The Clinical Implications of Treating Patients with LiFraumeni Syndrome

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The Clinical Implications of Treating Patients
with Li-Fraumeni Syndrome

• Julie Kanter, MD

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Case Presentation

• HPI __ is a 6½ year old male who presented to
  his PCP for a check-up. He was noticed to be
  pale in color with multiple bruises on his legs.
  His parents also noted some decreased energy at
  home. PCP sent the child to an outpatient lab
  where a CBC was notable for blasts, Hgb 7.2, and
  plt count of 17.
• __ was diagnosed with AML the following day after
  a bone marrow exam.
• LP was negative for any CNS disease

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Case Presentation

• Past medical history patient was diagnosed with
  a stage III embryonal rhabdomyosarcoma of his R
  thigh in 2/2002. He underwent treatment with
  chemotherapy, brachytherapy, external radiation,
  and surgical excision. He had been off-therapy
  for 4 years at the time of current presentation.

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Case Presentation

• Family History
• Pts father, was diagnosed with a fibrous
  histiosarcoma in 1991 at the age of 25
• Pts uncle (fathers brother) was diagnosed with
  metastatic melanoma in 2006
• Pts paternal grandfather was diagnosed with a
  histiosaromca in 1996 and later acute leukemia
• Pts maternal grandfather and great-grandfather
  had prostate cancer
• Pts mother is healthy with no problems
• Pts 9 year old brother is healthy with no
  problems

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Case Presentation

• New diagnosis AML
• FAB M7-acute megakaryoblastic leukemia
• Flow cytometric analysis revealed 21 in the
  blast gate that express CD33, CD34, CD41
  (partial), CD61 (partial), and CD117. Cells do
  not express CD13, CD14, CD56, or CD64
• Bone Marrow biopsy extensive fibrosis with gt90
  cellularity and minimum of 20 blasts with
  increased megakaryocyte numbers with
  hyperchromasia
• Cytogenetics Highly complex
• 36-44XY, del(2)(q3),del(5q), 8,12,add(12),der(13
  )t(1213),add(17)(p12),-18,-20,mar(2)/38
• amp(p53)(19/2000)

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add(17)(p?12)
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Li-Fraumeni syndrome

• A cancer predisposition syndrome
• Individuals with LFS are at increased risk for
  developing multiple primary cancers
• Age-specific cancer risks have been calculated
• Inherited in an autosomal dominant manner
• Highly penetrant cancer syndrome segregation
  analysis of families with LFS, revealed a 50
  chance of cancer before age 40 and up to 90 by
  age 60 (Lustbader et al, 1992)
• Occurs in approximately 1/50,000 individuals Two
  forms exist classic Li-Fraumeni syndrome (LFS)
  and Li-Fraumeni-like syndrome (LFL)

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Clinical Criteria for Classic LFS

• 1. A proband with a sarcoma diagnosed at less
  than 45 years of age AND
• 2. A first degree relative with any type of
  cancer less than 45 years of age AND
• 3. First or second degree relative with any
  cancer at less than 45 years of age OR a sarcoma
  at any age.

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Criteria for Li-Fraumeni-like syndrome (LFL)-two
definitions

• Birch et al 1994
• Proband with any childhood cancer or sarcoma,
  brain tumor, or adrenal cortical tumor diagnosed
  before age 45 AND
• First or second-degree relative with a typical
  LFS cancer (sarcoma, breast cancer, brain cancer,
  adrenal cortical tumor, or leukemia)
• Eeles 1995
• Two first or second-degree relatives with typical
  LFS-related malignancies at any age

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P53

• TP53 gene Recognized as the most common gene
  mutated in sporadic cancers
• Well known that tumor suppressor genes need both
  copies of the gene to be inactivated to cause
  tumor
• Howeverthis gene is unique in that it does not
  always obey the classical 2-hit hypothesis
• This property of the TP53 gene is a dominant
  negative effect a mutation of one copy of the
  gene will lead to inefficient protein formation

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LOH loss of heterozygosity

• Loss of Heterozygosity Accepted model for tumor
  suppressor gene mechanism in which there is a
  mutation in one allele and the secondary loss of
  the remaining wild type allele
• Less than 50 of tumors from members of LFS
  families show the LOH
• Supports the theory of a dominant negative effect

