Workshop Information / Case Studies

How to Schedule a Workshop
Calendar of Upcoming Workshops
    (This section is currently under development.)
CASE STUDIES
• Case 1: Breast Cancer
• Case 2: Hereditary Breast and Ovarian Cancer
• Case 3: Hereditary Nonpolyposis Colon Cancer
• Case 4: Familial Adenomatous Polyposis
• Case 5: Multiple Endocrine Neoplasia Type IIB
• Case 6: Li-Fraumeni
• Case 7: Neurofibromatosis

HOW TO SCHEDULE A WORKSHOP

Workshops are designed to provide education to healthcare practitioners about cancer risk assessment, genetic predisposition testing and potential interventions for the individual or family at high risk for cancer through the use of an interactive workshop format. Workshops can be arranged into teaching modules to focus on specific cancer syndromes of interest.

Contact us by calling 732-235-9374 to discuss available workshop topics and to arrange for an educational workshop for your hospital or practice.

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CASE STUDIES

• Family history?
• Who in the family would you ask about?
• What information would you want to know about each family member?
• What types of cancer would you be most concerned about?

How could you confirm the diagnosis in the affected patient?

Faculty teaching points:
(1) A family history needs to be taken- ideally a three-generation pedigree should be taken, including children, siblings, nieces and nephews, parents, aunts and uncles, cousins and grandparents on both the maternal AND paternal sides of the family. Ethnicity and race are also important because of the higher incidence o f certain cancer predisposing mutations in specific populations. Participants should inquire about all cancers in the family. It is also important to inquire about precursor lesions, such as colorectal adenomas or dysplastic nevi. If relatives have cancer, you want ask their age of diagnosis and, if applicable, whether the cancer was unilateral or bilateral. You want to ask for every family member's current age, or age of death. For deceased family members, knowing the cause of death can sometimes be helpful, even if it was not cancer related. Additional diagnoses of breast and/or ovarian cancer in the family would raise the suspicion of a hereditary breast/ovarian cancer syndrome.

(2) Personal medical history should be focused on risk factors for breast cancer, such as menstrual and pregnancy histories, use of female hormones (oral contraceptives, HRT), biopsies, and current screening practices.

(3) Diagnoses should ideally be confirmed by medical record review and (if possible) review of pathology slides. If records are not available, a death certificate can also be used as a source of documentation.

A pedigree was obtained and you see that there are two individuals with breast cancer diagnoses- Sara's mother at age 59 years and Sara's maternal aunt at age 61 years. Both are still living and ethnic background is Irish and English.

Is this family history suggestive of a cancer susceptibility syndrome?

• How could this be confirmed quantitatively?

What would you tell Sara about her own lifetime risks for developing breast or ovarian cancer?

• Can her risk to develop breast cancer be quantified?

Based on your risk assessment, what would you tell Sara about her own medical management options for the future?

• Screening
• Chemoprevention
• Prophylactic surgery

Faculty teaching points:
(1) This family history is not suggestive of a breast/ovarian susceptibility syndrome. The chance for Sara's mother to have a mutation in BRCA1 or BRCA2 is low. This could be confirmed using one of the available models to quantitatively predict BRCA1/2 mutation status (Couch, Shattuck-Eidens, Myriad, BRCAPRO). However, Sara is still at low to moderate increased risk for breast cancer because of familial clustering. To estimate Sara's chance to develop breast cancer, one could use the Gail, Claus, or BRCAPRO models.

It is important to note that if a family history is suggestive of a BRCA1 or BRCA2 mutation, it is not appropriate to use the Gail or Claus models to estimate breast cancer risk. Gail model takes into account a patient's age, reproductive history, history of breast disease and diagnoses ONLY in first-degree female relatives. Claus model considers all relatives (maternal and paternal) with breast cancer diagnoses along with ages of onset but does not take into account history of ovarian cancer.

(2) Based on Sara's moderate risk for the future development of breast cancer, a discussion regarding screening options, including monthly self breast exams, clinical breast exams every six months to a year, and annual mammography would be appropriate). Chemoprevention strategies, such as the use of tamoxifen, may be an attractive option for this patient. Prophylactic surgery would not be appropriate for this patient.

