Chest Wall Leiomyosarcoma After Breast-Conservative Therapy for Early-Stage Breast Cancer in a Young Woman With Li-Fraumeni Syndrome

Li-Fraumeni syndrome (LFS) is one of the most penetrant forms of familial cancer susceptibility syndromes, characterized by early age at tumor onset and a wide spectrum of malignant tumors. Identifying LFS in patients with cancer is clinically imperative because they have an increased sensitivity to ionizing radiation and are more likely to develop radiation-induced secondary malignancies. This case report describes a young woman whose initial presentation of LFS was early-onset breast cancer and whose treatment of this primary malignancy with breast conservation likely resulted in a secondary malignancy arising in her radiation field. As seen in this case, most breast cancers in patients with LFS exhibit a triple-positive phenotype (estrogen receptor–positive/progesterone receptor–positive/HER2-positive). Although this patient met classic LFS criteria based on age and personal and family history of cancer, the NCCN Clinical Practice Guidelines in Oncology for Genetic/Familial High-Risk Assessment: Breast and Ovarian Cancer endorse genetic screening for TP53 mutations in a subset of patients with early-onset breast cancer, even in the absence of a suggestive family history, because of the potential for de novo TP53 mutations.

Abstract

Li-Fraumeni syndrome (LFS) is one of the most penetrant forms of familial cancer susceptibility syndromes, characterized by early age at tumor onset and a wide spectrum of malignant tumors. Identifying LFS in patients with cancer is clinically imperative because they have an increased sensitivity to ionizing radiation and are more likely to develop radiation-induced secondary malignancies. This case report describes a young woman whose initial presentation of LFS was early-onset breast cancer and whose treatment of this primary malignancy with breast conservation likely resulted in a secondary malignancy arising in her radiation field. As seen in this case, most breast cancers in patients with LFS exhibit a triple-positive phenotype (estrogen receptor–positive/progesterone receptor–positive/HER2-positive). Although this patient met classic LFS criteria based on age and personal and family history of cancer, the NCCN Clinical Practice Guidelines in Oncology for Genetic/Familial High-Risk Assessment: Breast and Ovarian Cancer endorse genetic screening for TP53 mutations in a subset of patients with early-onset breast cancer, even in the absence of a suggestive family history, because of the potential for de novo TP53 mutations.

Li-Fraumeni syndrome (LFS) is one of the most penetrant forms of familial cancer susceptibility syndromes, characterized by an early age of tumor onset and a wide spectrum of malignant tumors. Patients with TP53 mutations are predisposed to develop sarcomas, early-onset breast cancer, brain tumors, leukemia, and adrenocortical carcinomas.1,2 The lifetime risk of cancer in these patients is extraordinarily high with 50% of patients having a diagnosis of cancer by the age of 30 and 90% by the age of 50.3 Identifying LFS in patients with cancer is clinically imperative because these patients have an increased sensitivity to ionizing radiation and are more likely to develop radiation-induced secondary malignancies.47 This case report describes a young woman whose initial presentation of LFS was early-onset breast cancer and whose subsequent treatment with breast conservation likely resulted in the rapid development of a secondary malignancy arising in her radiation field.

Case Report

A 24-year-old female presented after incidentally palpating a mass in the superior aspect of her left breast. Biopsy of the mass revealed invasive ductal carcinoma. She underwent a lumpectomy with axillary node dissection and was found to have a 2.7-cm moderately differentiated invasive ductal carcinoma that was estrogen receptor–positive/progesterone receptor–positive/HER2-positive (ER+/PR+/HER2+) on immunohistochemistry. Lymph node dissection was negative in 0 of 23 nodes. Surgical margins were negative. Imaging revealed no evidence of metastasis. She received adjuvant chemotherapy with 4 cycles of doxorubicin and cyclophosphamide, followed by 4 cycles of paclitaxel with concurrent trastuzumab. She underwent photon irradiation using an opposed tangent technique, which delivered 50.4 Gy in 28 fractions to the whole breast, followed by a 10-Gy boost to the lumpectomy cavity. She was then lost to follow-up and did not receive the intended course of adjuvant tamoxifen nor the recommended full year of trastuzumab therapy.

