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  1. 1. The Clinical Implications of Treating Patients with Li-Fraumeni Syndrome Julie Kanter, MD
  2. 2. 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
  3. 3. 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.
  4. 4. Case Presentation:  Family History:  Pt’s father, was diagnosed with a fibrous histiosarcoma in 1991 at the age of 25  Pt’s uncle (father’s brother) was diagnosed with metastatic melanoma in 2006  Pt’s paternal grandfather was diagnosed with a histiosaromca in 1996 and later acute leukemia  Pt’s maternal grandfather and great-grandfather had prostate cancer  Pt’s mother is healthy with no problems  Pt’s 9 year old brother is healthy with no problems
  5. 5. 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 >90% 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(12;13),add(17)(p12),-18,- 20,+mar(2)/38  amp(p53)(19/2000)
  6. 6. add(17)(p?12)
  7. 7. Note the amplification (4~6 signals) of P53 Normal 17 Abnormal 17 P53 Control probe (D17Z1)
  8. 8. 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)
  9. 9. 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.
  10. 10. 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
  11. 11. 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  However…this 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
  12. 12. 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
  13. 13. 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 >50% of patients  Mutation of p53 is significantly associated with deletion of 5q (p<0.0001) while deletion of 7q was not significant
  14. 14. 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
  15. 15. 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
  16. 16. 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 Birch’s 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
  17. 17. 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)
  18. 18. 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
  19. 19. 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
  20. 20. 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
  21. 21. 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
  22. 22. Genotype vs Phenotype Age in years at time of diagnoses
  23. 23. 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%
  24. 24. Risk of Developing Second Cancers among survivors of childhood soft tissue sarcomas  Cohen R, et al evaluated 1499 children (age<18yrs) who survived >1 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 >70fold 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
  25. 25. 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 family’s germline p53 gene status  (identifiable p53 mutation did not correlate with
  26. 26. 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
  27. 27. 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
  28. 28. For breast cancer patients with LFS:  Urgent TP53 testing if patient is <30yrs 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)
  29. 29. 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
  30. 30. 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
  31. 31. 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
  32. 32. Ethical Question: Do we test JM’s 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
  33. 33. 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
  34. 34. 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
  35. 35. 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
  36. 36. References  Schneider K, Li F. Li-Fraumeni Syndrome., 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: 21:2397-406  Birch J, Alston R, McNally R, et al. Relative frequency and morphology of cancers in carriers of germline TP53 mutations. Oncogene (2001) 20:4621-28  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 Syndrome. Cancer Research 51, 6094-97  Heyn R, Haeberlen V, Newton W. Second Malignant Neoplasms in children Treated for Rhabdomyosarcoma. Jour Clin Onco, vol 11, No 2, 1993:262-270  Cohen R, Curtis R, Inskip P. The Risk of Developing Second Cancers among Survivors Childhood Soft Tissue Sarcoma. Cancer, 2005. Vol 103. Number 11  Moule RN, Jhavar SG, Eeles R. Genotype phenotype correlation in Li-Fraumeni syndrome kindreds and its implications for management. Fam Cancer 2006. 5:129-133  Olivier M, Goldgar D, and Sodha N, et al. Li-Fraumeni and Related syndromes: correlation between tumor type, family structure, and TP53 genotype. Cancer Research, 2001, 63:6643  Boyapati A, Kanbe E, Zhang D, p53 Alterations in Myeloid leukemia. Acta Haematologica