Sara returns to your office six months later and states that she read about gene testing in a magazine and wanted to have gene testing for breast cancer. She is extremely anxious about developing cancer herself and heard about a neighbor who had prophylactic mastectomies because of her family history of breast cancer. Sara states she is done with childbearing and breast feeding and would like to have this surgery if she has the gene.

• What genetic testing, if any, would you offer to Sara at this point?
• Would testing of her mother or aunt be appropriate now? Why or why not?
• What would you tell Sara about prophylactic mastectomy?
• How might you help Sara with her anxiety over this diagnosis in her family?

Faculty teaching points:
(1) Genetic testing for BRCA1/2 is still not indicated for Sara or her relatives based on this family history. With education regarding the low chance of getting informative results for her family, and the significant cost (currently Myriad Genetics charges $2680 for full sequencing), many patients decide on their own not to have testing. Although most insurance companies cover this testing for high-risk families, based on this family history insurance may not cover the testing. Additionally, discussion regarding the meaning of positive and negative results, psychosocial impact of results, and genetic discrimination may help Sara to understand why this testing is not routinely offered to families at this level of risk.

(2) The surgical risks and benefits of mastectomies should be explained to Sara, emphasizing her own relatively low risks for developing breast cancer. Additionally, Sara should be told that even bilateral prophylactic mastectomies do not reduce the risk of breast cancer to zero.

(3) Healthcare professional might acknowledge Sara's anxiety and consider counseling with a trained therapist (possibly in conjunction with a high risk center and trained genetic counselor). In addition, a thorough review of Sara's risk factors, including her calculated risks may benefit Sara in understanding how her risk is quantified.

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Case 2: Hereditary Breast and Ovarian Cancer:
Andrea Cohen is a 46-year-old female of Ashkenazi Jewish ancestry. She comes to discuss possible genetic testing because of a family history of bilateral breast and ovarian cancer in her paternal aunt and breast and fallopian tube cancer in her father's mother's sister's daughter. Her aunt was diagnosed with breast cancer at age 51 years and ovarian cancer at age 52 years.

• What additional family history information would be helpful?

Faculty teaching points:
(1) A family history needs to be taken- ideally a three-generation pedigree should be taken, including children, siblings, nieces and nephews, parents, aunts and uncles, cousins and grandparents on both the maternal AND paternal sides of the family. Ethnicity and race are also important because of the higher incidence o f certain cancer predisposing mutations in specific populations. Participants should inquire about all cancers in the family. It is also important to inquire about precursor lesions, such as colorectal adenomas or dysplastic nevi. If relatives have cancer, you want ask their age of diagnosis and, if applicable, whether the cancer was unilateral or bilateral. You want to ask for every family member's current age, or age of death. For deceased family members, knowing the cause of death can sometimes be helpful, even if it was not cancer related. Additional diagnoses of breast and/or ovarian cancer in the family would raise the suspicion of a hereditary breast/ovarian cancer syndrome.

(2) Personal medical history should be focused on risk factors for breast cancer, such as menstrual and pregnancy histories, use of female hormones (oral contraceptives, HRT), biopsies, and current screening practices.

(3) Diagnoses should ideally be confirmed by medical record review and (if possible) review of pathology slides. If records are not available, a death certificate can also be used as a source of documentation.

The above pedigree was constructed and diagnoses were confirmed through review of medical records made available by family members.

• What specific genes or gene mutations would you consider in light of this family history?
• Who would be the best person to test in this family if all individuals were available and willing to be tested?

Faculty teaching points:
(1) The common BRCA1 and BRCA2 mutations in the Ashkenazi population should be the number one consideration.

(2) Testing an affected person is the most appropriate step when feasible.

In the meantime, Andrea's paternal aunt underwent DNA testing for the common Ashkenazi Jewish mutations in BRCA1 and BRCA2 and was found to have one of the BRCA1 mutations - known as 5382insC.

• What are Andrea's risks of carrying the 5382insC mutation?
• What testing would you consider offering to Andrea based upon the above pedigree?

Faculty teaching points:
(1) Andrea's risks for carrying the same mutation as her aunt is 1 in 4.

