In 1995, Drs. Hellman and Weichselbaum proposed an intermediate state of metastasis between purely localized disease and widespread metastasis, which they named oligometastasis. . The concept of oligometastasis has important implications for cancer treatment because patients with limited numbers of metastasis previously thought by some clinicians to be incurable might be cured with local cancer treatments such as radiotherapy or surgery. At the Ludwig Center, we have conducted several clinical trials and laboratory experiments in order to better understand the mechanism of metastasis in general and oligometastasis specifically. We also investigate the molecular markers of oligometastasis to identify patients who might benefit from metastasis directed therapies.
MECHANISMS OF OLIGOMETASTASIS
Recently, we identified patterns of microRNA expression from tumor samples from oligometastatic patients treated with high-dose radiotherapy. Patients who failed to develop full metastases are characterized by unique prioritized features of a microRNA classifier that includes the microRNA-200 family. The results of this study demonstrated a biological basis for oligometastasis and the potential for using microRNA expression to identify patients most likely to remain oligometastatic after treatment. We were able to change the oligo- to polymetastatic phenotype by expression of microRNA 200c in oligometastatic experimental murine tumors In a separate study, we investigated a more homogenous group of pateints who underwent resection for lung metastasis. We discovered that oligo- and polymetastatic progression in lung metastasis patients is also associated with expression specific microRNAs. Patients were stratified into subgroups based on their rate of metastatic progression. A prioritized set of microRNAs distinguished high rates of progression from low rates of progression and were associated with rate of metastatic progression and survival in an independent validation dataset (the first more heterogenous patient group descrived above). Interestingly, there was little overlap between the microRNA sets; however, common biological themes emerge in the context of the metastatic cascade. This work was done in collaboration with Drs, Mitchell Posner (Surgical Oncology); Mark Ferguson (Thoracic Surgery); Nikolai Khodarev, Steve Chmura, and Joe Salama (Radiation Oncology); and Yves Lussier (Bioinformatics at the University of Illinois, Chicago). We are expanding our investigation to a broader definition of the role of microRNA within the metastatic cascade with Dr Geoffrey Green D.K. Ludwig Professor, Associate Director of the Ben May Department for Cancer Research and Co-Director of the Ludwig Center for Metastasis Research.
TREATMENT OF OLIGOMETASTASIS WITH STEREOTACTIC BODY RADIOTHERAPY (SBRT)
One of the most promising treatments for oligometastasis is SBRT, which offers greater precision and allows much higher doses to limited target volumes than previous radiation delivery technologies. In an initial study of the safety and effectiveness of metastasis-directed SBRT for multisite extracranial oligometastases, we reported progression-free survival rates of 33.3% and 22.0% at the one and two year marks. The overall survival rate was 81.5% and 56.7% at the one and two year mark. Of the patients whose tumors did progress, 72% did so in limited (1-3) metastatic sites. This study considered with the previous biological studies suggest that the oligometastatic state exists and that some patients may experience a survival benefit from SBRT or surgery.
We have also investigated the use of SBRT for the treatment of oligometastatic renal cell carcinoma. Although renal cell carcinoma (RCC) is widely considered to be radioresistant, SBRT can control intracranial metastases associated with RCC. In this study, patients with RCC and limited metastases were treated on a 3-fraction dose-escalation protocol or an off protocol with 10 fractions. The treatment was well tolerated by most patients, with the most common acute toxicity being fatigue. After two years, local tumor (irradiated metastasis) control was 91.4% and the overall survival rate was 85%. Those patients who underwent treatment for all metastatic sites had a 2 year lesion control rate of 100% and distant control rate of 35.7%.
In another clinical investigation of SBRT for patients with limited volume metastatic non-small cell lung cancer (NSCLC), we reported that SBRT provides durable lesion control and may provide some patients with long-term progression-free survival. The 18-month local control, distant control, overall survival and progression-free survival rates were 66.1%, 31.7%, 52.9% and 28.0%. In the previous section on radiotherapy and immunity we noted that large fraction sizes may induce anti-tumor immunity. We are planning clinical studies in oligometastasis with immune modifiers such as Ipilimumab.
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Salama JK, Hasselle MD, Chmura SJ, Malik R, Mehta N, Yenice KM, Villaflor VM, Stadler WM, Hoffman PC, Cohen EE, Connell PP, Haraf DJ, Vokes EE, Hellman S, Weichselbaum RR. Stereotactic body radiotherapy for multisite extracranial oligometastases: final report of a dose escalation trial in patients with 1 to 5 sites of metastatic disease. Cancer. 2012 Jun 1; 118 (11) :2962-70. PubMed PMID:22020702.
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Hasselle MD, Haraf DJ, Rusthoven KE, Golden DW, Salgia R, Villaflor VM, Shah N, Hoffman PC, Chmura SJ, Connell PP, Vokes EE, Weichselbaum RR, Salama JK. Hypofractionated image-guided radiation therapy for patients with limited volume metastatic non-small cell lung cancer. J Thorac Oncol. 2012 Feb; 7 (2) :376-81. PubMed PMID:22198429.
Duarte CW, Willey CD, Zhi D, Cui X, Harris JJ, Vaughan LK, Mehta T, McCubrey RO, Khodarev NN, Weichselbaum RR, Gillespie GY. Expression signature of IFN/STAT1 signaling genes predicts poor survival outcome in glioblastoma multiforme in a subtype-specific manner. PLoS One. 2012; 7 (1) :e29653. PubMed PMID:22242177; PubMed Central PMCID: PMC3252343.
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Lussier YA, Xing HR, Salama JK, Khodarev NN, Huang Y, Zhang Q, Khan SA, Yang X, Hasselle MD, Darga TE, Malik R, Fan H, Perakis S, Filippo M, Corbin K, Lee Y, Posner MC, Chmura SJ, Hellman S, Weichselbaum RR. MicroRNA expression characterizes oligometastasis(es). PLoS One. 2011; 6 (12) :e28650. PubMed PMID:22174856; PubMed Central PMCID: PMC3236765.
Lussier, YA, Khodarev NN, Regan K, Corbin K, Li H, Khan SA, Gnerlich, J, Darga TE, Fan H, Karpenko O, Paty PB, Posner MC, Chmura SJ, Hellman S, Ferguson MK, Weichselbaum RR. Oligo- and polymetastatic progression in lung metastasis(es) patients is associated with specific microRNAs.IN PRESS.
Khodarev NN, Roach P, Pitroda SP, Golden DW, Bhayani M, Shao MY, Darga TE, Beveridge MG, Sood RF, Sutton HG, Beckett MA, Mauceri HJ, Posner MC, Weichselbaum RR. STAT1 pathway mediates amplification of metastatic potential and resistance to therapy. PLoS One. 2009 Jun 8; 4 (6) :e5821. PubMed PMID:19503789; PubMed Central PMCID: PMC2688034.