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, BostonBrigham and Women’s Hospital, BostonMemorial Sloan-Kettering Cancer Center, New York
CTOS 2008, London
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
Sabatini (2006) Nature Reviews Cancer 6:729
LAM/AML Tuberous Sclerosis-Associated or sporadic
Bissler et al (2008) NEJM 358:140
47% tumor reduction 14%
Sirolimus in LAM/AML
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
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 1Uterine PEComa, 6 weeks
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 PEComa70 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 2 – Perirenal PEComa6 months on sirolimus
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
Patient 3 Retroperitoneal PEComa, 9 months
Sabatini (2006) Nature Reviews Cancer 6:729
mTOR activation in malignant PEComa
Iza Malinowska and David Kwiatkowski, Brigham and Women’s Hospital
phospho-S6 Immunohistochemistry
Multiplex Ligation-Dependent Probe Amplification (MLPA)
Iza Malinowska, Wei Qin, David Kwiatkowski, Brigham and Women’s Hospital
Site Uterine Renal RP
Sirolimus Level
(ng/mL)22 5-10 36
TSC1/2
statusComplete TSC1 loss ? TSC2 LOH
ResponseTransient shrinkage,
SDPR PR
Conclusions
1. mTOR activation, through loss of inhibition by TSC1/2 or other means, is important in growth of malignant PEComa
2. Potential dose-dependent effect of mTOR inhibitor
3. A clinical study of mTOR inhibition in malignant PEComa is warranted
Thank You!DFCIAmy Potter, NPKathy Polson, NPBonnie Dirr, NPJames Butrynski, MDJeff Morgan, MDSuzanne George, MDGeorge Demetri, MDChan Raut, MD
BWHIza Malinowska, PhDWei Qin, PhDDavid Kwiatkowski, MD, PhD
Jason Hornick, MD, PhDAlessandra Nascimento, MDChristopher Fletcher, MD
MSKCCRobert Maki, MD, PhDCristina Antonescu, MD
Ludwig Center for Cancer Research at DF/HCC
SPECIAL Fund for PEComa Research
The Patients and their families