Concepts of palliative systemic chemotherapy for Metastatic Breast Cancer. Karen King April 16, 2016

Transcription

1 Concepts of palliative systemic chemotherapy for Metastatic Breast Cancer Karen King April 16, 2016

2 Faculty/Presenter Disclosure Presenter: Dr. Karen King Relationships with commercial interests: Grants/Research Support: Non Applicable Speakers Bureau/Honoraria: Non Applicable Consulting Fees: Non Applicable Other: Non Applicable

3 Disclosure of Commercial Support This Program is funded through AHS Operational Funding. Potential for conflict(s) of interest: None Dr. Karen King is presenting at this Program on a voluntary basis

4 Outline Overview of the metastatic process MBC behavior Chemotherapy: Old and New

5 Case Presentation 45 yo female initial diagnosis of breast cancer in 2012 T2N1 ductal carcinoma. ER+ve; Her2neu neg. Tx with surgery, adjuvant chemotherapy, RT and Tamoxifen Discharged from CCI post treatment Presents to family physician with recent onset back pain As per Transfer of Care Guidelines, bonescan done and shows suspicion of metastatic disease. Work up completed with CT and shows hepatic mets. Referral back to CCI

6 The Metastatic Process

7 Sir Stephen Paget Described tendency of some cancer types to metastasize to specific organs (Lancet, 1889) Patterns likely due to dependence of the seed (the cancer cell) on the soil (the secondary organ) Chambers AF, et al. Nat Rev Cancer. 2002;2:

8 Seed and Soil : A More Modern Understanding Initial seeding of cancer cells to specific organs seems to be primarily mechanical Subsequent growth depends on compatibility with soil in a particular organ Regulation of growth depends on molecular interactions between cancer cells and new organ environment Chambers AF, et al. Nat Rev Cancer. 2002;2:

9 Metastatic Process: Arrest in Host Organs Lung Liver Bone

10 MBC Behavior

11 The Spectrum of Metastatic Breast Cancer Rapid disease progression Extensive visceral involvement Resistance to hormones Resistance to chemotherapy Death within weeks of dx Long, indolent course Bone and soft tissue dz Sensitive to hormonal rx Sensitive to chemotherapy Extended survival (many yrs)

12 Breast Cancer is NOT a single disease

13 Goals of Therapy

14 Metastatic Breast Cancer Treatment is Palliative Goal = Disease Control Control symptoms Minimize toxicity from therapy Minimize interference in patient s life Quality Of Life Extend survival

15 Treatment of Micrometastases Number of Cancer Cells 10 9 Adjuvant Therapy Successful Visible Metastatic Disease Microscopic Metastatic Disease Time = treatment cycle

16 Treatment of Macrometastases Number of Cancer Cells 10 9 Treatment Stopped Treatment Resistance Visible Metastatic Disease Microscopic Metastatic Disease Time = treatment cycle

17 Chemotherapy

18 Chemotherapy Candidates ER / PR negative tumor Refractory to hormonal therapies Short disease-free interval Rapidly progressive disease Visceral crisis

19 Choice Chemotherapy for metastatic disease? Treatment options Monotherapy Combination therapy? Sequential vs. concurrent therapy? Duration of therapy

20 Do We Prolong Survival in Metastatic Breast Cancer? Survival difference difficult to demonstrate For years, no studies demonstrated improvements in survival comparing one treatment with another HOWEVER, no one (in the past 20 years) would have considered a randomized trial of best supportive care vs. active treatment

21 Overall Survival of Metastatic Breast Cancer Patients by Decade Proportion Total Fail s s s Months Overall survival from time of diagnosis of breast cancer recurrence for patients treated in the 1950s, 60s, and 70s at MD Anderson (Houston, Texas, USA)

22 Aggregated survival benefits of new systemic therapies Median survival from diagnosis of MBC 1950 s 8-10 months s 15 months Late Chia et. al. ASCO months patients from BCCA Outcomes Database diagnosed between 1997 & 2001 had better 2-yr OS than patients diagnosed between 1991 & 1995 (45% vs 34% ) Today Chia et al. Cancer months

