Role of Primary Resection for Patients with Oligometastatic Disease

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1 GBCC 2018, April 6, Songdo ConvensiA, Incheon, Korea Panel Discussion 4, How Can We Better Treat Patients with Metastatic Disease? Role of Primary Resection for Patients with Oligometastatic Disease Tadahiko Shien, Maya Uno, Ryo Yoshioka, Mariko Kochi, Takahiro Tsukioki, Yuko Takahashi, Kengo Kawada, Hirokuni Ikeda, Takayuki Iwamoto, Naruto Taira, Hiroyoshi Doihara. Dept. of Breast and Endocrine Surgery,Okayama University Hospital.

seed and soil theory of cancer spread The outcome of metastasis was not due to chance, but that certain tumour cells have specific affinity for the milieu of certain organs.

2 seed and soil theory of cancer spread The outcome of metastasis was not due to chance, but that certain tumour cells have specific affinity for the milieu of certain organs. He concluded that metastases formed only when the seed and soil were compatible. Metastatic Breast Cancer is systemic disease. The aim of treatment by the systemic drugs is to prolong survival and palliate symptoms. What is the aim of surgery for Stage IV BC? Stephen Paget ( ) Paget, S. The distribution of secondary growths in cancer of the breast. Lancet 1, (1889).

3 Primary tumor resection for Stage IV BC aim 1 Pathological and biological diagnosis of tumor aim 2 Treatment - prolongation of survival local symptom control

4 Primary tumor resection for Stage IV BC aim 1 Pathological and biological diagnosis of tumor : We can get enough specimen by needle biopsy. aim 2 Primary tumor resection is not needed. Treatment ~ prolongation of survival local symptom control

5 Primary tumor resection for Stage IV BC aim 1 Pathological and biological diagnosis of tumor aim 2 Treatment : Can the primary tumor resection prolong the overall survival or progression free survival? Is the early surgery effective to control the local symptoms?

6 Meta-analysis of retrospective study reports. Surgical treatment of the primary tumour improves the overall survival in patients with metastatic breast cancer: A systematic review and meta-analysis Headon H, et al. Mol Clin Oncol May;4(5): Prognostic factors: complete excision of the primary tumor, metastasis only to bone and/or soft tissue, few metastases younger

ELIGIBLE PATIENTS FROM 14 DIFFERENT INSTITUTIONS WERE ENROLLED IN TWO COHORTS COHORT A: INTACT PRIMARY

7 ELIGIBILITY DE NOVO STAGE IV BREAST CANCER WITH AN INTACT PRIMARY TUMOR METASTATIC DISEASE IDENTIFIED WITHIN 3 MOS OF PRIMARY SURGERY TISSUE FROM PRIMARY TUMOR AND METASTATIC LESION FROM 7/09-4/12, 127 ELIGIBLE PATIENTS FROM 14 DIFFERENT INSTITUTIONS WERE ENROLLED IN TWO COHORTS COHORT A: INTACT PRIMARY TUMOR (N=112) COHORT B: METASTASES WITHIN 3 MONTHS OF PRIMARY SURGERY (N=15) King T. et al 2013 SABC Symposium

8 Prospective cohort study intact primary tumor (n=112) metastases within 3 months of primary surgery (n=15) King T. et al 2013 SABC Symposium

9 Prospective cohort study King T. et al 2013 SABC Symposium

10 Prospective cohort study King T. et al 2013 SABC Symposium

11 Prognostic Impact of 21-Gene Recurrence Score in Patients With Stage IV Breast Cancer: TBCRC 013. King TA, et al. J Clin Oncol Jul 10;34(20):

12 Prognostic Impact of 21-Gene Recurrence Score in Patients With Stage IV Breast Cancer: TBCRC 013. King TA, et al. J Clin Oncol Jul 10;34(20):