(2) Although most participants might offer the 5382insC mutation alone, if one looks at the maternal family history and the ethnic background (as well as low cost of doing all mutations) it makes sense to do all three.

You sit down with Andrea to discuss DNA testing. Remembering that Andrea herself is currently unaffected, you explore with her some of the implications of testing. She tells you she does not speak to her mother and she and her sister "barely talk". She wishes to be tested for her own information as well as for her daughters (ages 6 years and 2 years).

• What are the possible risks and benefits of testing for Andrea?
• With Andrea's family dynamics, what issues about informing family members should be explored?
• How would your recommendations change in terms of surveillance if she tested positive or negative for the 5382insC mutation?
• At what point would you consider testing of her minor children for the mutation if Andrea tested positive?

Faculty teaching points:
(1) Discuss concerns about insurance discrimination, privacy of test results, etc.

(2) It would be optimal for the participants to discuss referral to a genetic counselor and/or high risk center.

(3) Breast self exam and mammography should be discussed for a positive or negative result whereas chemoprevention and prophylactic surgery (mastectomy and/or oophorectomy) should be mentioned in addition for a positive result.

(4) Minor children should NEVER be tested for BRCA mutations.

Andrea decides to have the mutation testing based upon her aunt's DNA result. The lab tests for all three common Ashkenazi mutations and although Andrea does not carry the BRCA1 mutation identified in her aunt, she is found instead to carry a BRCA2 mutation known as 6174delT.

• Are these results surprising? Why or why not?
• If there was no identified mutation in the family because there were no living affected family members, what testing would have been offered to Andrea?
• If Andrea's aunt and mother were tested for the common Ashkenazi mutations and were found to be negative would you have offered any other molecular studies? Why or why not?

Faculty teaching points:
(1) Not surprising with the additional family history - don't be lulled into complacency.

(2) If there was no mutation identified in the family (because there were no living affected family members)It is still ideal to test an affected individual and tissue blocks could possibly be used to do Ashkenazi mutations. Or, in this same scenario, Andrea could be tested herself for the Ashkenazi mutations, but a negative results would be of limited value.

(3) If Andrea's aunt and mother were negative for the Ashkenazi mutations, it still might be worthwhile to do complete BRCA1 and BRCA2 sequencing on one or both of them for optimal information.

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Case 3: Hereditary Non-Polyposis Colon Cancer Patient Summary:
Christina Perez, an obese 23 year old Hispanic woman, began a volitional weight loss program in December of 1993. Initially delighted over a significant reduction in her weight of 80 pounds, she chooses to embark on a maintenance program. To her surprise, she continues to lose weight with her total loss being greater than 100 pounds. Concurrently, she develops bloody diarrhea and is diagnosed with ulcerative colitis by barium enema.

• What is the differential diagnosis of bloody diarrhea in a 23-year-old woman?
• Has the work-up this far been appropriate given her symptoms?
• Is there additional information you would like to ascertain about Christina's history?

Faculty teaching points:
(1) Differential for bloody diarrhea includes colorectal cancer, ulcerative colitis, and Crohn's disease.

(2) Work-up should include a barium enema and colonoscopy.

(3) A family history needs to be taken- ideally a three-generation pedigree should be taken, including children, siblings, nieces and nephews, parents, aunts and uncles, cousins and grandparents on both the maternal AND paternal sides of the family. Ethnicity and race are also important because of the higher incidence o f certain cancer predisposing mutations in specific populations. Participants should inquire about all cancers in the family. It is also important to inquire about precursor lesions, such as colorectal adenomas or dysplastic nevi. If relatives have cancer, you want ask their age of diagnosis and, if applicable, whether the cancer was unilateral or bilateral. You want to ask for every family member's current age, or age of death. For deceased family members, knowing the cause of death can sometimes be helpful, even if it was not cancer related.

(3) Ask about other medical problems, and medications, including what she is doing for weight loss.

Christina continues to have intermittent bloody stools over the next six months and ultimately presents to her local emergency room after she develops "gluteal swelling." While giving her history of weight loss and intermittent bloody stools, she discloses that her mother had colon cancer at age 39.

