Breast Cancer Advanced Disease. Stefan Aebi Luzerner Kantonsspital

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1 Breast Cancer Advanced Disease Stefan Aebi Luzerner Kantonsspital

2 How to Guidelines and Consensus

3 Breast Cancer Advanced Disease Prognosis Clonal (and diagnostic) evolution: Biopsy of metastases Endocrine vs. chemotherapy Endocrine Therapy Everolimus Chemotherapy Single drugs vs. combinations Duration of therapy HER2-targeting agents Pertuzumab and trastuzumab-emtansin Bone targeting agents

4 Prognostic factors e.g. Yamamoto no yes Adjuvant chemotherapy 0 1 Non-regional lymph node metastases 0 1 Liver metastases 0 1 LDH > upper limit of normal 0 1 DFS < 2 years 0 2 Sum = Risk-Index 0-1 low 2-3 intermediate 4-6 high Yamamoto N et al. J Clin Oncol

5 Prognostic factors z.b. Yamamoto Yamamoto N et al. J Clin Oncol

6 Prognostic and Decision-related Factors Cardoso Ann Oncol Suppl 7 vii11

7 Prognosis: MDACC Complete remission after anthracycline-containing chemotherapy Greenberg JCO pdf

8 Tumor Evolution Tumor heterogeneity is a clinical fact The expression of predictive markers is not stable over time (and between different metastatic locations) Science

9 Re-biopsy Metastatic Disease? Discordance between primary and recurrent breast cancer ER Relapse + Primary % 7.8% HER2 24.6% 20.5% Relapse + Primary % 7.7% 33.0% 33.9% Relapse + Primary % 5.8% PR 8.7% 66.3% Lindström JCO

10 Re-biopsy Metastatic Disease? Biopsy leads to a change of management in about 15% to 20% of patients Do biopsies improve the prognosis? Amir JCO

11 General Principles of Treatment 1 Use endocrine therapy for potentially endocrine disease in patients with bone and soft tissue metastases low volume visceral metastases Use sequential single drug chemotherapy for endocrine non-responsive non life-threatening disease Use combination chemotherapy for highly symptomatic or immediately life-threatening metastatic disease

12 General Principles of Treatment 2 Use HER2-targeted agents for HER2 positive (gene amplified or protein overexpressing) metastases Use denosumab or a bisphosphonate to prevent «skeletal related events» in patients with (osteolytic?) bone metastases

13 Endocrine vs. Chemotherapy Meta-Analysis Six RCTs comparing chemotherapy alone with endocrine therapy alone; N = 692 women No significant difference in survival (HR=0.94, 95%CI , p=0.5). Response rate: Advantage for chemotherapy RR=1.25 ( , p=0.04). Six published trials commented on increased toxicity with chemotherapy Conclusion In women with metastatic breast cancer and where hormone receptors are present, a policy of treating first with endocrine therapy rather than chemotherapy is recommended except in the presence of rapidly progressive disease. Wilcken Cochrane Database Syst Rev CD002747

14 Endocrine therapy Premenopause Tamoxifen+LHRH agonist vs. LHRH agonist Response rate 39 vs. 30% (OR 0.67) Klijn JCO

15 Meta-Analysis LHRH-Agonist ± Tamoxifen Median duration of response 20 vs months HR = 0.70 Median Survival 33 vs. 30 months HR = 0.78 Klijn JCO

16 Endocrine Therapy Postmenopause Aromatase Inhibitors Buzdar Cancer Mouridsen JCO Paridaens JCO *after failure of tamoxifen, AIs are superior to megestrol acetate Progression-free Anastrozole Letrozole are superior to tamoxifen* Exemestane Smith IE NEJM Months

17 Endocrine Therapy Postmenopause Mauri JNCI rd generation AI

18 2nd Line Endocrine Therapy Postmenopause 1st line 2nd line Anastozole tamoxifen Non-steroidal AI steroidal Steroidal AI non-steroidal AI fulvestrant «Clinical benefit» rate* 79% (! SAKK 21/95) 38% to 66% > 50% 28% to 35% *no evidence of progressive disease after 6 months of therapy Thürlimann Breast Cancer Res Treat Lönning EJC Ingle JCO , Perey Ann Oncol

