Radioterapia nella malattia oligometastatica. Fiorenza De Rose, M.D., Radiotherapy and Radiosurgery Dep. Humanitas Clinical and Research Hospital

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1 Radioterapia nella malattia oligometastatica Fiorenza De Rose, M.D., Radiotherapy and Radiosurgery Dep. Humanitas Clinical and Research Hospital

2 OUTLINE Definition of oligometastatic state Local ablative approach : SBRT Selection of patients SBRT in OMBC: clinical results Future directions

3 Definition of oligometastatic state An oligometastatic state is an intermediate state between purely localized lesions and those widely metastatic. The state was expounded to be amenable to a curative therapeutic strategy and amenable to localized therapy. Hellman S, Weichselbaum RR. JCO 1995

4 Definition of oligometastatic state Widely Metastatic Disease Limited Metastatic Disease Distinct clinical state Metastases limited in number and site (3 to 5 in 1-3 sites) More indolent biology Amenable to local ablative approaches

5 Definition of oligometastatic state Oligometastatic state includes different clinical situations Oligometastases de novo

6 Definition of oligometastatic state Oligometastatic state includes different clinical situations Induced oligometastases CT / OT

7 Definition of oligometastatic state Oligometastatic state includes different clinical situations Oligoprogression Follow up

8 Oligometastatic Breast Cancer Prevalence of OMBC «49 57 % of metastatic breast cancer patients enrolled on major phase II and phase III clinical trials of systemic therapy have 2 or fewer clinically detected metastases» Salama JK, Chmura SJ. The role of Surgery and ablative radiotherapy in oligometastatic breast cancer. Seminars in Oncology 2014; 41 (6):

9 OUTLINE Definition of oligometastatic state Local ablative approach : SBRT Selection of patients SBRT in OMBC: clinical results Future directions

10 Local ablative therapies Surgery SBRT MWA RFA HIFU

11 Surgery Of the 5 most common cancer types, colorectal cancer has been the subject of the largest number of studies of metastasectomy with demonstrated 5-year survival rates of >50%, and 10-year survival ranging from 17% to 36%. The role of metastasectomy in other cancer types remains more controversial. Multiple metastasectomy series have now been published for breast cancer, lung cancer, and melanoma, all of which with relatively favorable survival in carefully selected patients, but the series are smaller and less frequently report long-term follow-up. Bartlett EK Cancer 2015

12 Surgery vs SBRT Metastasectomy increases local control with significant improvement of survival in selected patients Most patients are inoperable for comorbidities or sites of metastases

13 SBRT 2010 Stereotactic body radiation therapy (SBRT) is an external beam radiation therapy method used to very precisely deliver a high dose of radiation to an extracranial target within the body, using either a single dose or a small number of fractions. The ability to deliver a single or a few fractions of high-dose ionizing radiation with high targeting accuracy and rapid dose falloff gradients encompassing tumors within a patient provides the basis for the development of SBRT.

14 SBRT 2015 Most common sites: lung (90%) spine (68%) liver (63%) bones (58%) adrenals (39%)

15 OUTLINE Definition of oligometastatic state Local ablative approach : SBRT Selection of patients SBRT in OMBC: clinical results Future directions

16 Selection of patients 2017 desouza NM et al 18 F-FDG PET/CT is favoured in breast cancer (with WB-MRI as an alternative) but needs supplementing with liver-specific MRI Brain imaging (MRI) is only warranted in the presence of extra-cranial disease or in patients with neurological symptoms

17 Selection of patients MicroRNA Expression Characterizes Oligometastasis(es) Yves A. Lussier 1,2,3,4 *, H. Rosie Xing 1,2,5,6., Joseph K. Salama 8., Nikolai N. Khodarev 1,5., Yong Huang 1,3., Qingbei Zhang 3,6., Sajid A. Khan 7., Xinan Yang 3., Michael D. Hasselle 5., Thomas E. Darga 5, Renuka Malik 5, Hanli Fan 6, Samantha Perakis 5, Matthew Filippo 5, Kimberly Corbin 5, Younghee Lee 3, Mitchell C. Posner 7, Steven J. Chmura 5, Samuel Hellman 2,5, Ralph R. Weichselbaum 1,2,5 * 1 Comprehensive Cancer Center, University of Chicago, Chicago, Illinois, United States of America, 2 Ludwig Center for Metastasis Research, University of Chicago, Chicago, Illinois, United States of America, 3 Department of Medicine Center for Biomedical Informatics, University of Chicago, Chicago, Illinois, United States of America, 4 Institute for Genomics and Systems Biology, University of Chicago, Chicago, Illinois, United States of America, 5 Department of Radiation and Cellular Oncology, University of Chicago, Chicago, Illinois, United States of America, 6 Department of Pathology Committee on Cancer Biology, University of Chicago, Chicago, Illinois, United States of America, 7 Department of Surgery, University of Chicago, Chicago, Illinois, United States of America, 8 Department of Radiation Oncology Duke University Medical Center, Durham, North Carolina, United States of America Abst we racthave identified microrna expression features of a potential Background: Cancer classifier staging and treatment that presumes predict a division into the localized distinct or metastatic disease. outcomes We proposed anof intermediate state defined by # 5 cumulative metastasis(es), termed oligometastases. In contrast to widespread metastatic polymetastases, oligometastatic patientswho may benefit maintained from metastasis-directed stable local treatments. oligometastatic However, many patients who initially present with oligometastases progress to polymetastases. Predictors of progression could improve patient selection for metastasis-directed therapy. disease from those who progressed to polymetastases. Methods: Here, we identified patterns of microrna expression of tumor samples from oligometastatic patients treated with We high-dose also radiotherapy. provide biological confirmation for molecular differences, Results: Patients who failed in tothis develop case polymetastases the are characterized microrna by unique prioritized regulation, features of a microrna that classifier that includes the microrna-200 family. We created an oligometastatic-polymetastatic xenograft model in which the patient-derived micrornas discriminated between the two outcomes. MicroRNA-200c enhancement in an underlie oligometastic to polymetastatic progression. oligometastatic cell line resulted in polymetastatic progression. 2011

