1. Best practice for chemotherapy for treatment of breast cancer Andreas Makris Mount Vernon Cancer Center Royal College of Radiologists, London, 17 th June 2015

4. CMF ACx4 NSABP B15 FAC FECFE 100 C FASG05 Ax4  CMFx4 alt vs seq Ex4  CMFx4 NEAT ± Anthracyclines ACx4  Px4 (Q2W) CALGB 9741 ± IntensificationIntensification ACx4±Px4 CALGB 9344 NSABP B28 FE 100 Cx3  Tx3 PACS01 TAC BCIRG001 ACx4±Tx4 NSABP B27 APx4  CMFx4 ECTO ACx4 v ATx4 E2197 FECx4  Tx4 TACT (also v FECx8) ± TaxoidsTaxoids TECvTx4  ECx4 AERO B03 (Q2W) Ex4 q3vq2  CMFx4 or Cap TACT II

5. Effects of chemotherapy on breast cancer survival EBCCTG Lancet 2005 365: 1687

6. 2000 NIH Consensus Conference on adjuvant therapy for breast cancer Adjuvant polychemotherapy should be recommended to most women with primary breast cancers larger than 1 cm in diameter, regardless of nodal, menopausal, or hormone receptor status

7. Adjuvant on Line

8. Microarray Expression Analysis Breast Tumor Subtype Predictions Sorlie T, et al., Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8418-23.

9. Oncotype DX ® 21-Gene Recurrence Score (RS) Assay RS = + 0.47 x HER2 Group Score - 0.34 x ER Group Score + 1.04 x Proliferation Group Score + 0.10 x Invasion Group Score + 0.05 x CD68 - 0.08 x GSTM1 - 0.07 x BAG1 PROLIFERATION Ki-67 STK15 Survivin Cyclin B1 MYBL2 ESTROGEN ER PR Bcl2 SCUBE2 INVASION Stromelysin 3 Cathepsin L2 HER2 GRB7 HER2 BAG1GSTM1 REFERENCE Beta-actin GAPDH RPLPO GUS TFRC CD68 16 Cancer and 5 Reference Genes From 3 StudiesCategory RS (0 -100) Low risk RS <18 Int risk RS 18 - 30 High risk RS ≥ 31 Paik et al. N Engl J Med. 2004;351:2817

10. Oncotype DX: RS as Continuous Predictor in tam treated patients data from NSABP B14: Paik NEJM 2004, 351:2817

11. OPTIMA design Radiotherapy given according to local practise Adequate surgery Age ≥ 40 ER +ve, HER2 –ve N+/ N0 & T>30mm Central confirmation of ER & HER2 Endocrine therapy continued to 5+ yrs Permitted chemotherapy:FEC75-100 x 6 cycles pre-specified by patientTC x 4 cycles before randomizationFEC100-T E-CMF Permitted endocrine therapy: postmenopausal - any AI premenopausal - GnRH agonist (3 yrs) + tamoxifen Exclusion: advanced stage = ≥ 10 N+/ IM+ Sample size to demonstrate non-inferiority (-3%) = 1860 per arm chemo. endocrine R chemo. endocrine 1 1 Test Patients receiving chemotherapy blind to randomisation

12. Neoadjuvant Chemotherapy What do we know? If same chemotherapy is given before or after surgery –Equal survival –Fewer mastectomies –Patients achieving pCR have better outcome

13. CAF –CPA/cDDP/BCNU CMF-VP VATH CMFVP High-dose chemotherapy early promise Peters et al JCO, 1993; 11 1132-43

14. Chemotherapy for EBC Support for best practice Local guidelines Regional guidelines –eg LCA NICE clinical guideline 80 –Early and locally advanced breast cancer (issued Feb 2009 last modified Jul 2014) –guidance.nice.org.uk/cg80 –Clinical guideline 81 for metastatic breast cancer International guidelines –ASCO –NCCN –St Gallen

15. Chemotherapy for EBC Summary Adjuvant CT improves survival in EBC Anthracycline containing regimens are more effective than CMF Addition of taxanes improves survival compared to anthracycline containg regimes, most of the benefit is in HER+ and triple –ve Recommendation largely on risk stratification rather than tumour biology In the presence of optimal local/hormonal/biological therapy, what is the contribution of chemotherapy?