• What is the differential diagnosis in light of this additional information? What is the appropriate work-up?
• What is the relative risk to first degree relatives of individuals with early onset colon cancer?

Faculty teaching points:
(1) Obtain mother's pathology reports. Comprehensive work-up for Christina regarding colon cancer should be performed, including ultrasound and CT scan.

(2) The lifetime risk of colorectal cancer in relatives of patients with colorectal cancer <45 is 1 in 10, compared with the general population risk of 1 in 50.

Christina's work-up includes a sonogram, which reveals a large rectal mass. This is confirmed by CT scan. During her evaluation, Christina's mother volunteers that not only did she have colon cancer at age 39, but her brother (Christina's uncle) had colon cancer in his early 50's. She also recalls her mother dying of a "female" cancer.

• Based on the pedigree, what is the most likely mode of inheritance, if this is an inherited cancer syndrome?
• If this is an inherited cancer syndrome, what would Christina's risk be of having inherited the susceptibility?
• What is the differential diagnosis of inherited colon cancer syndromes?
• What do you want to know about the grandmother's female cancer?

Faculty teaching points:
(1) Based on the family history, this form of inheritance is consistent with autosomal dominant transmission.

(2) If this is an inherited cancer syndrome, based on her mother's cancer diagnosis, Christina's risk of inherited the cancer susceptibility would be 50%.

(3) The differential includes HNPCC, FAP, and familial colon cancer.

(4) Request pathology reports on uncle and grandmother. If grandmother had uterine cancer, this would be consistent with a diagnosis of HNPCC.

Colonoscopy and biopsy confirm a rectal adenocarcinoma. In addition, Christina's mother obtains her mother's medical records and discovers that she died of metastatic uterine cancer.

• Which colon cancer syndrome seems most likely?
• What are features of the above syndrome? Is this family consistent with this diagnosis?
• Does the diagnosis of this syndrome affect your plans for management (i.e., surgical options, treatment, and surveillance)?
• Do you want to get more information about the family (i.e. identify those at risk)?

Faculty teaching points:
(1) Consider the family history and clinical guidelines for HNPCC and constellation of tumors; including Amsterdam, Amsterdam #2 and Bethesda criteria.

(2) Reiterate importance of full pedigree including three generations to identify those at risk.

(3) Discuss Christina's options for surgical options and post surgical management.

(4) Discuss benefits and limitations of colonoscopy versus flex sigmoidoscopy based on each cancer predisposition syndrome.

Christina undergoes an abdominoperineal resection with placement of a permanent colostomy. She is told that the tumor is locally extensive with positive lymph node involvement. She is told that she will require chemotherapy.

In addition to concern about Christina, her mother is now very concerned that there may be a "gene" responsible for the early onset cancer. Although she realizes that Christina cannot be cured of her disease, she has a younger daughter for whom she is concerned. She states that the younger daughter is unwilling to acknowledge her sister's diagnosis.

• Is genetic testing appropriate for this family?
• What family members would you initially test?
• What would be the benefits, risks, and limits to testing for different family members?
• What are the options if the family is not interested in genetic testing?

Faculty teaching points:
(1) Genetic testing is appropriate for this family. Based on family history, this family meets the clinical criteria associated with HNPCC. Genetic testing could provide a definitive diagnosis for this family, and allow for testing of unaffected family members to help quantify individual risk. Optimally genetic testing should begin with an affected family member, which in this case would be either Christina or her mother. If the family is not interested in pursuing genetic testing, screening recommendations for family members would include colonoscopies and medical management assuming a hereditary cancer predisposition syndrome in the family. Prior to the advent of genetic testing, clinical criteria was the sole method of identifying cancer predisposition syndromes within a family. However all family members needed to be considered at risk since there was no method of determining who had inherited the familial predisposition and who had not. Other options for testing for HNPCC include microsatellite instability testing and immunohistochemistry staining of a tumor specimen. These tests can be suggestive of the presence of HNPCC syndrome within an affected individual.

(2) Risks, benefits and limitations of pursuing genetic testing needs to be considered for each family member individually. Genetic testing should not be offered to an unaffected family member unless there is a known genetic mutation in the family or unless there are no living affected family members to test (in which case negative genetic test results are uninformative).