18 Selection of patients 2016 Wong AC, et al. A candidate classifier using expression levels of 3 micrornas (mir-23b, mir-449a, and mir-449b) predicted survival among 17 patients who had primary tumor microrna expression data available

19 2013 Selection of patients

20 2018 Selection of patients

21 Selection of patients metastatic lesion (versus 2 5) Smaller tumor volume Bone-only disease Stable or regressing lesions prior to SBRT Positive hormone receptor status Pathologic nodal stage of primary cancer Solitary bone metastasis Whole-lesion RT 2015 DFI >12 months Hormonal receptor positivity Medical therapies after SBRT 2016

22 OUTLINE Definition of oligometastatic state Local ablative approach : SBRT Selection of patients SBRT in OMBC: clinical results Future directions

23 Clinical results: SBRT in OMBC 59% 4-year OS MBC patients 25.9% 5-year OS (SEER database Cancer Statistic Review, 2015)

24 Clinical results: SBRT in OMBC «This review provides preliminary evidence that ablative radiotherapy may play an important role in management of oligometastatic breast cancer and its use is rapidly gaining consensus due to its non-invasive nature, excellent safety profile, established efficacy in achieving durable local control in a cost-effective manner»

25 Clinical results: SBRT in OMBC BMBC incidence between 3% and 6% in early-stage, and up to 30% in stage IV disease Triple negative MBC patients have 25-46% estimated probability of brain recurrence (vs 10% in Hormone receptor positive HER2 negative MBC) High heterogeneity in dose/fractionation and modalities (WBRT/SRS/Surgical resection) 2-year LC ranged from 73% to 83% and 2-year OS from 41% to 21% Radionecrosis ranged from 4% to 10,6% (excluding Geraud et al study)

26 Clinical results: SBRT in OMBC OS 2-years 66% - 95% PFS 2-years TOX </= 18% 2-53% LC 1-3 years. 87% - 98%

27 OUTLINE Definition of oligometastatic state Local ablative approach : SBRT Selection of patients SBRT in OMBC: clinical results Future directions

28 2016 Future directions

29 Future directions 2017 local SBRT is able to induce systemic effects influencing the antitumor immune response in oligometastatic BC patients. Liquid biopsy may thus represent a useful resource to monitor the potential immunogenic effect of SBRT that in turn could contribute to the curative potential of this treatment not only locally but also systemically.

30 Ongoing trials SABRT-COMET Trial: Standard of care (Palliative RT and CT) +/- SBRT - Any primary tumor site - Maximum 3 metastases in any single organ system (i.e. lung, liver, brain, bone) - Primary endpoint: OS - Closed for accrual (99 partecipants) NRG BR002: Standard of care systemic therapy +/- SBRT or Surgery - Breast cancer only Metastatic lesions - Primary endpoints: PFS - OS - Open for accrual (402 partecipants) CORE Trial: Standard of care (CT, HT, Surgery or Palliative RT) +/- SBRT - Breast, Stereotactic Prostate and radiation NSCLC also doubled survival without cancer growth. -Patients A maximum who received of 2 different stereotactic organs (e.g ablative liver, radiotherapy lung, bone, nodal) experienced may contain a median metastases overall survival but the of total 41 months number vs of 28 lesions months must in not the exceed standard 3 radiation arm (P =.09). -Progression-free Primary endpoint: survival PFS was 12 months in the stereotactic arm vs 6 months for those -who Open received for accrual standard (206 radiation partecipants) (P =.001).

31 Ongoing trials Prospective Non-randomized Phase II Study on SBRT for Medically Inoperable Lung and Liver Oligometastases From Breast Cancer Breast cancer only Lung and liver lesions < 5 (with maximum diameter < 5 cm) DFI (Disease-free interval) > 1 year No extrapulmonary and/or extrahepatic disease or other metastatic sites stable or responding after chemotherapy Partecipating centers: Humanitas Rozzano, IRCCS Negrar (57 partecipants) Primary endpoints: Toxicity and LC Start date July 2015 Standard of Care + SBRT Lung and liver stereotactic radiation therapy (SRT) in oligometastatic breast cancer patients medically inoperable, using VMAT RapidArc approach. Chemotherapy completed at least 3 weeks before treatment and started at least 2 weeks after treatment is allowed. Systemic therapies other than chemotherapy allowed (i.e hormonal therapies and/or immunotherapy) OPEN FOR ACCRUAL

32 Registry Trials

33 Conclusions Oligometatatic BC is a distinct state characterized by an indolent biology and associated with a favorauble prognosis SBRT should improve clinical outcome Selection of the true oligometastatic patient is the challenge Level 1 evidence lacking Need to enroll oligometastatic patients into randomized trials

34 Thank you