13 Prognostic Impact of 21-Gene Recurrence Score in Patients With Stage IV Breast Cancer: TBCRC 013. TTP 2-Year OS HR (95% CI) P HR (95% CI) P RS, 50 points 5.36 (1.28 to 22.51) (1.89 to 224.2).013 RS, 10 points 1.40 (1.05 to 1.86) (1.14 to 2.95).013 Age at diagnosis, years 0.99 (0.96 to 1.02) (0.97 to 1.06).655 Tumor size, cm 1.07 (0.94 to 1.22) (0.79 to 1.25).972 Site first metastases 0.57 (0.28 to 1.16) (0.28 to 2.48).737 Multivariable Cox Regression Models for TTP and 2-Year OS Among Patients With ER- Positive/HER2-Negative De Novo Stage IV Disease King TA, et al. J Clin Oncol Jul 10;34(20):

14 Randomized clinical trials to evaluate surgery for Stage IV BC. Country Initial therapy Accrual period Sample size Accrual As of India CAF±T (done) finish Japan USA and Canada Systemic therapy Systemic therapy / /367 May / / (done) finish Turkey Surgery (done) finish Netherlands Surgery Low Oct 2013 Austria Surgery Dec 2013

15 Prospective randomized trials Locoregional treatment versus no treatment of the primary tumour in metastatic breast cancer: an open-label randomized controlled trial. MBC Anthracycliens +/- taxanes (CR/PR) R Loco-Regional Rx No Loco- Regional Rx Stahel RA, et al. Lancet Oncol Dec;16(16):

16 Locoregional treatment of the primary tumor did not affect overall survival. Kaplan-Meier plot of overall survival Forest plot of overall survival subgroup analyses, unadjusted hazard ratios Stahel RA, et al. Lancet Oncol Dec;16(16):

17 The primary tumor surgery cannot prolong the OS and moreover, will induce the worse prognosis for de novo stage IV BC patients. locoregional Distant Surgery No Surgery No Surgery Surgery Kaplan-Meier plot of locoregional progression-free survival (A) and distant progression-free survival (B) Stahel RA, et al. Lancet Oncol Dec;16(16):

18 The systemic therapies were not selected according to breast cancer subtypes and not continued satisfactory. Locoregional treatment group No locoregional treatment group Patients with disease progression 142/173 (82%) 128/177 (72%) Lines of systemic chemotherapy* (taxane based, platinum based, capecitabine, and others), range (mean) 1 3 (1.3) 1 4 (1.6) Patients with HER2 3+ tumours 35/173 (20%) 55/177 (31%) HER2 targeted therapy received Lines of endocrine therapy* (tamoxifen, aromastase inhibitors, and progestins), range (mean) Premenopausal patients with hormone sensitive tumours 0/35 (0%) 8/55 (15%) 1 4 (1.17) 1 3 (1.36) 12/173 (69%) 7/177 (4%) Ovarian suppression 3/12 (25%) 5/7 (71%) Stahel RA, et al. Lancet Oncol Dec;16(16):

cancer at the presentation (Protocol MF07-01) MF07-01:

19 Randomized trial comparing locoregional resection of primary tumor with no surgery in stage IV breast cancer at the presentation (Protocol MF07-01) MF07-01: DESIGN Presented By Atilla Soran at 2016 ASCO Annual Meeting

20 Primary tumor resection as the initial treatment for newly diagnosed Stage IV breast cancer significantly prolonged overall survival. SLIDE 13 Presented By Atilla Soran at 2016 ASCO Annual Meeting

21 SLIDE 21 Presented By Atilla Soran at 2016 ASCO Annual Meeting

22 A randomized controlled trial comparing primary tumor resection plus systemic therapy with systemic therapy alone in metastatic breast cancer [PRIM-BC] I) ER-positive patients with no life-threatening diseases Premenopausal Post menopausal Oral tamoxifen 20 mg/body daily plus goserelin 3.6 mg/body every 4 weeks Oral letrozole 2.5 mg/body daily for 4 weeks II) ER-negative and/or life-threatening diseases HER2- positive HER2- negative [before Jan 2014] Paclitaxel (PTX) plus weekly trastuzumab every 4 weeks [after Jan 2014] Docetaxel plus trastuzumab, pertuzumab every 3 weeks PTX every 4 weeks