Twenty-seven months after completing adjuvant radiotherapy, she presented with blurry vision that rapidly progressed to right eye blindness. Brain MRI showed right globe enhancement concerning for choroidal metastasis. She had no parenchymal brain lesions. A PET/CT showed a new 4 x 3–cm left chest wall mass involving the serratus anterior muscle, extensive left breast skin thickening, bilateral pulmonary nodules, and enlarged cervical and mediastinal lymph nodes (Figure 1).

The patient received urgent radiation therapy to the right orbit to a dose of 40 Gy in 16 fractions and was started on tamoxifen and trastuzumab for presumed metastatic breast cancer. A CT-guided biopsy of the chest wall mass revealed a high-grade soft tissue spindle cell neoplasm consistent with leiomyosarcoma (Figure 2). Review of her prior radiation therapy fields showed the left chest wall mass to be within the prior radiotherapy field (Figure 3). Biopsy of a lung nodule, however, was consistent with metastatic breast cancer.

The patient had an extensive family history of cancer (Figure 4). Although she had previously tested negative for BRCA1 and BRCA2 germline mutations, she met the classic LFS criteria, including a diagnosis of sarcoma before age 45 years and a family history of early-onset (< 40 years of age) of malignancy in 2 maternal aunts and her paternal grandmother.8 After her diagnosis of leiomyosarcoma, the patient underwent genetic evaluation and tested positive for a germline mutation in TP53 (14525G>T; glu286stop), confirming a molecular diagnosis of LFS.

Figure 1
Figure 1

CT thorax with a left chest wall mass arising from the serratus anterior muscle (arrow).

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 10, 8; 10.6004/jnccn.2012.0097

Discussion

Although breast cancer is the most frequent neoplasm in women with TP53 mutations, it is less commonly the first presentation of LFS. The first clinical report of breast cancer as a primary presentation found 8 cases among 43 families with known LFS.9 The infrequency of LFS in the general population and the rarity of breast cancer as a primary presentation makes the diagnosis of LFS difficult in patients with early-onset breast cancer. In all patients with early-onset breast cancer, only an estimated 5% to 7% of cases can be attributed to a mutation in TP53.2,10

Despite the relative rarity of this diagnosis, this case highlights the clinical importance of considering diagnostic testing for TP53 mutations in patients with early-onset breast cancer at diagnosis. Locoregional management recommendations for these patients may be significantly influenced if LFS is detected, because the TP53 mutation confers an increased sensitivity to ionizing radiation, resulting in an increased frequency of radiation-induced secondary malignancies.47 Young patients are statistically more likely to choose breast conservation therapy with lumpectomy followed by adjuvant radiation therapy.11 Patients with LFS syndrome, however, are cautioned to avoid radiation therapy when possible and may be advised to pursue mastectomy.12,13

Figure 2
Figure 2

Spindle cell lesion with hyperchromatic, pleomorphic nuclei with increased mitotic activity. Desmin/actin positive; p63/S100/CD31/CD34 negative. Hematoxylin-eosin, original magnification x400.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 10, 8; 10.6004/jnccn.2012.0097

Figure 3
Figure 3

Isodose distribution of left breast irradiation.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 10, 8; 10.6004/jnccn.2012.0097

In the general population, radiation-induced malignancies are rare and usually occur 10 or more years after radiation therapy.14 Even in patients with LFS, the earliest latent period to develop a second malignancy after irradiation is generally considered to be 4 years.15,16 The patient in this case developed a secondary malignancy only 2 years after the completion of whole breast radiation therapy, representing one of the shortest reported latent periods to secondary malignancy in a patient with LFS.