19 Everolimus: BOLERO-2 Postmenopausal ER-positive, HER2-negative Resistant to non-steroidal AI Progression on non-steroidal AI Relapse within 12 months after adjuvant AI 2:1 Randomization Exe + Everolimus (10 mg) vs. Exe + Placebo Treatment until progression Baselga NEJM

20 Everolimus Adverse Effects in BOLERO-2 Treatment-associated Grade 3 7 vs. 1 and 4 AEs Stomatitis Anemia Dyspnea Hyperglycemia Fatigue Pneumonitis deaths: 8% vs. 1% 6% vs. <1% 4% vs. 1% 4% vs. <1% 4% vs. 1% 3% vs. 0% Baselga NEJM

21 OVERALL SURVIVAL EVE+EXE vs. Placebo +EXE Approx. HR Interim 2/2011 (7 months) 10.7 vs. 13.0% 0.91 Update 7/2011 (12.5 months) 17.3 vs. 22.7% 0.85 PFS Final 12/2011 (18 months) 25.4 vs. 32.2% 0.83 Piccart SABCS 2012 P pdf Progression--free Survival Everolimus: BOLERO-2 visceral non-visceral bone only

22 Does palliative polychemotherapy prolong survival? There is no trial with a no therapy control group : 63 RCTs with 150 participants 8 RCTs with statistically prolonged overall survival Wilcken EJC

23 Does palliative polychemotherapy prolong survival? In 4 of these 8 trials, a combination regimen was compared with a single agent, and we might expect modest benefits in response rates, progression free survival and overall survival in this setting A critical unanswered question for the clinician and patient is whether the same survival benefit might be seen when the agents in a polychemotherapy regimen are administered sequentially, perhaps reducing toxicity. Wilcken EJC

24 Sequential Monochemotherapies or Polychemotherapy? Adriamycin+Paclitaxel Adriamycin Paclitaxel Paclitaxel Adriamycin Overall Survival Switch at progression Response rate (CR+PR) AP: 47% A P: 36% 20% P A: 34% 22% Months Sledge J Clin Oncol

25 Cardoso JNCI

26 In the absence of such evidence to guide daily clinical decision making in MBC, both combination and sequential single agent chemotherapy are reasonable options as first-line systemic therapy. An important question for future research is the clear definition of patients who may benefit from a combination approach. Until such data are available, the ESO-MBC Task Force believes that sequential single-agent therapy should be the preferred choice for most MBC patients, in the absence of rapid clinical progression, lifethreatening visceral metastases, or the need for rapid symptom and/or disease control. These recommendations reflect consensus expert opinion and represent level 5 clinical evidence. Cardoso JNCI

27 Optimal Sequence of Therapies Endocrine therapy if ER/PR positive HER2-directed therapy if HER2 amplified or overexpressed Chemotherapy Anthracycline ± cyclophosphamide Taxane Capecitabine Eribulin The position of vinorelbine, gemcitabine is less clear «Historical sequence», not based on RCTs

28 Bevacizumab = Avastin Bevacizumab + chemotherapy improves PFS and RR in various trials Does not improve survival in any RCT and in a meta-analysis of RCTs Is registered in Switzerland (but not in US, UK) Indication? Miles DW Ann Oncol 2013 epub

29 Optimum Duration of Palliative Chemotherapy? Fixed number of cycles or tratment until progression or excessive toxicity? No single RCT reported prolonged overall survival with treatment until progression Some RCTS reported improved time to progression Cumulative toxicity! - Anthracyclines - Taxanes

30 Optimum Duration of Palliative Chemotherapy? Gennari JCO

31 Optimal Duration of Palliative Chemotherapy Recommendations 2013 Therapy until maximum effect Therapy until the occurrence of limiting side effects Without side effects: Therapy until progression With side effects: Therapy «holidays» until (almost) symptomatic progression