16. MBC Surgery Psychological / social / spiritual support Targeted therapies based on genomic analysis Anti HER-2 therapy Bisphosphonates / RANK ligand inhibitors Endocrine therapy Chemotherapy Bevacizumab Radiotherapy Treatments of metastatic breast cancer

17. Palliation of symptoms improvement in quality of life Improved survival Test new treatments  Ultimately for use in the adjuvant setting Metastatic breast cancer aims of therapy

19. Patient and disease characteristics influence treatment decisions Systemic therapy Prior adjuvant therapy Cumulative dose of anthracyclines Cardiac impairment Increasing use of taxanes Long-term side effects Disease-free interval Disease characteristics Sites of metastases Tumor biology Tumor burden Patient characteristics Age Performance status Preference Comorbidities e.g. diabetes, impaired cardiac function Trial versus clinic patients

20. Cost/benefits: palliative chemotherapy BENEFITS symptom relief improved PS extended survival objective response

21. BENEFITS symptom relief improved PS extended survival objective response COSTS physical toxicity psychological morbidity social disruption economic Cost/benefits: palliative chemotherapy

22. Dose/complexity of chemotherapy Probability that patients will experience indicated endpoint 0 1 Chemotherapy for palliation Influence of dose/complexity Tumour response Absence of drug-induced toxicity Effective palliation Ian Tannock JCO

23. Anthracyclines CMF Mitomycin-C Vincristine SERMS (tamoxifen) AIs (aminoglutethamide) MPA etc 1st line 2nd line 3rd line Therapeutic cascade in MBC The 80’s

24. Anthracyclines CMF Vinorelbine Various Taxanes Capecitabine SERMS (tamoxifen) AIs (letrozole) 1st line 2nd line Therapeutic cascade in MBC The 90’s MPA etc

25. Anthracyclines Vinorelbine Various Taxanes Capecitabine SERMS (tamoxifen) AIs (letrozole) SERDS (faslodex) 1st line Therapeutic cascade in MBC The 00’s Taxanes Trastuzumab Lapatinib

26. Anthracyclines Eribulin Various Taxanes Capecitabine SERMS (tamoxifen) AIs (letrozole) SERDS (faslodex) 1st line Therapeutic cascade in MBC The 10’s Trastuzumab Taxanes Trastuzumab Pertuzumab T-DM1 Exemestane & everolimus

27. Sequence of chemotherapy for MBC MVCC Audit by M Chiu  82 patients with MBC treated at MVCC between 2001 and 2014  Only 3 patients followed the sequence recommended by NICE clinical guideline 81  Anthracycline>taxotere>capecitabine>vinorelbine  Recent ASCO guidance supports that there is no single agent or regimen that has demonstrated superiority in the 1 st, 2 nd and 3 rd line setting  Strenger M et al: ASCO Post March 2014

28. Rapid/symptomatic progression, visceral disease’ crisis’ Systemic treatment of MBC HR +ve, long DFI, low burden of disease, non-visceral HR –ve, HER2 +ve short DFI, visceral disease ‘visceral crisis’ Exemestane ± Everolimus Chemotherapy ± trastuzumab & pertuzumab Letrozole or Tamoxifen ± OFS Tamoxifen or Letrozole ± OFS Faslodex

29. Chemotherapy for MBC Common Practice Use of multiple lines of single-agent chemotherapy 2 to 3 cycles: evaluate efficacy and toxicity Duration of chemotherapy? –arbitrary and dependent on tolerability/cumulative toxicity Chemotherapy combinations may improve activity but at the expense of additional toxicity Addition of biological agents to chemotherapy improves outcome Crown J, Dieras V, Kaufmann M et al. Lancet Oncology 2002;3:719-727.