Because of the expense and psychosocial stress associated with genetic testing, screening all patients with early-onset breast cancer for LFS generally has not been recommended, except in those who have a compelling family history.17 Concern exists, however, that patients are being missed by this standard practice.18 In one study of women with early-onset breast cancer who tested negative for BRCA1 and BRCA2 mutations, 4% tested positive for a TP53 mutation who had no family history of cancer at all.10 Because of the possibility of de novo TP53 mutations, the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Genetic/Familial High-Risk Assessment: Breast and Ovarian Cancer recommend TP53 testing for individuals with multiple primary tumors, 2 of which belong to the LFS tumor spectrum (ie, sarcoma, breast cancer, adrenocortical carcinoma, brain tumor, leukemia, lung bronchoalveolar cancer) with initial cancer diagnosed at younger than 36 years regardless of family history, and in individuals diagnosed with breast cancer at younger than 30 years who have a negative BRCA1 and BRCA2 test (to view the most recent version of these NCCN Guidelines, visit NCCN.org).17 The NCCN Guidelines also recommend genetic counseling for patients who are considering p53 testing.17 A multidisciplinary approach with professional geneticists, counselors, psychologists, and oncologists may improve patient understanding of the risks and benefits associated with genetic testing.19

Figure 4
Figure 4

Pedigree.

Abbreviations: ca, cancer; d, age at death; dx, age at diagnosis; ER, estrogen receptor; PR, progesterone receptor.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 10, 8; 10.6004/jnccn.2012.0097

Research now indicates that most breast cancer in patients with LFS exhibits a “triple-positive” phenotype (ER+/PR+/HER2+).2022 Although family history alone may not be enough to detect all patients with LFS, a thorough family history, attention to tumor histology, and a high level of clinical suspicion may allow physicians to identify and optimize therapy for their LFS patients and minimize the potential late effects associated with this syndrome.

The authors have disclosed that they have no financial interests, arrangements, or affiliations with the manufacturers of any products discussed in this article or their competitors.

References

  • 1

    OlivierMGoldgarDESodhaN. Li-Fraumeni and related syndromes: correlation between tumor type, family structure, and TP53 genotype. Cancer Res2003;63:66436650.

    • Search Google Scholar
    • Export Citation
  • 2

    GonzalezKDNoltnerKABuzinCH. Beyond Li Fraumeni syndrome: clinical characteristics of families with p53 germline mutations. J Clin Oncol2009;27:12501256.

    • Search Google Scholar
    • Export Citation
  • 3

    LustbaderEDWilliamsWRBondyML. Segregation analysis of cancer in families of childhood soft tissue sarcoma patients. Am J Hum Genet1992;51:344356.

    • Search Google Scholar
    • Export Citation
  • 4

    HisadaMGarberJEFungCY. Multiple primary cancers in families with Li-Fraumeni syndrome. J Natl Cancer Inst1998;90:606611.

  • 5

    LimacherJMFrebourgTNatarajan-AmeSBergeratJP. Two metachronous tumours in the radiotherapy fields of a patient with Li-Fraumeni syndrome. Int J Cancer2001;96:238242.

    • Search Google Scholar
    • Export Citation
  • 6

    CohenRJCurtisREInskipPDFraumeniJFJr. The risk of developing second cancers among survivors of childhood soft tissue sarcoma. Cancer2005;103:23912396.

    • Search Google Scholar
    • Export Citation
  • 7

    KonySJde VathaireFChrompretA. Radiation and genetic factors in the risk of second malignant neoplasm’s after a first cancer in childhood. Lancet1997;350:9195.

    • Search Google Scholar
    • Export Citation
  • 8

    LiFPFraumeniJFJrMulvihillJJ. A cancer family syndrome in twenty-four kindreds. Cancer Res1988;48:53585362.

  • 9

    HeymannSDelalogeSRahalA. Radio-induced malignancies after breast cancer post operative radiotherapy in patients with Li-Fraumeni syndrome. Radiat Oncol2010;5:104109.

    • Search Google Scholar
    • Export Citation
  • 10

    TinatJBougeardGBaert-DesurmontS. 2009 version of the Chrompret criteria for Li-Fraumeni syndrome. J Clin Oncol2009;27:108109.