23 Effective Treatment Does Improve Survival Taxotere vs. MV (Nabholtz et al, JCO 1999) Taxol vs. CMFP (Bishop et al, JCO 1999) ATaxol vs. FAC (Puzlanska et al, JCO 2001) Taxotere + Xeloda vs. Taxotere (O Shaunessey, JCO 2002) Taxotere vs. Taxol ( Ravdin, JCO 2003) Chemo + Herceptin vs. Chemo (Slamon et al, NEJM 2001) chemo + Her2neu directed therapy vs chemo (see end slides)

24 How do we improve survival with chemotherapy for metastatic breast cancer? Better empiric selection of agents Figure out which drugs work Molecular predictive assays Pick the right drugs in advance Understand other real + potential targets Stromal support cells? Breast Cancer Stem cell Cell signals

25 Prognostic vs. Predictive Prognostic assay How bad is my cancer, Doc? Predictive assay What is the right way to treat my cancer, Doc? Is this drug going to work? Am I going to get severe side effects?

26 Prognostic factors to consider Interval between initial therapy and relapse Number of metastatic sites Presence or absence of visceral mets Biologic markers Weight loss Performance status Increased LDH

27 Predictive factors to consider Hormone receptor status and HER2 overexpression are the most important predictors of treatment response Progression with prior chemotherapy Relapse within 12 months from completing adjuvant chemotherapy Poor PS Multiple (visceral) disease sites Triple negatives?low Ki67?mutated p53

28 Why do we need predictive assays for chemotherapy? All treatments carry toxicity Ineffective therapy is costly patient time unnecessary reduction in Quality of Life financial burden A predictive assay would, by definition, improve the risk / benefit ratio of therapy

29 How to choose which one? A fine balance Empiric Drug Benefit Availability of a Predicitive assay? Pharmacogenetics Cancer biology Patient preference Chemotherapy Cookbook Cross Cancer Institute Style Side effects / cumulative toxicity General Health (PS) Co-morbidity Potential Drug interaction Previous treatments and responses to date

30 Which drugs do we use?

31 General principles for systemic therapy Endocrine therapy is best for ER/PR positive tumours HER2 therapy for HER2 overexpressing tumours Chemotherapy for hormone insensitive *consider goals of treatment (earlier slide) *consider spectrum of disease (earlier slide) Aggressive/visceral ~ chemotherapy Indolent/bone or soft tissue ~ endocrine

32 MBC : Chemotherapy Options Alkylator-based (CMF) Anthracycline-based (FAC, A, E) Taxane (docetaxel, paclitaxel, nab-paclitaxel) Vinorelbine Gemcitabine Capecitabine (Xeloda) Eribulin platinums

33 Metastatic Breast Cancer Single-Agent Chemotherapy Drug First line CR+PR (%) Second line CR+PR(%) Doxorubicin Taxotere ( mg/m 2 /1h) Taxol ( mg/m 2 /3 24h) Navelbine Xeloda Gemcitabine

34 What do we see in clinic? Heterogeneity and unpredictability De novo chemoresistance Extreme chemosensitivity Effects of disease burden

35 Clinical Drug Resistance: A harsh reality

36 3 months after adjuvant AC x 4 for T1 N0 M0 Infiltrating Ductal Carcinoma

37 Progression during docetaxel, irradiation, and vinorelbine

38 Therapy can select resistant clones doxorubicin

39 Different drugs may kill different clones paclitaxel

40 Combination therapy may overcome drug resistance doxorubicin Improved survival? paclitaxel

41 Combination Chemotherapy Principles Add agents together to improve potential response Each agent used should have single agent efficacy Different mechanisms of action Non-overlapping toxicities No cross resistance

