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Responses to the mTOR Inhibitor Sirolimus in Patients with Malignant PEComa. Andrew Wagner , Robert Maki, Cristina Antonescu, Christopher Fletcher, Jeffrey Morgan Dana-Farber Cancer Institute, Boston Brigham and Women’s Hospital, Boston Memorial Sloan-Kettering Cancer Center, New York

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responses to the mtor inhibitor sirolimus in patients with malignant pecoma

Responses to the mTOR Inhibitor Sirolimus in Patients with Malignant PEComa

Andrew Wagner, Robert Maki, Cristina Antonescu, Christopher Fletcher, Jeffrey Morgan

Dana-Farber Cancer Institute, Boston

Brigham and Women’s Hospital, Boston

Memorial Sloan-Kettering Cancer Center, New York

CTOS 2008, London

pecoma family of tumors
PEComa Family of Tumors
  • Lymphangioleiomyoma (LAM)
    • Cystic lung disease and numerous small lung nodules
    • Retroperitoneal masses
  • Angiomyolipoma (AML)
    • benign renal tumors
    • epithelioid AML = PEComa
  • Perivascular Epithelioid Cell tumor (PEComa)
  • Share common histologic appearance
  • Express MITF/TFE3 and melanocytic markers
lam aml tuberous sclerosis associated or sporadic
LAM/AML Tuberous Sclerosis-Associated or sporadic

Sabatini (2006) Nature Reviews Cancer 6:729

sirolimus in lam aml
Sirolimus in LAM/AML

47% tumor reduction

14%

Bissler et al (2008) NEJM 358:140

case series
Case Series
  • Review of 3 consecutive patients with metastatic or advanced PEComa
    • no known effective systemic therapies
  • Dana-Farber Cancer Institute
  • Memorial Sloan-Kettering Cancer Center
  • Clinical management with sirolimus by treating physician
patient 1 uterine pecoma
Patient 1 – Uterine PEComa

61 F with uterine bleeding in 2007

TAH - 9 cm PEComa arising from cervix

Staging studies – numerous bilateral pulmonary metastases

Sirolimus 4 mg, transiently increased to 8 mg but reduced to 4 mg for mild stomatitis

patient 1 uterine sarcoma
Patient 1 – Uterine Sarcoma

Restaging at 3 months showed significant progression of disease

  • Sirolimus level 5 ng/mL
  • Dose increased to 8 mg

Restaging 1 month later: further progression

  • Sirolimus level 7 ng/mL
  • Dose reduced to 2 mg and CYP450 3A4 inhibitor (clarithromycin) added; level 20 ng/mL

Restaging 1 month later showed decrease/stabilization in size of disease

patient 2 renal pecoma
Patient 2 – renal PEComa

70 M with hematuria in 2001

  • Radical nephrectomy – 9 cm mass
  • Poorly differentiated sarcomatoid variant

of clear cell adenocarcinoma

2006 Local recurrence resected

2007 Right flank pain from local-regional recurrence

  • Sunitinib started; progression of disease after 6 weeks

2008 Pathology review at MSKCC: PEComa

  • Sirolimus 4 mg oral daily – diarrhea and fatigue
  • Dose reduced to 1 mg oral daily with improvement in symptoms.
  • Restaging at 6 weeks – PR
  • Dose reduced to 1 mg qod. Sirolimus level 5-10 ng/mL
patient 3 retroperitoneal pecoma
Patient 3 – Retroperitoneal PEComa

65 M with 20 cm RP PEComa resected in 2005, complicated by preoperative tumor rupture

2007 multifocal RP recurrence resected, with further recurrence 3 months later

Phase I Met inhibitor – rapid progression

2008 – started sirolimus 8 mg/d; level 36 ng/mL

mtor activation in malignant pecoma
mTOR activation in malignant PEComa

Sabatini (2006) Nature Reviews Cancer 6:729

phospho s6 immunohistochemistry
phospho-S6 Immunohistochemistry

Iza Malinowska and David Kwiatkowski, Brigham and Women’s Hospital

multiplex ligation dependent probe amplification mlpa
Multiplex Ligation-Dependent Probe Amplification (MLPA)

Iza Malinowska, Wei Qin, David Kwiatkowski, Brigham and Women’s Hospital

conclusions
Conclusions
  • mTOR activation, through loss of inhibition by TSC1/2 or other means, is important in growth of malignant PEComa
  • Potential dose-dependent effect of mTOR inhibitor
  • A clinical study of mTOR inhibition in malignant PEComa is warranted
thank you
DFCI

Amy Potter, NP

Kathy Polson, NP

Bonnie Dirr, NP

James Butrynski, MD

Jeff Morgan, MD

Suzanne George, MD

George Demetri, MD

Chan Raut, MD

BWH

Iza Malinowska, PhD

Wei Qin, PhD

David Kwiatkowski, MD, PhD

Jason Hornick, MD, PhD

Alessandra Nascimento, MD

Christopher Fletcher, MD

MSKCC

Robert Maki, MD, PhD

Cristina Antonescu, MD

Ludwig Center for Cancer Research at DF/HCC

SPECIAL Fund for PEComa Research

The Patients and their families

Thank You!