Hormone-Independent Metastatic Breast Cancer. Beth Overmoyer MD, FACP Assistant Professor of Medicine HMS Dana Farber Cancer Institute SOBO 2012

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1 Hormone-Independent Metastatic Breast Cancer Beth Overmoyer MD, FACP Assistant Professor of Medicine HMS Dana Farber Cancer Institute SOBO 2012

2 Metastatic Breast Cancer MBC is a heterogeneous disease without a standardized approach to treatment Goals of treatment reduce cancer-related symptoms and balance toxicities of treatment with benefit Goal is to extend life FDA gold standard improved OS Not necessarily feasible with current highlypretreated patient population PFS may be not be an adequate surrogate for OS

3 Association between progression-free survival (PFS) and overall survival (OS) by SPP* *SPP = Survival postprogression Broglio K R, Berry D A JNCI J Natl Cancer Inst 2009;101:

4 OS in MBC is it improving? Effect of therapy and improved imaging Overall Survival mo mo 22 mo mo Years Kaplan-Meier curves for OS for the 4 time cohorts from date of diagnosis of MBC. ECOG: OS by year of recurrence Year dx MBC DRFI < 3 yr DRFI > 3 yr P-value mo 34 mo < mo 33 mo < mo 31 mo < mo -- P=0.15 P=0.57 Chia SK et al. Cancer. 2007;110: Tevaarwerik, SABCS 2011 #P

5 What are the key decision factors needed to approach the treatment of MBC? Determine tumor subtype Hormone receptor positive, Her2 positive, triple negative, BRCA-associated: targeted therapy Hormone receptor positive primary endocrine therapy is indicated unless there is visceral crisis or short disease-free interval 1 Her2 positive Her2 directed therapy Triple negative or BRCA-associated PARP inhibitors? 1 Cochrane Database Vol 2, 2004

6 Changes in ER, PgR, and HER2 between the original primary and metastasis Heterogeneity within the original tumor and metastatic sites Amir E et al. JCO 2012;30:

7 Survival by discordance No compromise in outcome when therapy is directed to MBC ER/HER2 status Keep in mind differences in IHC b/ central and local laboratories Amir E et al. JCO 2012;30:

8 Understand the patient s disease course Determine type and number of prior therapies Is the cancer hormone-resistant? After 3-4 endocrine agents unlikely to gain further benefit Hormone receptor positive disease recurrence within a short DFI Know the disease-free interval Hormone receptor positive < 2 years = short DFI Was the adjuvant chemotherapy < 1 year or > 2 years prior to metastasis? Recurrence > 2 years cancer may be responsive to same drugs Recurrence < 1 year resistant to adjuvant therapy treatment

9 When should we use combination chemotherapy?

10 Principles of treatment with combination chemotherapy Metastatic breast cancer has inherent drug resistance Combination chemotherapy should reduce the different sensitive subpopulations of cancer cells leading to an improved disease response Cochrane analysis (2009) 43 randomized trials of single agent vs. combination chemotherapy (9742 pts) Combination therapy improved OS: HR=0.88, p< Combination therapy improved OS with taxanes (HR = 0.83) but not with anthracyclines (HR = 0.94) Cross-over design was absent in the majority of studies Conclusion insufficient data to state the net clinical benefit of combination therapy c/w sequential therapy Cochrane Rev, 2005

11 Combination vs sequential therapy: Landmark study = ECOG 1193 Response Median TTF Median Survival QOL Primary Endpoint was Response Rate Doxorubicin 60 mg/m 2 Paclitaxel 175 mg/m 2 /24 hr Doxorubicin + Paclitaxel 50/150 mg/m 2 /24 hr 36% 34% 47%* 6 mos. 6 mos. 8 mos.* 19 mos. 22 mos. 22 mos. = = = Crossover Responses: In the pre-taxane era, anthracyclines were considered the most effective therapy for metastatic disease Active single agent 43% RR A T T = 22% A = 20% NS Sledge et al. JCO 21:588-92, 2003