42 Do we need to use combination therapy?

43 Adding more agents to combination regimens has not led any further improvements in time to progression or overall survival Jones et al Cochrane database 2006 A review of all randomized trials comparing chemotherapy regimens for metastatic breast cancer that were reported between found little evidence of major survival differences among many common chemotherapy regimens Wilcken et at, Eur J Cancer 2008

44 How long do we treat for?

45 Meta-analysis of Published Trials of More vs. Fewer Cycles of Chemotherapy for Metastatic Breast Cancer fewer cycles better more cycles better Harris 90 Ejiertson 93 Gregory 97 Cosies (95% CI ) combined P = Ratio of median survivals

46 In general terms For as long as patient can tolerate (i.e toxicities) For as long as it is working (no progression, no new mets) For as long as it is safe to give (anthracycline dose limits, poor PS) Patient preference

47 General chemo treatment algorithms

48 Things to consider Prior treatments (anthracyclines) and when given? (toxicities) Cardiac concerns? (prob not anthracyclines) Poor GI absorption? (prob not Xeloda) Issues with steroids? (prob not taxanes) General health/performance status? Patient preference? Tumour burden? Clinical trials?

49 Standard Chemotherapy Options HER-2 negative Eg.Visceral disease, ECOG 0-2, < 65 years, no prior chemo (kind of in order) FAC (500/50/500 mg/m 2 ) q21d Taxotere 100mg/m2 q21d Eribulin 1.4mg/m2 D1&D8 q21d Xeloda 1000 mg/m 2 bid x 14 d of 21d Gemcitabine or Vinorelbine or CMF HDCT/SCT is not an option for MBC you d be surprised how often I get asked. No survival benefit, too toxic.

50 Gentle Chemotherapy Options More stable disease, elderly, unwilling to accept side effects - choice of (in no particular order) : Xeloda 1000 mg/m 2 bid x 14d q 21 days Mitoxantrone 12 mg/m 2 d1 q 21 d CMF IV or oral Gemcitabine 1200 mg/m 2 d1, d8, d15 q 28 Vinorelbine 30 mg/m 2 d1, d8 q 21 d Weekly taxane Taxotere 36 mg/m 2 q 7day Taxol 90 mg/m 2 q 7 days Eribulin 1.4mg/m2 D1 &D8 q21 days.

51 Her 2 MBC treatment options

52 Herceptin is the foundation of care for women with HER2-positive breast cancer EBC MBC Adjuvant HERA Neo NOAH Relapse 1st line HO648g Progression 2nd+ lines GBG-26 NSABP B-31 MDACC M77001 BO17929 NCCTG N9831 GeparQuattro US Oncology EGF BCIRG 006 Numerous Phase II studies BCIRG 007 CHAT TAnDEM Numerous Phase II studies EMILIA RHEA HER2, human epidermal growth factor receptor 2; EBC, early breast cancer; MBC, metastatic breast cancer CLEOPATRA

53 Herceptin prolongs survival in women with 1st-line MBC H0648g (IHC 3+) M77001 BCIRG 007 US Oncology (IHC 3+) P alone PH D alone DH DCarboH DH PCarboH PH Median survival (months) IHC, immunohistochemistry; P, paclitaxel; H, Herceptin; D, docetaxel; Carbo, carboplatin Smith et al 2001; Marty et al 2005; Robert et al 2006; Pegram et al 2007

54 Her2-directed agents available Trastuzumab (Herceptin): monoclonal Ab binds extracellular domain of Her2 Ado-trastuzumab emtansine (TDM1): antibody drug conjugate of trastuzumab + thioether linker + antimicrotubule agent called emtansine

55 Her2-directed agents available Lapatinib (Tykerb): tyrosine kinase inhibitor of EGFR1 and Her2 which inhibits downstream pathways of Her2 Pertuzumab (Perjeta): binds extracellular domain of Her2 and prevents it from binding to itself or other EGFR family

56 TDM1 Antibody drug conjugate with trastuzumab and emtansine Approved if progress during OR within 6 months of adjuvant herceptin OR progress after herceptin based regimen in metastatic setting