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AML and p53

• 10 of leukemias contain mutant p53 in their
  malignant chromosomes (in contrast to solid
  tumors)
• In AML, the deletion or rearrangement of p53
  occurs in about 17 of patients
• In pts without LFS who have p53
  abnormalities-most common observation is the loss
  of p53
• In LFS, most common observation is a missense
  mutation at p53
• Therapy-related AML and MDS is also associated
  with p53 alterations in addition to deletion of
  chromosome 5/5q or 7/7q in gt50 of patients
• Mutation of p53 is significantly associated with
  deletion of 5q (plt0.0001) while deletion of 7q
  was not significant

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Li-Fraumeni (as discussed by Dr. Li and Dr.
Fraumeni in 1988)

• 1969 Described four families with autosomal
  dominant pattern of soft tissue sarcoma, breast
  cancer, and other neoplasms in children and young
  adults
• 1988 Analyses of 24 families and further
  defining the component neoplasms
• Cancer developed in 151 blood relatives, 79
  prior to 45 years of age
• Majority of cancers 50 bone and soft tissue
  sarcomas of diverse histological subtype and 28
  breast cancers
• Additional cancers in excess brain tumors (14),
  leukemia (9), and adrenocoritcal carcinoma (4
  cases)
• 15/151 blood relatives had a secondary
  malignancy, 73 of which were in the above
  categories
• 6/15 patients had second cancers linked to
  radiotherapy

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Molecular genetics

• P53 gene has been mapped to chromosome 17p13
• It is 20kb in length, comprises 11 exons and
  encodes a 393 amino acid protein
• It has been called guardian of the genome
  because of its role in the cellular response to
  DNA damage

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Molecular testing

• In patients with classic LFS, approximately
  50-60 will have a genetically detectable p53
  mutation
• In patients with LFL, 22 of families defined by
  Birchs definition will have an identifiable
  mutation
• Of those, 95 can be detected by sequence
  analysis of exons 4 through 9.
• Why not more?
• The methods used to detect p53 mutations neglect
  the regulatory region of the gene
• P53 protein may undergo faulty regulation at the
  protein level by interacting with other cellular
  proteins
• LFS could result from germline defects in other
  genes that participate in the p53 cell cycle
  regulatory pathway

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Relative frequency of cancers in carriers of
germline p53 mutations

• Birch J et al Cohort of individuals from 28
  families with LFS (with p53 mutation identified)

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Relative frequency of cancers in carriers of
germline p53 mutations

• The previous analyses identified seven cancer
  types as being strongly associated with germline
  TP53 mutations
• Carcinoma of the female breast, tumors of the
  brain and spinal cord, soft tissue sarcoma,
  osteosarcoma, and adrenocortical carcinoma (of
  the original group defined by Li in 1988)
• Wilms Tumor and phyllodes tumor
• Moderate association Carcinoma of the pancreas
• Weak association Leukemia and neuroblastoma
• Cancers that did not occur in excess lung,
  colon, bladder, prostate, cervix, and ovary
• TP53 mutations have tissue specific effects with
  regard to their increased cancer risk

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Incidence of multiple primary cancer in patients
with LFS

• Hisada et al reviewed the data from the original
  24 families discussed by Li and Fraumeni and
  quantified the risk for secondary malignancy
• 200 cancer patients in 24 families were eligible
  for study
• These 200 patients accumulated 1142 person-years
  of follow-up before diagnosis of second primary
  cancer (30 patients), death (120 patients), loss
  to f/u (2 patients)
• 30/200 patients had a second cancer occurrence
  with range in time b/n 1-27 years (median 6
  years). 9 of these patients had received
  radiotherapy
• 8/30 developed a third cancer and 4/8 developed a
  4th cancer

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Incidence of multiple primary cancer in patients
with LFS

• Cumulative second cancer probability of 57 at 30
  years of follow up
• Cumulative probability was highest among patients
  initially diagnosed with a soft tissue sarcoma
• Rate was highest among those patients with cancer
  initially diagnosed before age 20 years and
  declined with age at initial dx
• RR of second cancer differed markedly by age at
  first cancer
• Patients with LFS who had cancer after 45 years
  of age had no increased RR of secondary cancer