12 Combination taxane chemotherapy options Line of Rx 1 st 3 rd ORR (%) TTP (mo) OS (mo) X vs. XD (511) Capecitabine (X) 30% Cape/docetaxel (XD) 42%* 6.1* 14.5 * T vs. GT (529) 1 st Paclitaxel (T) 26.9% Gemcitabine/Paclitaxel (GT) 43.1%* 6.1* 18.6* Caution the use of combination chemotherapy may limit therapeutic options for future treatment O Shaughnessy J JCO 2002;20:2812 Albain K JCO 2008;26:3950

13 What is the optimal single agent taxane and what is the best schedule? ORR TTP OS CALGB 9840 (9342) Wkly paclitaxel 42% * 9 mo. * HR = 1.28 Q3w paclitaxel 29% 5 mo. Docetaxel Wkly docetaxel 20.3% 5.5 mo 18.6 mo Q3w docetaxel 35.6% * 5.7 mo 18.3 mo There is no best taxane Be aware of optimal schedule for the taxane of choice Siedman JCO 26:1642; Verrill ASCO 2007 #LBA 1005; Rivera E Cancer 112:1455, 2008

14 What is the role of nab-paclitaxel as first-line therapy for MBC? 302 first-line patients with MBC were accrued and randomized to 4 arms (300 received study drug and were evaluable) Arm A:nab-paclitaxel 300 mg/m 2 q3w n = 76 Randomization Arm B:nab-paclitaxel 100 mg/m 2 qw 3/4 n = 76 Arm C:nab-paclitaxel 150 mg/m 2 qw 3/4 n = 74 Arm D: Docetaxel 100 mg/m 2 q3w n = 74 Arms A, C, and D administered at the MTD MBC, metastatic breast cancer; MTD, maximum tolerated dose; qw 3/4, first 3 of 4 weeks; q3w, every 3 weeks. Gradishar WJ et al. J Clin Oncol. 2009;27(22):

15 First-Line nab -Paclitaxel vs Docetaxel Results: Overall Response Rate P =.024 P =.002 P <.001 % of Patients * 300 mg/m 2 q3w 100 mg/m 2 qw 3/4 150 mg/m 2 qw 3/4 100 mg/m 2 q3w nab-paclitaxel Docetaxel For overall comparisons, P =.224 for independent radiologist assessed ORR and <.001 for investigator assessed ORR. ORR, overall response rate; q3w, every 3 week; qw 3/4, first 3 of 4 weeks. Gradishar WJ, et al. J Clin Oncol. 2009;27(22):

16 First-Line nab -Paclitaxel vs Docetaxel Results: Progression-Free Survival (Independent Review) Progression-Free Survival (Proportion), Independent Assessment Months (A) nab-paclitaxel 300 mg/m 2 q3w 11.0 months (B) nab-paclitaxel 100 mg/m 2 qw 3/ months (C) nab-paclitaxel 150 mg/m 2 qw 3/ months (D) Docetaxel 100 mg/m 2 q3w 7.5 months Arms Overall B vs C C vs D Median PFS Independent P value.0498 NS.0065 The 150 mg/m 2 qw 3/4 dose of nab-paclitaxel demonstrated a longer median PFS than docetaxel NS, not significant; PFS, progression-free survival; q3w, every 3 weeks; qw 3/4, first 3 of 4 weeks. Gradishar WJ, et al. J Clin Oncol. 2009;27(22):

17 First-Line nab -Paclitaxel vs Docetaxel Results: Overall Survival Probability of Survival Months (A) nab-paclitaxel 300 mg/m 2 q3w 27.7 months (B) nab-paclitaxel 100 mg/m 2 qw 3/ months (C) nab-paclitaxel 150 mg/m 2 qw 3/ months (D) Docetaxel 100 mg/m 2 q3w 26.6 months Arms Overall C vs B C vs D Median OS P Value Hazard Ratio The 150 mg/m 2 qw 3/4 nab-paclitaxel arm resulted in the longest median OS compared with the other nab-paclitaxel regimens or docetaxel NS, not statistically significant; OS, overall survival; q3w, every 3 weeks; qw 3/4, first 3 of 4 weeks. Gradishar WJ, et al. Presented at ASCO Breast Cancer Symposium Sept 8-10, 2011, San Francisco, CA [abstract 275 ].