30. Chemotherapy for MBC Typical Order of Drug Use Guidelines? Anthracyclines (if not used adjuvantly?) Taxanes (if not used adjuvantly?) 1 –With Herceptin if HER-2 Positive Vinorelbine/Capecitabine 2,3 Capecitabine/Vinorelbine 3,2 Eribulin Everything else –Gemcitabine- Platinum –CMF- Caelyx –Re-challenge? 1. NICE Guidance 30: Taxanes 2001. 2. NICE Guidance 54: Vinorelbine 2002. 3. NICE Guidance 62 Capecitabine 2003.

31. Trials of bevacizumab in 1 st -line MBC Overall survival Non-bevacizumab (n = 1,008) Bevacizumab (n = 1,439) Median, months26.4 26.7 HR (95% CI)0.97 (0.86–1.08) P =.56 1-year OS rate, % 77 82 P =.003 1.0 0.8 0.6 0.4 0.2 0 0612182430364248 Time, months OS Estimate Number at risk: Non-bevacizumab100889274662142617851198 Bevacizumab14391333112791659120455235 Miles DW, et al. Ann Oncol. 2013;24(11):2773-2780.

32. Finn RS, et al. SABCS 2012. Abstract S1-6. TRIO-18 (PALOMA 1) addition of CDK4/6 Inhibitor to letrozole improvement in PFS in ER+ MBC 0 0.2 0.4 0.6 0.8 1.0 06121014 Months 16202228 PD 991 + LET (n = 84) 21 (25) 26.1 (12.7-26.1) PFS Probability 2426 18 8 2 4 0.3 0.5 0.7 0.9 0.1 LET (n = 81) 40 (49) 7.5 (5.6-12.6) Events, n (%) Median PFS, mos (95% CI) HR (95% CI) P value 0.37 (0.21-0.63) <.001 Outcome PD 991 + letrozole (n=83) Letrozole (n=77) Median duration of treatment8.9 months5.1 months Dose interruptions, % of cycles71%22% Cycle delays75%NA Dose reductions35%NA

33. 376 patients with metastatic (91%) or recurrent locally advanced (9%) ER-, PgR- and HER2- breast cancer randomised to either: Carboplatin AUC 6 every 3 weeks for 6-8 cycles n=188 Docetaxel 100mg/m2 every 3 weeks for 6-8 cycles n=188 Carboplatin vs Docetaxel Triple-Negative Trial (TNT) Allocation: randomised Endpoint Classification: Efficacy Study Intervention Model: Crossover Assignment Masking: Open Label Primary Purpose: Treatment Crossover permitted on progression Tutt A et al. The TNT trial: A randomized phase III trial of carboplatin (C) compared with docetaxel (D) for patients with metastatic or recurrent locally advanced triple negative or BRCA1/2 breast cancer (CRUK/07/012). As presented at SABCS 2014. Excluded: adjuvant taxane<12months prior, prior platinum, non-anthracycline for MBC Planned analyses: BRCA mutated, basal like sub groups, biomarkers of HRD

34. carboplatindocetaxelabsolute difference p value ORR 31.4% 95%CI 25-38 35.6% 95%CI 29-42 -4.2% 95%CI -13.7-5.3 p=0.44 Median PFS 3.1 months 95%CI 2.5-4.2 4.5 months 95%CI 4.1-5.2 -0.4 (95%CI -1.1-0.3) p=0.29 Median OS 12.4 months 95%CI 10.4-15.3 12.3 months 95%CI 10.5-13.6 -0.2 95% CI -1.1-0.8 p=0.31 Tutt A et al. The TNT trial: A randomized phase III trial of carboplatin (C) compared with docetaxel (D) for patients with metastatic or recurrent locally advanced triple negative or BRCA1/2 breast cancer (CRUK/07/012). As presented at SABCS 2014. Carboplatin vs Docetaxel(TNT) Results