32 HER2-directed Therapies A Short History Slamon 2001: CTx+Trastuzumab > CTx NEJM works for Docetaxel, too: Marty JCO Geyer 2006: NEJM Lapatinib+Capecitabine > Capecitabine works also for paclitaxel: Di Leo JCO von Minckwitz 2009: Trastuzumab beyond progression JCO Blackwell 2012: JCO Trastuzumab+lapatinib > lapatinib

33 Pertuzumab Hudis NEJM

34 Pertuzumab - CLEOPATRA Baselga NEJM Swain SABCS 2012 P

35 Pertuzumab - CLEOPATRA Baselga NEJM Swain SABCS 2012 P

36 T-DM1, Trastuzumab Emtansine LoRusso Clin Cancer Res

37 T-DM1 EMILIA HER2+ (central) LABC or MBC (N=980) Prior taxane and trastuzumab Progression on metastatic tx or within 6 mos of adjuvant tx T-DM1 3.6 mg/kg q3w IV PD 1:1 Capecitabine 1000 mg/m2 orally bid, days 1 14, q3w + Lapatinib PD 1250 mg/day orally qd Stratification factors: World region, number of prior chemo regimens for MBC or unresectable LABC, presence of visceral disease Primary end points: PFS by independent review, OS, and safety Key secondary end points: PFS by investigator, ORR, duration of response, time to symptom progression Verma ESMO 2012

38 T-DM1 EMILIA Verma NEJM

39 T-DM1 EMILIA Verma ESMO 2012

40 T-DM1 1st Line Therapy Randomized phase 2, n=137 T-DM1 (3.6 mg/kg) vs. trastuzumab + docetaxel (75 or 100 mg/m2) ¼ prior trastuzumab, ⅓ prior taxanes Hurvitz JCO 2013 epub

41 T-DM1 1st Line Therapy Hurvitz JCO 2013 epub

42 Bisphosphonates What is the relative reduction of skeletal related events? 16% Clodronate 23% Pamidronate 41% Zoledronate What is the absolute reduction? Do bisphosphonates have an analgetic effect? Pamidronat, Ibandronat, Zoledronat Do bisphosphonates delay skeletal-related events? 1.4- bis 1.8-fold (with substantial variance between studies) Pavlakis Cochrane Database Syst Rev 2005 CD Kohno JCO

43 Bisphosphonates Is there a best bisphosphonate? Zoledronate > pamidronate for osteolytic metastases Rosen Cancer Longer survival?

44 Bisphosphonates Survival Pavlakis Cochrane Database Syst Rev 2005 CD003474

45 Denosumab SRE: pathologic fracture (excluding major trauma), radiation therapy to bone, surgery to bone, or spinal cord compression. Hypercalcemia of malignancy was assessed separately. Stopeck J Clin Oncol

46 Denosumab vs. Zoledronic Acid Stopeck J Clin Oncol

47 Toxicity Stopeck J Clin Oncol

48 Take Home Messages Bisphosphonates & Denosumab Bisphosphonates and Denosumab prevent fractures (and hypercalcemia) Dental examination and if needed dental surgery before start of therapy Bisphosphonates und Denosumab do not prolong survival

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50 Re-biopsy Metastatic Disease? Tumor heterogeneity is an unresolved challenge! Gerlinger NEJM

51 Prognosis: British Columbia British Columbia : Baseline : +Paclitaxel +Vinorelbine : +Docetaxel +Aromatase Inhibitoren : +Trastuzumab +Capecitabine Chia Cancer

52 Prognosis Minor progress likely in the past years Taxanes Eribulin Trastuzumab (and pertuzumab) Aromates inhibitors (?, and everolimus) or just lead time bias and stage migration? Tumor markers including CTCs CT and CT-PET Will Rogers,

53 Stage-Migration Will-Rogers-Phenomenon When the Okies left Oklahoma and moved to California, they raised the average intelligence level in both states. Feinstein AR, Sosin DM, Wells CK. The Will Rogers Phenomenon. Stage migration and new diagnostic techniques as a source of misleading statistics for survival in cancer. N Engl J Med 1985; 312: Will Rogers,

