The Three Ages of Systemic Adjuvant Therapy for EBC 1896-2018 Nicholas Wilcken Westmead Hospital Petersham Institute University of Sydney
Questions to be answered (concentrating on chemotherapy) Why should you give adjuvant chemotherapy? To whom should you give it? What should you give?
Non-chemo issues of importance: ER pos (pre-menopausal) duration of tam ovarian suppression (SOFT and TEXT) POEMS (ovarian protection) ER pos (post-menopausal) AI v tam, and duration Bisphosphonates/denosumab as adjuvant therapy? HER2 pos small tumours duration of trastuzumab ALTTO, APHINITY Triple neg disease platins, PARPi Immuno-oncology?
CMFx6 CEFx6 FEC(90)x6 TACx6 FECx3..Dx3 ACx4 FACx6 FEC(100)x6 ACx4..CMFx3 ACx4..Paclitaxel ACx4..Paclitaxel dose dense
The Lancet, July 1896 PCPA Advanced Trainee Program 2018
The worse the disease the greater the gain 1-3 nodes >4 nodes
BMJ 2005. 30 year follow-up HR=0.7 P=0.005
Treatment outcome in node negative and oestrogen receptor negative tumours: 20 year results. Gianni Bonadonna et al. BMJ 2005;330:217 2005 by British Medical Journal Publishing Group
Mature data 1896-1988 PCPA Advanced Trainee Program 2018 (the Oxford overview) Chemotherapy reduces recurrence, improves overall survival Same for tam, AI and herceptin The effect lasts for decades
same relative benefit, different absolute benefit 100% % cancer free 3% 30% 10 years
Adjuvant systemic therapy 1988-2005 1. Working out who to treat 2. Lots of different chemotherapy regimens 3. Tamoxifen and aromatase inhibitors 4. Targeted therapy - trastuzumab
Overall, anthracycline better than CMF PCPA Advanced Trainee Program 2018
Overall, taxane plus anthracycline better than anthracycline
Adjuvant taxane hit parade don t try this at home ACx4 D 100 x 4 = TAC x 6 BCIRG 005 > AT x 4 NSABP B30 > TAC x 4 E 90 Cx4 D 100 x 4 FEC 100 x 3 D 100 x 3 > FEC 100 x 6 AGO FEC 100 x 6 PACS 01 (ddac x4 ddpx4 > AC x4 Px4) ACx4 D 100 x 4 = ACx4 wpx12 (Sparano)
Good easy CMFx6 ACx4 Better Not so easy ACx4..CMFx3 FACx6 FEC(90) FEC(100) Best But hard TACx6 ACx4..Paclitaxel CEF ACx4..Paclitaxel dd FECx..Dx3
same relative benefit, different absolute benefit 100% % cancer free 3% 30% 10 years
Keeping it in perspective 1 (invalid comparison) 5yr DFS 1980 no CT 40% 2000 CT 80%
HR for relapse 1986-94 v 2004-08 CMF, tam Anthra, taxane, AI, trastuz
Adjuvant systemic therapy 2005-2018 Perou Nature 2000
Sorlie et al. PNAS 2003 Low grade, ER pos HER 2 pos Triple negative
Probability 1 0.8 0.6 0.4 0.2 0 p<0.01 ERBB2+ Bas 0 24 al 48 72 96 Overall survival months Luminal subtype A Normal breast like Luminal subtype B Sorlie et al PNAS (2001) 98:10869 n=49
Oncotype Dx (for ER+ tumours)
All pts Low oncdx (high ER, low grade) high oncdx (low ER, high grade) Paik JCO
FECx6 v FEC-D ER pos cohort The lower the proliferative rate, the less the difference Penault-Llorca JCO 2009
Endocrine sensitivity (ER positivity, grade) (oncotype Dx score) Risk (size, nodes) nil uncertain definite Standard CT Standard CT no CT CT plus Standard CT Standard CT? CT plus plus CT plus CT plus? (it s wrong, but not very wrong) (and not nearly as wrong as all the other ways of looking at it) after M Piccart SABCS 2005
CMFx6 CEFx6 FEC(90)x6 TACx6 FECx3..Dx3 ACx4 FACx6 FEC(100)x6 ACx4..CMFx3 ACx4..Paclitaxel ACx4..Paclitaxel dose dense
Adjuvant systemic therapy 2005-2018 Tailoring treatments: Approximating molecular subtypes Separating out HER2 positives Determining risk Determining chemo-sensitivity
Keeping it in perspective 2PCPA Advanced Trainee Program 2018 Tamoxifen
Keeping it in perspective 3 100 Trastuzumab 1 yr Anastrozole 80 60 40 20 No trastuzumab 2-yr DFS % Events HR p value 127 85.8 0.54 <0.0001 220 77.4 p value 0.01 Tamoxifen 0 0 5 10 15 20 25 Months from randomization
Non-chemo issues of importance: ER pos (pre-menopausal) duration of tam ovarian suppression (SOFT and TEXT) POEMS (ovarian protection) ER pos (post-menopausal) AI v tam, and duration Bisphosphonates/denosumab as adjuvant therapy? HER2 pos small tumours duration of trastuzumab ALTTO, APHINITY Triple neg disease platins, PARPi Immuno-oncology?
The endocrine hierarchy Postmenopausal tamoxifen aromatase inhibitors 5 v 10 years How bad is the cancer? How endocrine sensitive is the cancer? What about the patient? (preference, fitness)
The endocrine hierarchy Premenopausal tamoxifen 5 v 10 years adding zoladex aromatase inhibitors How bad is the cancer? How endocrine sensitive is the cancer? What about the patient? (preference, fitness)
Adjuvant HER2 treatment: unresolved issues How low should you go? (Tolaney, 2015) How long should you go? (PHARE, HERA) Do you need anthracyclines? (BCIRG, 2011) Do you need other anti-her2 drugs? (ALTTO, APHINITY)
2018-2026 Chemotherapy questions largely resolved Patient selection will get tighter gene expression assays, ctdna technology Toxicity issues will become more important de-escalation trials Triple negative disease will be further refined and treated differently Adjuvant use of drugs being tested in MBC: PARPi, CDKi, PI3Ki, mtori The role of immune-activating therapies will be clarified