18 Is there an optimal strategy for sequencing single agent chemotherapy? NO! Be aware of prior treatment because of cumulative toxicity Anthracyclines cardiac Taxanes - neurotoxicity Other options of single agent treatment capecitabine, vinorelbine, gemcitabine New microtubule-targeting agents increase options of single agent therapy

19 Is there a benefit of chemotherapy beyond second or third-line? Novel microtubule-targeting agents

20 Single agent ixabepilone Epothilones effective in taxane-resistant and taxaneinsensitive cell lines Multiple phase II trials with single agent ixabepilone Beneficial in taxane, anthracycline, capecitabine resistant patients (N=113) Ixabepilone 40mg/m2 IV every 3 weeks ORR = 18.3%, CBR = 24.8% TTP = 3.1 mo, OS = 8.6 mo Toxicity: Neurotoxicity resolves after 5 weeks Neutropenia caution with liver dysfunction and CYP2D6 inhibitors The only epothilone FDA approved for use as single agent and in combination with capecitabine Perez EA, et al. JCO 2007, 25:3407

21 Capecitabine +/- Ixabepilone 048 (N=1221) 046 (N=752) Dosereduced I+C=609 C=612 I+C=375 C=37 7 I+C > 4 cycles=566 Primary Outcome OS PFS ORR (%) v PFS mo v. 7.0 HR P value (CI) ( ) OS mo HR P value HR (adj) P value * Sparano JCO 2010; ; Hortobagyi Br Ca Res Treat 2010;122:409;Valero Clin Br Ca 2012;12:240

22 Single agent eribulin : Halichondrin B analog HO HO HO H O H H O Me Me H H O O O O H H Halichondrin B H H Me O O Right Half O O O H O O Me O O H O H H 2 N OH E7389 OMe O O O O Me O H O O O H O H Marine sponge Halichondria okadai okadai.jpg Unique tubulin-based mechanism microtubule destabilizer Sequesters tubulin into nonfunctional aggregates binds to the ends of tubules Functionally irreversible mitotic block - accumulates cells in G2 - Induces apoptosis Full activity against taxane-resistant cell lines, specifically those with resistance based upon mutations in β-tubulin Mary Ann Jordan, Mol Can Ther 4:1086, 2005

23 Phase III EMBRACE Trial of Eribulin Versus Treatment of Physician s Choice for Heavily Pretreated MBC Eligibility criteria: Locally recurrent or metastatic breast cancer 2-5 prior chemotherapies: 2 for advanced disease Prior anthracycline and taxane Progression 6 months since last chemotherapy Neuropathy grade 2 R A N D O M I Z E 2 : 1) Eribulin mesylate 1.4 mg/m 2, days 1, 8 q 3 weeks Treatment of Physician s Choice (TPC) Any monotherapy approved for treatment of cancer or supportive care only Primary endpoint: OS Secondary endpoints: PFS, ORR, safety Twelves et al. J Clin Oncol 2010; 28(suppl):958s (abstract CRA1004).

24 Phase III EMBRACE Trial: Survival advantage TPC received: 96% chemotherapy: vinorelbine (25%), gemcitabine (19%), capecitabine (18%), taxanes (15%), anthracyclines (10%), or other (10%) 4% hormonal therapy No best supportive care or biologic therapies only Survival Eribulin (n = 508) TPC (n = 254) Median overall survival months months Median progressionfree survival a 3.7 months 2.2 months HR (95% CI) 0.81 ( ) 0.87 ( ) P Value.041*.14 b Response (n = 468) (n = 214) Overall response rate a 12% 5% NR.002 Clinical benefit rate a,c 23% 17% NR NR a Independent review b P =.02 for per-protocol patient population c CBR = CR + PR + SD 6 months Twelves et al. J Clin Oncol 2010; 28(suppl):958s (abstract CRA1004).

25 Phase III EMBRACE Trial: Overall Survival Cortes J Lancet 2011;377:914

26 Phase III EMBRACE Trial: Grade 3/4 Adverse Events Eribulin (n = 503) TPC (n = 247) Neutropenia 45% 21% Leukopenia 14% 6% Anemia 2% 4% Febrile Neutropenia 4% 1% Asthenia/Fatigue 9% 10% a Peripheral Neuropathy 8% 2% a Nausea 1% a 2% a Dyspnea 4% a 3% Hand-Foot Syndrome < 1% a 4% a a Grade 3 only The incidence of fatal adverse events related to treatment was 1% in both arms. Twelves et al. J Clin Oncol 2010; 28(suppl):958s (abstract CRA1004).