35. Carboplatin vs Docetaxel (TNT) Results by BRCA1/2 status gBRCA+ patients (n=43) gBRCA- patients (n=273) carboplatindocetaxelp value ORR 68% 95%CI 46.5-85.1 33.3% 95%CI 13.3-59.0 p=0.03 carboplatindocetaxelp value ORR 28.1% 95%CI 20.5-36.8 36.6% 95%CI 28.7-44.9 p=0.16 Tutt A et al. The TNT trial: A randomized phase III trial of carboplatin (C) compared with docetaxel (D) for patients with metastatic or recurrent locally advanced triple negative or BRCA1/2 breast cancer (CRUK/07/012). As presented at SABCS 2014.

36. 36Stanford Cancer Center36 Median OS (m) Pac +trast (n=92)22 p=0.17 Pac (n=96)18.4 Slamon D, et al. N Eng J Med 2001;344:783–92 Treatment of HER2+ve MBC

37. CLEOPATRA: addition of pertuzumab to trastuzumab + docetaxel (PFS) Analysis was exploratory only D, docetaxel; PFS, progression-free survival; Pla, placebo; Pjt, Pertuzumab; H, Herceptin 0510152025303540 0 10 20 30 40 50 60 70 80 90 100 Time (months) Progression-free survival (%) 4550 0 0 0 0 8 8 34 26 67 42 108 72 178 110 218 148 284 223 341 329 402 406 Pjt + H + D: median 18.7 months Pla + H + D: median 12.4 months HR=0.69 95% CI 0.58−0.81 ∆=6.3 months n at risk Pjt + H + D Pla + H + D Swain et al. San Antonio Breast Cancer Symposium 2012, Poster P5-18-26

38. 38 ITT population. Stratified by geographic region and neo/adjuvant chemotherapy. CI, confidence interval; Pla, placebo; Ptz, pertuzumab. 38 OS (%) 0 10 20 30 40 50 60 70 80 90 100 010203040507060 Time (months) HR 0.68 95% CI = 0.56, 0.84 p = 0.0002 Ptz + T + D: median 56.5 months Pla + T + D: median 40.8 months Δ 15.7 months 128104226268318371 02391179230289350 n at risk Ptz + T + D Pla + T + D 402 406 Median follow-up 50 months CLEOPATRA: addition of pertuzumab to trastuzumab + docetaxel. Overall Survival

39. TDM-1 Mechanism of action

40. 496471453435403368297240204159133110866345271774 49548547445743941834929324219716413611186623828135 Cap + Lap T-DM1 No. at risk: Median (months)No. of events Cap + Lap25.1182 T-DM130.9149 Stratified HR=0.682 (95% CI, 0.548–0.849) P=.0006 Efficacy stopping boundary P=.0037 or HR=0.727 Time (months) 78.4% 64.7% 51.8% 85.2% 024681012141618202224262830323436 0.0 0.2 0.4 0.6 0.8 1.0 Proportion surviving Data cutoff July 31, 2012; Unstratified HR=0.70 (P=.0012). Swain et al SABCS2012 EMILIA: T-DM1 vs lapatinib and capecitabine Overall Survival

41. Chemotherapy for MBC Summary Chemotherapy can be an effective means of palliation and may have benefits in improving QOL and survival Choice of agent/schedule/duration needs to be individualised as different patients have their own trade offs with regards to benefit and toxicity Addition of bevacizumab adds little benefit except for triple negative disease Anti-HER2 therapy has transformed the outlook of women with this disease Further improvements require all of us to enter patients into clinical trials Cost of new cancer treatments is escalating and becoming increasingly unaffordable

42. Best practice Use of guidelines Guidelines are a good starting point but the more you learn about a disease the more you understand their limitations Need regular updating Wide multidisciplinary participation in producing them Probably a good idea to record why you have deviated from local/national guidelines Engage in regular audit of your practice against local/national guidelines