  • 11

    GreenburgCCLipsitzSRHughsME. Institutional variation in the surgical treatment of breast cancer: a study of the NCCN. Ann Surg2011;254:339345.

    • Search Google Scholar
    • Export Citation
  • 12

    LimacherJMFrebourgTNatarajan-AmeSBergeratJP. Two metachronous tumors in the radiotherapy fields of a patient with Li-Fraumeni syndrome. Int J Cancer2001;96:238242.

    • Search Google Scholar
    • Export Citation
  • 13

    PierceLJHafftyBG. Radiotherapy in the treatment of hereditary breast cancer. Semin Radiat Oncol2011;21:4350.

  • 14

    RubinoCde VathaireFShamsaldinA. Radiation dose, chemotherapy, hormonal treatment and risk of second cancer after breast cancer treatment. Br J Cancer2003;895:840846.

    • Search Google Scholar
    • Export Citation
  • 15

    KleinermanRA. Radiation-sensitivie gentetically susceptible pediatric sub-populations. Pediatr Radiol2009;39(Suppl 1):S2731.

  • 16

    SchneiderKGarberJ. Li-Fraumeni syndrome. In: PagonRABirdTDDolanCR eds. Gene Reviews. Seattle, WA: University of Washington; 1999.

  • 17

    DalyMBAxilbundJEBuysS. NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 12012. Available at NCCN.org. Accessed June 18 2012.

    • Search Google Scholar
    • Export Citation
  • 18

    GonzalezKDBuzinCHNoltnerKAHigh frequency of de novo mutations in Li-Fraumeni. J Med Genet2009;46:689693.

  • 19

    MalkinDSmythKShumanC. Establishment of a dedicated cancer genetics program in a tertiary pediatric center [abstract]. Am J Hum Genet1999;65:Abstract 386.

    • Search Google Scholar
    • Export Citation
  • 20

    MasciariSDillonDDickMG. Breast cancer phenotype in women with TP53 germ-line mutations: an LFS consortium effort [abstract]. J Clin Oncol2011;29(Suppl):Abstract 1519.

    • Search Google Scholar
    • Export Citation
  • 21

    WilsonJRBatemanACHansonsH. A novel Her2 positive breast cancer phenotype arising from germline TP53 mutations. J Med Genet2010;47:771774.

    • Search Google Scholar
    • Export Citation
  • 22

    Melhem-BertrandtABojadzievaJReadyKJ. Early onset Her2-positive breast cancer is associated with germline TP53 mutations. Cancer2012;118:908913.

    • Search Google Scholar
    • Export Citation

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Correspondence: Eve Henry, MD, 300 Pasteur Drive, Room S-101, Stanford CA 94305. E-mail address: eve.henry@gmail.com

Article Sections

Figures

  • View in gallery

    CT thorax with a left chest wall mass arising from the serratus anterior muscle (arrow).

  • View in gallery

    Spindle cell lesion with hyperchromatic, pleomorphic nuclei with increased mitotic activity. Desmin/actin positive; p63/S100/CD31/CD34 negative. Hematoxylin-eosin, original magnification x400.

  • View in gallery

    Isodose distribution of left breast irradiation.

  • View in gallery

    Pedigree.

    Abbreviations: ca, cancer; d, age at death; dx, age at diagnosis; ER, estrogen receptor; PR, progesterone receptor.

References

  • 1

    OlivierMGoldgarDESodhaN. Li-Fraumeni and related syndromes: correlation between tumor type, family structure, and TP53 genotype. Cancer Res2003;63:66436650.

    • Search Google Scholar
    • Export Citation
  • 2

    GonzalezKDNoltnerKABuzinCH. Beyond Li Fraumeni syndrome: clinical characteristics of families with p53 germline mutations. J Clin Oncol2009;27:12501256.

    • Search Google Scholar
    • Export Citation
  • 3

    LustbaderEDWilliamsWRBondyML. Segregation analysis of cancer in families of childhood soft tissue sarcoma patients. Am J Hum Genet1992;51:344356.