54 Does Imaging Influence Prognosis? 1. Stage migration 2. Interval between imaging does influence the PFS estimate 500 mg q 4 weeks is the standard dose of fulvestrant Di Leo SABCS 2012

55 A Useful Estimate of Prognosis W: L: M: U: B: W L M Worst case : 10% die before W Lower typical : 25% die before L Median: 50% die before, 50% survive after M Upper typical : 25% survive after U Best case : 10% survival after B U B Median Typical survival: 50% live between L and U

56 A Useful Estimate of Prognosis 36 randomized clinical trials ( ) Extraction of OS (and PFS), 10%, 25%, median, 75% und 90% survival times Kiely JCO

57 Worst case W 0.25 M Lower typical L 0.5 M Median = M Upper typical U 2 M Best case B 3 M Kiely JCO

58 A Useful Estimate of Prognosis W: L: M: U: B: W L M Worst case : 10% die before W Lower typical : 25% die before L Median: 50% die before, 50% survive after M Upper typical : 25% survive after U Best case : 10% survival after B U B Median Typical survival: 50% live between L and U

59 Endocrine Therapy Postmenopause: Aromatase Inhibitors adapted Smith IE NEJM

60 AI Tamoxifen? SAKK 21/95 Anastrozole Tamoxifen Clinical benefit rate = 79% (vs. 44% for Tam Ana) Thürlimann Breast Cancer Res Treat

61 Lohnt sich ein Wechsel des AI? Steroidal Nicht-steroidal: CB 38-66% Nicht-steroidal Steroidal Lönning EJC

62 Ovarektomie oder LHRH-Agonist? Boccardo Ann Oncol

63 Everolimus Johnston Clin Cancer Res

64 Stomatitis? Grade 3: Severe pain; interfering oral intake (CTC 4.03) with

65 Palliative Monochemotherapien oder Polychemotherapie? Rascher Wirkungseintritt erforderlich: POLYchemotherapie Ansprechen wichtiger als Toxizität Lymphangiose der Lunge, multiple Lebermetastasen,... Nicht- lebensbedrohliche Situation: MONOchemotherapie Minimierung der Toxizität wichtiger als hohe Ansprechwahrscheinlichkeit Weichteilmetastasen, einzelne Lungenmetastasen,...

66 Optimale Abfolge der palliative Chemotherapien Es gibt keine wissenschaftlich fundierte optimale Sequenz Auswahl nach Vorbehandlung Erwarteter Toxizität Erforderlicher Ansprechwahrscheinlichkeit Erhältlichkeit und Finanzierbarkeit There is no "one size fits all" approach to selecting optimal treatment for women with endocrine-unresponsive metastatic breast cancer. Dan Hayes

67 Pertuzumab - CLEOPATRA Baselga NEJM Swain SABCS 2012 P

68 Pertuzumab - CLEOPATRA Baselga NEJM Swain SABCS 2012 P

69 Finn RS SABCS 2012

70 Finn RS SABCS 2012

71 Finn RS SABCS 2012

72 The drug company has initiated a randomized, multicenter, doubleblind Phase 3 study evaluating palbociclib in combination with letrozole versus letrozole alone as a first-line treatment for post-menopausal patients with certain types of breast cancer. Breast cancer is the most commonly diagnosed cancer in women and the leading cause of cancer death among women worldwide. Shares edged up 15 cents to $29.26 in recent premarket trading. The stock has risen 32% in the past 12 months.

73 Denosumab? Zoledronsäure 4 mg/4 Wochen +s.c. Placebo Denusomab 120 mg/4 Wochen +i.v. Placebo Stopeck J Clin Oncol

74 Toxicity Zoledronic acid Denusomab Renal toxicity Severe renal Serious 8.5% renal AEs 2.2% 1.5% 4.9% 0.4% 0.2% Renal AEs among patients with baseline renal clearance < 60 ml/min Creatinine clearance > 60 < 60 ml/min 20.0% 5.9% 16.1% 12.7% 0.5% 1.2% 2.0% 0.8% 1.9% 1.4% Osteonecrosis of the jaw 1 year 2 years 3 years P Stopeck J Clin Oncol