27 What is the optimal duration of chemotherapy for MBC?

28 Optimal duration of first-line chemotherapy: Improved Progression-free survival. Gennari A et al. JCO 2011;29:

29 Optimal duration of first-line chemotherapy: Improved overall survival. Gennari A et al. JCO 2011;29:

30 Approach to chemotherapy in MBC Determine the subtype of MBC and use targeted therapy if possible Triple negative disease Her2 positive disease Responsive hormone receptor positive disease without visceral crisis Sequencing treatment with single agents decreases toxicity and allows more options of treatment over a longer period of time Combination chemotherapy should be used for rapidly progressing disease The optimal duration of first-line chemotherapy is based upon the balance between toxicity and efficacy

31 What is the role of targeted therapy in hormone-independent, Her2 negative MBC?

32 Do angiogenesis inhibitors add to the benefit of chemotherapy?

33 Cochrane Breast Cancer Analysis of bevacizumab in MBC Chemotherapy w/wo bevacizumab 4 RCT first-line = 2,889 patients Superior PFS with bevacizumab First-line: HR=0.67 Second-line: HR=0.85 No benefit in OS First-line: HR=0.93 Second-line: HR=0.98 Higher rates of adverse events, but fewer treatment-related deaths (HR=0.60) Cochrane Library; on-line July 12, 2012

34 What is the optimal taxane to use with bevacizumab as first-line therapy for MBC? CALGB 40502/NCCTG N063H: stratified by adjuvant taxane use and hormonal status Arm A: paclitaxel 90 mg/m 2 qw3/4 n = 283 Randomization Arm B:nab-paclitaxel 150 mg/m 2 qw 3/4 n = 271 Arm C:ixabepilone 15 mg/m 2 qw 3/4 n = % with Bevacizumab 10mg/kg q2w Rugo H, ASCO 2012 #CRA1002

35 First-line taxane and bevacizumab for MBC Planned interim analysis PFS b/ paclitaxel and ixabepilone Crossed futility boundary closed July 2011 Prior exposure to taxanes correlated with shorter PFS Paclitaxel Nab-paclitaxel (P) Ixabepilone (P) Median PFS (mo) (P=.12) 7.6 (P<.001) TTF (mo) (P=.0005) 5.1 (P=.0014) OS (mo) (P=.92) 21 (P=.10) Rugo H, ASCO 2012 #CRA1002

36 First-line taxane and bevacizumab for MBC More hematologic and non-hematologic toxicity > grade 3 with nab-paclitaxel v. paclitaxel Fewer hematologic, more non-hematologic AE occurred with ixabepilone v. paclitaxel Grade 3 sensory / motor neurotoxicity Paclitaxel 16% / 2% Nab-paclitaxel 25% / 10% Ixabepilone -25% / 6% Unplanned subset analysis of PFS ER positive no difference TNBC no difference Exploratory analysis more d/c nab-paclitaxel (45% v. 15% other arms) Rugo H, ASCO 2012 #CRA1002

37 Conclusions bevacizumab Significant PFS advantage but no OS difference with BV across first-line studies and meta-analysis In MBC, the ability of Phase III trials to demonstrate treatment effect upon OS depends on the duration of survival postprogression (SPP) Higher chance of affecting OS in populations with short SPP (20 month SPP in 3 first-line trials) Low incidence of treatment-related deaths with BV Safety profile consistent with previous BV experience Paclitaxel is standard single agent first-line taxane to use with bevacizumab Broglio and Berry J Natl Cancer Inst. 101: Saad, Katz, and Buyse J Clin Oncol. 28: Burzykowski, et al J Clin Oncol. 26: O Shaughnessy et al. J Clin Oncol 2010; 28(suppl):115s (abstract 1005).