57 Pertuzumab: Monoclonal ab Pertuzumab HER2 dimerisation inhibitor (HDI) Interferes with HER2 s ability to collaborate with other HER family receptors (EGFR/HER1, HER2, HER3, HER4) thus inhibits cancer cell growth and leads to cell death NEOSPHERE (ph II, neoadjuvant) Inc CR in docetaxel+herceptin+pertuzumab arm CLEOPATRA (ph III, metastatic)

58 N=808, her2pos metastatic breast cancer randomized to Pertuz + Trastuz + docetaxal vs Trastuz + docetaxel (ph III) At 19 months: Improv PFS (19 vs 12 mo) Improv ORR (80% vs 69%) Improv OS (56.5 vs 40.8 months at final analysis)!!!

59 Other targets?

60 Bevacizumab Tumour growth dependent on angiogenesis Bevacizumab humanised mab directed against VEGF recognises all VEGF-A isoforms Bevacizumab inhibition of VEGF results in regression of immature tumour vasculature Normalization of remaining tumour vasculature Inhibition of further angiogenesis

61 In patients with MBC, significant improvements in PFS and ORR have been seen with Bevacizumab plus docetaxel (AVADO) Bevacizumab plus paclitaxel (E2100) Miles, et al ASCO 2008 Miller et al, NEJM 2007 Bevacizumab plus investigator selected (xeloda/taxane/anthracycline) (RIBBON-1 & RIBBON-2) O Shaughnessy J et al

62 Bevacizumab trials ECOG 2100 AVADO RIBBON 1 1 st line, & pooled analysis improves PFS by 2.5 months but not OS (26.7 vs 26.4mo) RIBBON 2 (second line) Unclear if 2.5 month PFS benefit is clinically meaningful given toxicities (HTN, proteinuria, thromboembolic)

63 PARP inhibitors Poly (ADP-ribose) Polymerase-1 (PARP-1) is a DNA binding protein involved in detection and repair of DNA strand breaks Hopeful for cancers defective in DNA repair (BRCA1/2 and triple negatives) appear to be sensitive to PARP-1 inhibition

64 Hormonal therapy in combination with targeted treatments?

65 Hormonal Therapy and Targeted Treatments Everolimus: mtor inhibitor combination with endocrine therapy SE? Stomatitis 8% Dyspnea 4% Non-infectious pneumonitis 3% Elevated Liver enzymes 3%

66 Hormonal Therapy and Targeted Treatments Palbociclib is an orally active selective inhibitor of CDK 4/6 that inhibits cell proliferation and DNA synthesis by preventing cell-cycle In an open-label, randomized phase 2 study (PALOMA-1), palbociclib in combination with letrozole significantly improved PFS over letrozole alone as initial treatment for patients with newly diagnosed advanced ER+ breast cancer. 3 (1 st line)

67 Immunotherapy Programmed Death-1 (PD-1): inhibitor signalling receptor on activated T cells Down regulates T cell activity on binding to PD-L1 present on Ag presenting cells Tumours expressing PD-L1 include NSCLC, Melanoma, RCC Concept is PD-1 targeted agents block binding to and activation of PD-1, thereby activating T-cell immune mediated response against tumour cells Many new agents are currently available, and more are on the horizon

68 Chemotherapy: Take home messages Treatment of MBC remains a major challenge Chemotherapy is palliative, but overall improves quality of life and duration of life Attempt to balance efficacy with toxicity New combinations are highly active but more toxic, and are not for everyone Sequential monotherapy is a good option for many women

69 Chemotherapy: Take home messages Steps are being made toward a better understanding of breast cancer biology Progress in treatment will follow Many new agents are currently available, and more are on the horizon Enrolling patients in clinical trials

70 Other Topics in MBC Role for local therapy (RT, Surgery) Adjunctive therapy (bisphosphonates, Xgeva) Always consider clinical trial options Pain management Best supportive care is an option for all patients (patient preference) Complications: brain mets, spinal cord compression, hypercalcemia

71 QUESTIONS?