    • Search Google Scholar
    • Export Citation
  • 4

    HisadaMGarberJEFungCY. Multiple primary cancers in families with Li-Fraumeni syndrome. J Natl Cancer Inst1998;90:606611.

  • 5

    LimacherJMFrebourgTNatarajan-AmeSBergeratJP. Two metachronous tumours in the radiotherapy fields of a patient with Li-Fraumeni syndrome. Int J Cancer2001;96:238242.

    • Search Google Scholar
    • Export Citation
  • 6

    CohenRJCurtisREInskipPDFraumeniJFJr. The risk of developing second cancers among survivors of childhood soft tissue sarcoma. Cancer2005;103:23912396.

    • Search Google Scholar
    • Export Citation
  • 7

    KonySJde VathaireFChrompretA. Radiation and genetic factors in the risk of second malignant neoplasm’s after a first cancer in childhood. Lancet1997;350:9195.

    • Search Google Scholar
    • Export Citation
  • 8

    LiFPFraumeniJFJrMulvihillJJ. A cancer family syndrome in twenty-four kindreds. Cancer Res1988;48:53585362.

  • 9

    HeymannSDelalogeSRahalA. Radio-induced malignancies after breast cancer post operative radiotherapy in patients with Li-Fraumeni syndrome. Radiat Oncol2010;5:104109.

    • Search Google Scholar
    • Export Citation
  • 10

    TinatJBougeardGBaert-DesurmontS. 2009 version of the Chrompret criteria for Li-Fraumeni syndrome. J Clin Oncol2009;27:108109.

  • 11

    GreenburgCCLipsitzSRHughsME. Institutional variation in the surgical treatment of breast cancer: a study of the NCCN. Ann Surg2011;254:339345.

    • Search Google Scholar
    • Export Citation
  • 12

    LimacherJMFrebourgTNatarajan-AmeSBergeratJP. Two metachronous tumors in the radiotherapy fields of a patient with Li-Fraumeni syndrome. Int J Cancer2001;96:238242.

    • Search Google Scholar
    • Export Citation
  • 13

    PierceLJHafftyBG. Radiotherapy in the treatment of hereditary breast cancer. Semin Radiat Oncol2011;21:4350.

  • 14

    RubinoCde VathaireFShamsaldinA. Radiation dose, chemotherapy, hormonal treatment and risk of second cancer after breast cancer treatment. Br J Cancer2003;895:840846.

    • Search Google Scholar
    • Export Citation
  • 15

    KleinermanRA. Radiation-sensitivie gentetically susceptible pediatric sub-populations. Pediatr Radiol2009;39(Suppl 1):S2731.

  • 16

    SchneiderKGarberJ. Li-Fraumeni syndrome. In: PagonRABirdTDDolanCR eds. Gene Reviews. Seattle, WA: University of Washington; 1999.

  • 17

    DalyMBAxilbundJEBuysS. NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 12012. Available at NCCN.org. Accessed June 18 2012.

    • Search Google Scholar
    • Export Citation
  • 18

    GonzalezKDBuzinCHNoltnerKAHigh frequency of de novo mutations in Li-Fraumeni. J Med Genet2009;46:689693.

  • 19

    MalkinDSmythKShumanC. Establishment of a dedicated cancer genetics program in a tertiary pediatric center [abstract]. Am J Hum Genet1999;65:Abstract 386.

    • Search Google Scholar
    • Export Citation
  • 20

    MasciariSDillonDDickMG. Breast cancer phenotype in women with TP53 germ-line mutations: an LFS consortium effort [abstract]. J Clin Oncol2011;29(Suppl):Abstract 1519.

    • Search Google Scholar
    • Export Citation
  • 21

    WilsonJRBatemanACHansonsH. A novel Her2 positive breast cancer phenotype arising from germline TP53 mutations. J Med Genet2010;47:771774.

    • Search Google Scholar
    • Export Citation
  • 22

    Melhem-BertrandtABojadzievaJReadyKJ. Early onset Her2-positive breast cancer is associated with germline TP53 mutations. Cancer2012;118:908913.

    • Search Google Scholar
    • Export Citation

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