23 A randomized controlled trial comparing primary tumor resection plus systemic therapy with systemic therapy alone in metastatic breast cancer [PRIM-BC] Primary endpoint: Overall survival Secondary endpoints: The proportion of patients without tumor progression at the metastatic sites Yearly local recurrence-free survival Proportion of local ulcer/local bleeding Yearly primary tumor resection-free survival Adverse events of chemotherapy, operative morbidity, serious adverse events This study was supported by a Grant-in-Aid for the Practical Research for on Innovative Cancer Control from the Japan Agency for Medical Research and Development, AMED (17ck h0001).

24 Accrual in JCOG1017 (2 nd registration n=410)

25 Difference of treatment strategy for Stage IV BC according to prospective studies Country Sample size Primary therapy Adjuvant RT after Op. Systemic therapy after Op. India 350 systemic X X Japan 600/410 systemic X USA and Canada 368/258 systemic Turkey 281 surgery X

26 JCOG gastric cancer group Gastrectomy plus chemotherapy versus chemotherapy alone for advanced gastric cancer with a single non-curable factor (REGATTA) REGATTA was an open-label, randomised, phase 3 trial done by the Japan Clinical Oncology Group (JCOG; JCOG0705) and the Korean Gastric Cancer Association (KGCA; KGCA01). advanced gastric cancer with a single non-curable factor liver (H1), peritoneum (P1), para-aortic lymph nodes (16a1/b2) R Primary endpoint: overall survival Secondary endpoints: progression free survival, adverse events etc. Patients (chemo alone 86 vs. Chemo + Surgery 89) Chemotherapy alone Gastrectomy + Chemotherapy Fujitani K, Han-Kwang Yang,et al. Lancet Oncol Mar;17(3):

27 Results of REGATTA trial Median OS: Chemo alone 16.6 mo. Chemo + Gastrectomy. 14.3mo. Discussion We believe that this impaired compliance with chemotherapy after gastrectomy accounted for the worse overall survival than with chemotherapy alone. No. of chemotherapy regimens Pts with upper-third tumours: gastrectomy, median 3 cycles chemotherapy alone, median 6 cycles Fujitani K, Han-Kwang Yang,et al. Lancet Oncol Mar;17(3):

28 JCOG colorectal cancer group A randomized controlled trial comparing resection of primary tumor plus chemotherapy with chemotherapy alone in incurable Stage IV colorectal cancer. (ipacs trial) Resectable colorectal cancer with distant metastatic disease R Primary endpoint:overall survival Secondary endpoints: Progression free survival, safety etc Chemotherapy alone Primary tumor surgery + Chemotherapy patients: (recruiting)

29 Conclusion Primary tumor resection for Stage IV BC is... unnecessary for pathological and biological diagnosis Overall survival benefit is under debate. (waiting other two studies reports.) PFS may be worse for patients without continuous systemic therapy after primary tumor surgery from Indian and GC trials. There is no prospective data indicating the efficacy of primary tumor surgery according to local symptom control. ( 10% pts including nosurgery arm received surgery in Indian and Turkish study.)

30 Please wait the report of JCOG trial! Thank you for your attention and invitation.

Mauricio Camus Appuhn Associate Professor Chief, Department of Surgical Oncology, Pontificia Universidad Católica de Chile

Mauricio Camus Appuhn Associate Professor Chief, Department of Surgical Oncology, Pontificia Universidad Católica de Chile May 18-20, 2017 18 a 20 de Maio / 2017 Castro's Park Hotel Surgery for metastatic breast cancer: the controversy of local surgery for metastatic breast cancer Cirurgia em câncer de mama metastático: a