38 Who Benefits from anti-vegf Therapy?

39 Subtype that specifically benefits from addition of bevacizumab is not yet known Pooled analysis of 621 patients with TNBC from phase III trials of first-line bevacizumab plus chemotherapy benefit with bevacizumab Was not supported in CALGB Was an unplanned subset analysis Unclear who benefits from this therapy Bevacizumab/ Chemo (n = 363) Chemo (n = 258) HR (95% CI) P Value Median Progression- Free Survival 8.1 months 5.4 months ( ) <.0001 Overall Response Rate 42% 23% NR <.0001 Median Overall Survival 18.9 months 17.5 months ( ).6732 O Shaughnessy et al. SABCS 2010; abstract P

40

41 What does the future hold for personalized medicine?

42 Finding Cellular Targets for Breast Cancer: Personalized Medicine Source: Seminars in Oncology 2011; 38: (DOI: /j.seminoncol )

43 Intracellular vascular endothelial growth factor (VEGF) signal transduction pathway Reddy S et al. The Oncologist 2012;17:

44 Novel agents currently in clinical trials Target Drug Phase PI3Kinase GDC-0941 I paclitaxel/bev PI3K/ mtorc1/2 AKT GDC-0980 BEZ235 MK-2206 Ib-paclitaxel/bev/tras I and II - paclitaxel I-paclitaxel II-PTEN loss or PI3K mutation mtor INK128 I-paclitaxel/tras C-MET ARQ197 MetMab II-TNBC II-paclitaxel/bev Alvarez R H et al. JCO 2010;28:

45 What is the benefit of localized therapy in metastatic disease?

46 European School of Oncology-Metastatic Breast Cancer Task Force 2010: Can MBC be Cured? Current statistics: Median OS hormone-resistant MBC = mo 5 yr OS = 26% <5% live longer than 5 years 1-2% are long-term survivors Is a need to identify characteristics of the few long-term survivors who may benefit from a multi-disciplinary approach to treatment. ESO-MBC task force; Pagain, JNCI 2010;102:456

47 What is the Role of Localized Therapy for the Primary Cancer in the Setting of Metastatic Disease? Based upon SEER data 3.5-7% newly diagnosed breast cancer present with metastatic disease and an intact primary Suggesting that 7,000 women present annually 50% have operable primary tumors Traditionally focus on systemic therapy, palliate the local disease Debulking surgery is beneficial in other solid tumors: ovarian cancer, renal cell, colon

48 Should We Resect the Primary Tumor? Data From Population Studies Number having surgery Total Mast Partial Mast Free Margins 3 yr OS Adjusted HR for OS in Surgical Group NCDB 1 (16,023) % % % PM - 45% TM 63% 25% vs. 17% 0.6 ( ) Geneva % 5yr BSS 0.5 (300) 42% 69% 31% 27% ( ) SEER NR NR 0.63 (9734) 47% 54% 40% ( ) Nether NR 5yr OS 0.62 lands 4 (728) 40% 65% 30% 25% vs. 13% ( ) Khan, S. Oncology 21(8): 924, 2007; 1. Khan, Surgery 2002;132: Rapiti JCO 2006;24: Gnerlich Ann Surg Oncol 2007;14: Ruiterkamp EJSO 2009;

49 Should We Resect the Primary Tumor? Data From Single Institutions Number having surgery Total Mast Partial Mast Free Margins Median OS Adjusted HR for OS in Surgical Group Wash U 1 (409) % % 61 33% 92 49% 32 mo vs. 15 mo 0.53 ( ) Baylor 2 (395) % % 53 22% 48% 27 mo vs. 17 mo 0.71 ( ) MD Anderson 3 (224) 82 37% 43 52% 39 48% 51 69% NR 0.5 ( ) Med Coll VA 52 33% NR NR NR 25 mo vs. 13 mo NR (157) 4 BWH/MGH 5 (147) 61 41% 40 65% 21 35% NR 4.1 yr vs. 2.4yr vs Fields Ann Surg Oncol 2007;14: Blanchard Ann Surg 2008;247: Babiera Ann Surg Oncol 2006;13: Leung J Surg Res 2010;161:83. Bafford Br Ca Res Treat 2009;115:7

50 Do Surgical Margins Matter in MBC? Five-year adjusted breast cancer specific survival: Negative margins 27% Positive margins 16% Unknown margins 12% No surgery 12% Rapiti, E. et al. J Clin Oncol; 24:

