≥1 close blood relative with breast cancer ≤50y or
≥1 close blood relative with invasive ovarian cancer at any age or
≥2 close blood relatives with breast cancer and/or pancreas cancer at any age
From a population at increased risk
Personal and/or family history of three or more of the following
Pancreas cancer, prostate cancer (Gleason score ≥7, sarcoma, adrenocortical carcinoma, brain tumors, endometrial cancer, thyroid cancer, dermatologic manifestations, macrocephaly, hamartomatous polyps of the GI tract, diffuse gastric cancer
Invasive ovarian cancer
Male breast cancer

46. REFERRAL CRITERIA – no cancer dx
Family history of:
A known mutation in a cancer susceptibility gene within the family
≥2 breast cancer primaries in a single individual
≥2 individuals with breast cancer primaries on the same side of the family
≥1 invasive ovarian cancer primary
First or second degree relative with breast cancer ≤45y
Personal and/or family history of three or more of the following:
Pancreas cancer, prostate cancer (Gleason score ≥7, sarcoma, adrenocortical carcinoma, brain tumors, endometrial cancer, thyroid cancer, dermatologic manifestations, macrocephaly, hamartomatous polyps of the GI tract, diffuse gastric cancer
Male breast cancer

47. REFERRAL CRITERIA- CRC
Individual meets revised Bethesda criteria
Individual from a family meeting Amsterdam Criteria
Individual with >10 adenomas
Individual with multiple GI hamartomatous polyps or serrated polyps
Individual from a family with a known hereditary CRC syndrome (mutation known or not)
Individual with a desmoid tumor, variant of papillary thyroid cancer or hepatoblastoma
Bethesda- CRC dx <50yrs, presence of synchronous or metachronous Lynch-related tumors regardless of age, CRC with MSI-H histology dx at <60yrs, CRC dx in a patient with 1st degree relatives with a Lynch-related cancer, or CRC dx in a patient with multiple 1st or 2nd degree relatives with Lynch-related tumors regardless of age

48. CONTACT INFO
Alix D’Angelo, MGC, CGC
Office: CSRB 652
Phone: (504)
Fax: (504)