(3) Another option for this family to consider is DNA banking if they are not ready (psychologically, emotionally, financially, etc) to pursue genetic testing at this time.

After a thorough discussion with Marcie, a genetic counselor, Christina's mother wishes to have the family tested for the gene. She feels Christina is too ill to consider participating in this process. Her mother decides to undergo the testing. The first step in testing for HNPCC (studying microsatellite instability in tumor tissues) is performed on archived tissue from Christina's mother and is suggestive of HNPCC. Subsequent genetic testing on Christina's mother is positive for a germline mutation in a mismatch repair gene.

• What is Christina's sister's risk of having this mutation?
• What options are available to the sister?
• What screening and intervention are available to the mother?

Faculty teaching points:
(1) HNPCC is inherited in an autosomal dominant pattern. Based on the family history, one would assume Christina has the same mutation that her mother carries. Christina's unaffected sister has a 50% chance of having inherited this same mutation from her mother.

(2) Christina's sister now has the option of also pursuing genetic testing. A positive genetic test results would confer an increased risk of several cancers and her medical management should be changed accordingly. A negative test result would relieve her of this family history and she would be considered to have the same risk for colon cancer (and endometrial cancer) as the general population. If Christina's sister is not ready to pursue genetic testing at this time, she should undergo screening as if she had a positive genetic test result.

(3) Christina's mother should be engaged in a discussion of the risks, benefits and limitations of prophylactic surgery for individuals with HNPCC.

At the next visit, both her mother and sister accompany Christina. Her sister does not want to hear anything about genetic testing, as she feels her sister is fine. Christina's mother asks you to "do something" for her daughter.

• What referrals can you offer the sister?
• Why might genetic testing be particularly helpful for the sister?
• What surveillance recommendations should you make for the sister if she continues to refuse testing?

Faculty teaching points:
(1) Christina's sister could be offered a referral to a mental health professional to help her deal with her sister's cancer diagnosis and her feelings regarding these genetic test results. This sister should also be offered a referral to a gastroenterologist based on this family history and in light of these genetic testing results.

(2) A discussion of the implications of a negative genetic test result on an unaffected family member may be of benefit to Christina's sister. At this point she should be considered a high risk unless she has genetic testing to prove that she does not carry the familial mutation. Pursuing genetic testing would relieve Christina's sister of invasive screening procedures and of her family history of colon cancer.

(3) Surveillance for putative HNPCC should be followed for Christina's sister if she opts not to proceed with genetic testing at this time.

Christina passes away 6 months later. He sister has come to terms with her sister's diagnosis and her own risk. She is now pregnant and wishes to be tested. After being counseled by Marcie, she undergoes testing and is negative.

• What is her risk of developing colon cancer given her test results?
• What is the risk to the child she is carrying?
• What screening would you recommend?

Faculty teaching points:
(1) Based on the genetic test results, Christina's sister is not at increased risk for colon cancer. However, a negative genetic test result does not reduce her risk of colon cancer (or any cancer) to zero. Christina's sister has the same risks as the general population, which is 1 in 50 and must be screened according to the general population screening guidelines. At the minimum, Christina's sister should begin screening for colon cancer at the age of 50.

(2) Since Christina's sister did not inherit the familial mutation, she cannot pass it on to any of her offspring. However Christina's children would all have a 50% risk of having inherited the mutation from Christina and could be offered testing after the age of 18.

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Case 4: Familial Adenomatous Polyposis
This section is in development. Please check back with us!

Case 5: Multiple Endocrine Neoplasia Type IIB
This section is in development. Please check back with us!

Case 6: Li-Fraumeni
This section is in development. Please check back with us!

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Case 7: Neurofibromatosis Patient Summary: Richard Miller is a 17-year-old male who presents to your office for routine care. Exam is significant for multiple brown macules and several firm, non-tender freely moveable subcutaneous nodules. Blood pressure is 162/98 in the left arm and 165/102 in the right arm.

• What other findings would you now check for on physical exam?
• What other medical or family history questions would you now ask?