51 What are the Variables that are Associated with Favorable Outcome in MBC? Resection of the primary tumor: negative margins SEER HR = % CI Systemic therapy: either chemo or endocrine Number of metastatic sites: fewer Type of metastatic disease: soft tissue/bone Hormone receptor positive HER2+

52 Does the Molecular Subtype Influence Outcome after Surgery for MBC? MSKCC - N=186 ( ); 69 (37%) surgery Median OS with resection = 40 mo Median OS without resection = 33 mo HR = 0.68* Improved OS with Her2 positive and ER/PR positive disease ER pos: HR = 0.47* Her2 pos: HR = 0.51* No benefit with TNBC Neuman Cancer 2010;122:1226

53 What is the Role of Radiation Therapy? St. Cloud, France N=581 Group A = 320 (55%) 249 (78%) XRT 41 (13%) Surgery followed by XRT 30 (9%) Surgery alone Group B = 261 (45%) no surgery or radiation OS* grp A vs. grp B Median: 32 mo. vs. 21 mo. 3-yr OS: 43.4% vs. 26.7% LRT 30% reduction in risk of death (HR=0.70) Le Scodan R, JCO 27:1375, 2009 This trend all subtypes: With chemotherapy With endocrine therapy Irrespective of number of mets.

54 Approach to surgical resection of the primary tumor in MBC: We do not have data from controlled randomized trials Have a national randomized trial ongoing SUBMIT: randomized trial Dutch Breast Cancer Trialist Group (BOOG) There is a small subset of breast cancer patients who may benefit from surgical resection need to discuss pros and cons thoroughly Patients with an excellent tumor response Hormone receptor positive, HER2 positive Patients with isolated metastasis Patients with oligometastasis MUST achieve a negative surgical margin

55 What is the Role of Localized Therapy for Pulmonary Metastasis? 15-25% pulmonary metastasis as first recurrence > 50% will be solitary (lung or pleura) 5% nodules will be benign 50% will be second primary lung 5-year survival ranges from 27-54% Median survival of mo

56 Lung Metastasectomy in MBC International Registry of Lung Metastasis Established in 1997 with 5206 resections in Europe, US, Canada 467 with metastatic breast cancer ( ) 66% solitary lesions Overall survival: 5-yr survival rate = 35% 10-yr survival rate = 20% 15-yr survival rate = 18% Median OS = 35 months Friedel, et al. European Journal of Cardiothoracic Surgery, 22:335,2002

57 Prognostic Features Associated with Resection of Pulmonary MBC 84% complete resection (R0), 16% incomplete resection (R1=3%; R2=13%) R0 5yr OS = 38%, median OS = 37 mo. R1/R2 5yr OS = 18%; median OS = 25 mo. 33% received additional chemotherapy 5yr OS without chemo 39% 5 yr OS with chemo 44% DFI > 36 mo 5 yr OS = 45% vs. 28% 10 yr OS = 26% vs. 16% Prognostic features: Solitary nodule vs. > 1 nodules Ability to obtain complete resection = R0 DFI > 36 months Friedel, et al. European Journal of Cardiothoracic Surgery, 22:335,2002

58 Should Pulmonary Metastasis in MBC be Resected? No. 5 yr OS 10 yr OS DFI Favorable Prognosis Reno 2007 Welter 2008 Chen % 18% > 3 yr SPN DFI > 3yr 47 36% NR > 3.5 yr ER + (HER2 +) 41 51% 51% > 3yr < 4 mets DFI > 3yr Tanaka % NR > 5yr None Welter EJCTS 2008;34:1228; Chen EJSO 2009;35:393; Rena EJSO 2007;33:546; Tanaka Ann Thorac Surg 2005; 79:1711

59 European Society of Thoracic Surgery (ESTS) Recommendations for Pulmonary Metastasectomy Resection of a solitary pulmonary nodule is justified For diagnosis, for therapy (SPN) Usually performed by posterolateral thoracotomy VATS does not allow for manual palpation of the entire lung acceptable for solitary pulmonary nodules Palpation of the lungs is standard Number of metastasis is consistently associated with survival after surgery Greater than 3-4 nodules is associated with a shorter survival Long DFI (> 36 mo) important prognostic factor RFA remains investigational Garcia-Yuste, J Thorac Oncol 2010; 5, suppl 2:S161; Staren Arch Surg 1992;127:1282; Mcdonald Ann Thorac Surg 1994;58:1599