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Genotype vs Phenotype

• Total of 494 tumors identified in individuals who
  were confirmed TP53 carriers or with LFS or LFL
  (Olivier M, et al)
• Study done to further examine the tumor spectrum
  in LFS families with TP53 mutation versus a
  clinical background of LFS or LFL

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Genotype vs Phenotype
Age in years at time of diagnoses
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Tumor type, age at onset, and gender distribution
in TP53 germ-line mutation carriers from LFS/LFL
families
Most frequent cancer is breast cancer (30.6)
followed by STS at (17.8). A group of less
prevalent tumors including lung, hematopoietic,
stomach, colorectal , ovary, and melanoma account
for 15
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Risk of Developing Second Cancers among survivors
of childhood soft tissue sarcomas

• Cohen R, et al evaluated 1499 children
  (agelt18yrs) who survived gt1 year after diagnosis
  with STS to assess the risk of developing a SMN
  in patients treated for RMS, fibromatous
  neoplasms, and other STS
• 27 children developed 28 second primary
  malignancies vs 4.5 expected malignancies.
  Increased risk for a second solid tumor, AML,
  cutaneous melanoma, oral cancers, and female
  breast cancer
• Relative Risk of developing a SMN was highest
  during the first 5 years after initial treatment
• 4 patients with AML developed cancer within 29
  months of treatment
• Risk by Initial Treatment for RMS
• Combined radiotherapy with chemotherapy was
  associated with significantly higher risk than
  surgery alone
• Initial tx with chemotherapy OR radiation therapy
  was not associated with a significantly increased
  risk for SMN
• Fibromatous Neoplasms
• Combined radiotherapy and chemotherapy was
  associated with gt70fold increased risk for
  developing second cancer
• Radiation alone was associated with increased
  risk over chemotherapy alone
• Observed excess of AML in these trials was
  attributed to therapy with alkylating agents and
  topoisomerase II inhibitors

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How to avoid a second primary cancer in patients
with LFS?

• Uncertainty exist regarding strategies to reduce
  second cancer morbidity and mortality in families
  with LFS.
• Ionizing radiation is a known risk factor with
  dose-dependent effects
• Chemotherapy alone or surgery alone when feasible
  for treatment
• Second cancers can arise in diverse organs and
  anatomic sites regardless of the first tumor type
  or the familys germline p53 gene status
• (identifiable p53 mutation did not correlate with
  increased risk of second malignancy)

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Mechanisms for surveillance in patients with LFS

• Main recommendation Earlier and more frequent
  breast cancer screening for women
• There are no other universally agreed upon
  surveillance recommendations for most
  LFS-associated malignancies
• Other possible recommendations
• Annual CBC with slide review
• Annual physical exam
• Annual Urinary analyses with micro/macro
• Healthy lifestyle
• Avoid environmental carcinogens

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Treatment implications

• Increased sensitivity to DNA damaging agents
  (XRT) commonly used to treat the type of cancers
  seen in LFS can pose a major risk
• In addition, these tumors are commonly
  radioresistant
• Radiation therapy should be avoided whenever
  there are other feasible treatment options

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For breast cancer patients with LFS

• Urgent TP53 testing if patient is lt30yrs old
• Mastectomy vs conservative therapy with xrt
• Response to systemic therapy
• hormonal therapy vs nonanthracycline containing
  therapy vs anthracycline containing therapy
• Chemoprevention for recurrence of breast cancer
  and for occurrence of contralateral breast cancer
  with Tamoxifen when possible (as used in BRCA
  mutation carriers)

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Ethical Dilemma Who do you screen?

• The overall lifetime risk of cancer is high
  (80-90) but the variable expressivity and
  penetrance and diversity of tumor spectrum render
  clinical surveillance and genetic testing a
  difficult test
• What about the children or siblings of patients
  with LFS?
• When a child is not competent to give consent,
  the main consideration in genetic testing should
  be the welfare of the child
• Cornerstone of this process informed consent
  or at least assent

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Ethical Dilemma Who do you screen?