Faculty Teaching Points:
(1) There are several clinical criteria used to confirm the diagnosis of NF 1 and at least two must be present to be sure of the diagnosis. Two can be clearly seen and confirmed on exam (six or more CAL's great than or equal to 1.5 cm in diameter and axillary or inguinal freckles); three can be suspected on exam and confirmed if necessary (optic nerve glioma, neurofibromas, and pseudoarthrosis), while one requires slit lamp exam (Lisch nodules) and the last clinical criteria is a positive family history.
(2) For NF 2, the clinical criteria are somewhat different and would require an MRI to identify the intracranial lesions.
(3) In an otherwise healthy young man with NF 1, alternative causes of hypertension need to be considered: namely pheochromocytoma and renal artery stenosis.

More careful exam shows bilateral axillary and unilateral inguinal freckles as well as mild mid-thoracic scoliosis with convexity to the right. Family history is negative for other individuals with similar spots. He has never been found to be hypertensive in the past.

• Are there any tests you would now consider?
• What are your follow-up recommendations?

Faculty Teaching Points:
(1) The finding of freckles along with the many CAL spots confirms the diagnosis of NF 1.
(2) Molecular testing is not necessary to confirm the diagnosis since the diagnosis of NF 1 is a clinical one.
(3) Despite the negative family history, this diagnosis has serious genetic implications for Richard's future children. His condition most likely is a result of a new mutation or de novo event. The genetic issues may need to be addressed a little later after the medical issues are taken care of.
(4) A focused eye exam by an ophthalmologist and perhaps some preliminary labs are in order.

Richard returns to your office two weeks later. At your suggestion, Richard has since seen an ophthalmologist who reports his vision is 20/20 OU with correction for mild hyperopia and there are bilateral Lisch nodules. Fundoscopic exam is WNL. Laboratory studies reveal normal serum electrolytes, a BUN of 23 and creatinine of 1.0. Urinalysis is completely normal. His repeat blood pressure measurement is 160/99.

• What do you make of these eye findings?
• What type of eye findings would you expect to see in NF 2?
• What do you think of these labs?
• What additional work-up would you recommend at this point?

Faculty Teaching Points:
(1) The eye exam is not suggestive of an optic glioma, but the Lisch nodules are quite consistent with this diagnosis since over 95% of affected adults have this finding.
(2) These labs are normal and a more in-depth work-up for hypertension is now in order. This work-up should include a 24 hour urine for catecholamines and metanephrines and some type of renal vascular work-up such as renin, renal doppler study or renal arteriogram. Referral to a nephrologist would also be quite reasonable.

Renal artery doppler studies reveal apparently normal renal blood flow. However, the 24 hour urine test done for catecholamines and metanephrines is grossly abnormal, suggesting a probable pheochromocytoma.

• What studies would you now order?
• What treatments are available for pheochromocytomas?

Faculty Teaching Points:
(1) MRI of the abdomen followed by a nuclear scan is a reasonable approach for this diagnostic concern.
(2) Pheochromocytomas in NF 1 are usually solitary and surgical resection is the preferred approach.

MRI suggests a solitary left adrenal lesion that is confirmed on nuclear studies. Surgical resection of this tumor resutls in normalization of blood pressure and Richard makes a full recovery. Richard now has questions about his diagnosis and wonders if or how this could affect future children. He also is curious about the availability of DNA testing since he has been reading so much about the Human Genome project and the mapping of all of our genes.

• What is the prognosis for Richard in terms of the pheochromocytoma?
• What would you tell Richard about the genetics of NF 1?
• What would you tell Richard about the severity of NF 1 in his offspring?
• What would you tell him about molecular and/or prenatal diagnosis?

Faculty Teaching Points:
(1) The prognosis is excellent.
(2) The condition is autosomal dominant so offspring are at 50% risk of being affected. There is a great deal of variability in NF so a mildly affected parent can certainly have a severely affected child. There is no way to predict severity.
(3) Molecular testing consists of either linkage analysis in families with multiple affected members or direct DNA testing by mutation analysis or protein truncation assay. The latter detects up to 70% of NF 1 mutations and theoretically can be employed for prenatal testing although this is not readily available in the United States. Because of this and because Richard is the first affected in his family, prenatal testing cannot be done in the near future for this family.

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