60 What is the Role of Localized Therapy for Hepatic Metastasis? 15% of newly diagnosed MBC will have hepatic metastasis 5% (33% of all hepatic mets) - isolated may represent a more favorable histology 50% will eventually develop hepatic metastasis Median survival of 3-15 mo

61 Caveats about Surgical Resection of Hepatic Metastasis in MBC Goal is a R0 resection clearance of all visible macroscopic tumor with negative surgical margins Residual liver has to have enough functioning tissue 25-30% of normal liver volume Presence of extra-hepatic disease precludes surgical resection of hepatic mets Control of the primary tumor Maintain patient s quality of life Post-operative mortality = 0-0.6%, morbidity = %

62 What are the Outcomes of Hepatic Resection? Study N Treatment DFI OS 5yr S Raab, Surgery + chemotherapy Sakamoto, Surgery + chemotherapy + endocrine therapy Elias, Surgery + chemotherapy Vlastos, Surgery + chemotherapy Adam, Surgery + chemotherapy Hoffman, Surgery + chemotherapy 41.5 mo 27 mo 18% NR 36 mo 21% 16 mo 34 mo 34% 13 mo 25 mo 61% 20 mo 32 mo 37% 34 mo 58 mo 48% Sakamoto 2005;World J Surg 29:524; Vlastos, 2004, Ann Surg Onc 11:869;Adam, Ann Surg 2006, 244:897; Elias Am J Surg 2003;185:158; Raab Anticancer Res 1998;18:2231;Hoffman Ann Surg Oncol 2010;17:1546

63 Prognostic Factors Associated with Hepatic Resection (HR) for MBC Chemo prior to HR 72 (84%) median 8 cycles Lack of response to chemo P = HR = 3.5 likelihood of death with PD Chemotherapy Response Extra-hepatic mets treated prior to HR Presence of extrahepatic mets P = Adam et al, Ann Surg 244:897, 2006 Extra-hepatic Metastasis

64 Prognostic Factors Involved in Hepatic Resection (HR) for MBC 5 yr OS Pathologic evaluation R0 (negative) 66 (65%) R1 (micro +) 15 (18%) R2 (macro +) 14 (17%) An R2 resection P = HR = 5.6 likelihood of death with R2 Resection Margins Recurrences after HR 59 (69%) 10 mo. median Liver 28 (48%) Both liver and extra-hepatic 22 (37%) Absence of repeat hepatectomy P = HR = 2.4 likelihood of death without re-hr Adam et al, Ann Surg 244:897, 2006 Repeat Hepatectomy

65 RFA of Liver Metastases Study N Med OS (pt/mets) Sofocleous, / mo (3 yr = 70%; 5 yr = 30%) Lawes, / NA 42% at 30 mo Meloni, / mo (5 yr = 27%) Livraghi, / 64 63% at 4-44 mo Jakobs, / mo Lawes, 2006, Ann R Coll Engl 88:639, Sofocleous, 2007, AJR 189:883; Jakobs Cardio Inter Radiol 2009;32:38; Livraghi Radiol 2001;220:145; Meloni 2009;253:861

66 Who is the Ideal Candidate for Local Treatment of Hepatic Metastasis? Surgical Resection: Disease-free interval of > 1 year Good response to chemotherapy Isolated hepatic metastasis Ability to achieve an R0 resection RFA: Heterogeneous patient population consider patients who are not candidates for surgery Tumor size < 2.5 cm Other directed therapies: Very investigational

67 The multidisciplinary approach to MBC What are the implications of pursuing this approach? Suggest that there is a population of MBC whose goal of treatment is cure Need to modify the current approach of minimal post-diagnosis monitoring for metastatic disease Understand the economic impact this approach would have Both with cost / benefit ratio and impact on personal / societal health care cost

68 Conclusions Support patient enrollment in clinical trials!