• LFS screening is presymptomatic genetic testing
  testing a healthy person with no features or
  symptoms of a disease caused by a specific gene
• This testing is only justifiable when the test
  result will change medical care (especially in
  childhood). Specific syndromes that apply incl
• Familial adenomatous poposis, Multiple endocrine
  neoplasia I, Multiple endocrine neoplasia II, Von
  Hippel-Lindau, Retinobastoma, Neurofibromatosis

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Ethical Question Do we test JM for Li-Fraumeni
syndrome

• Will it change our current treatment for this
  patient?
• TBI based transplant regimen
• Will it change future management for this patient
  and his family??
• Once an individual is diagnosed with LFS and the
  TP53 mutation is identified, predictive testing
  for yet unaffected relatives is easier

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Ethical Question Do we test JMs brother for
Li-Fraumeni syndrome

• Potential loss of autonomy for the child. When
  the child who has been tested matures, the right
  of that person to decline testing or the
  possibility of withholding genetic test results
  has been effectively lost
• Potential inability to minimize the risk of
  stigmatization and discrimination in later life
• Disruption in family dynamics. If the sibling of
  a proband is negative, feelings of guilt may be
  overwhelming to the child

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Evaluation of a decision aid for families
considering p53 genetic counseling and testing
(Peterson S, et al)

• Study population of 57 adults from 13 kindreds
  who had previously participated in research
  regarding the genetics of LFS at MD Anderson
• Eligibility criteria donated a blood sample
  before clinical testing for p53 mutation was
  available, having at least 25 carrier risk, 18
  yrs of age, speaking English. Individuals with
  and without personal dx of cancer were eligible
  to participate
• No one had undergone genetic counseling or p53
  clinical testing in anyway

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Evaluation of a decision aid for families
considering p53 genetic counseling and testing
(Peterson S, et al)

• Outcomes were evaluated by questionnaires after
  the administration of a video-based decision aide
  to enhance the understanding of the clinical and
  psychosocial aspects of LFS and facilitate
  informed decision making
• Results
• Knowledge scores increased in both men and women
  from baseline to post-DA assessment
• Perceived risk of developing cancer and cancer
  worries decreased significantly
• Participants intention to have genetic testing
  did not change following the use of the DA
• Participants did report lower levels of
  decisional conflict post-DA, suggesting that it
  may have helped reduce uncertainty and improve
  perceived effectiveness of genetic counseling and
  testing decisions
• 96 reported they would recommend the DA to
  others who were considering the genetic
  counseling and testing

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Ethical questions continue

• American Society of Clinical Oncology (ASCO) does
  consider LFS as a syndrome for which predictive
  testing should be considered.
• In these publications, predictive testing for
  TP53 mutations is included amount tests for
  hereditary syndromes with a high probability of
  linkage to known cancer susceptibility genes, and
  for which the medical benefit of the
  identification of a carrier is presumed but not
  established.
• The clinical value and reliability of the test is
  based on research studies.

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References

• Schneider K, Li F. Li-Fraumeni Syndrome.
  www.genetests.org, 2004.
• Hisada M, Garber J, Fung C, Fraumeni Jr, Li, F.
  Multiple Primary Cancers in families with
  Li-Fraumeni Syndrome. Journal of the NCI, vol 90
  (8), 1998
• Tischkowitz M, Rosser E. Inherited cancer in
  children practical/ethical problems and
  challenges. Eur Jour of Cancer 40 (2004)
  2459-2470
• American Society of Clinical Oncology policy
  statement update genetic testing for cancer
  susceptibility. J Clin Oncol 2003 212397-406
• Birch J, Alston R, McNally R, et al. Relative
  frequency and morphology of cancers in carriers
  of germline TP53 mutations. Oncogene (2001)
  204621-28
• Li F, Fraumeni J, et al. A Cancer Family
  Syndrome in Twenty-four Kindreds. Cancer
  Research 48, 5358-5362
• Garber J, Golstein A, Kantor A, et al. Follow-up
  study of twenty-four families with LI-Fraumeni
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• Heyn R, Haeberlen V, Newton W. Second Malignant
  Neoplasms in children Treated for
  Rhabdomyosarcoma. Jour Clin Onco, vol 11, No 2,
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• Cohen R, Curtis R, Inskip P. The Risk of
  Developing Second Cancers among Survivors
  Childhood Soft Tissue Sarcoma. Cancer, 2005.
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• Moule RN, Jhavar SG, Eeles R. Genotype phenotype
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• Olivier M, Goldgar D, and Sodha N, et al.
  Li-Fraumeni and Related syndromes correlation
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  genotype. Cancer Research, 2001, 636643
• Boyapati A, Kanbe E, Zhang D, p53 Alterations in
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