BREAST CANCER Adjuvant Therapy

BREAST CANCER Adjuvant Therapy Dr Anna Bashford Department of Oncology Auckland City Hospital 12 June 2015

No disclosures Unfortunately

PLAN Adjuvant Therapy Rationale for adjuvant therapy Chemotherapy Targeted therapy Hormonal manipulation Radiotherapy New drugs Survivorship, fertility, genetics Patterns of relapse

ADJUVANT THERAPY

ADJUVANT THERAPY Post operative treatment given in patients with no evidence of metastatic disease on history, clinical examination +/- staging investigations. Given with curative intent.

Many Women are Cured by Surgery

Some Women are not Cured by Surgery

Purpose of Adjuvant Therapy

Screening for Metastatic Disease History Physical examination Blood tests (LFTs, Ca15-3) If greater than 4 lymph nodes positive: CT Bone scan In 2012, ASCO identified staging CT, radionuclide or PET scans for asymptomatic, low risk breast cancer pts as one of the 5 big money wasters in Oncology.

The Anatomic Approach Size and nodes A little treatment A lot of treatment

Node ve EBC Risk of Recurrence

Heterogeneity of Breast Cancer On the level of histopathology On the molecular level Size Nuclear Grade LVI Nodal involvement HR HER2 Basal-like HER2 + Luminal B Luminal A Shift to A New Approach Based on the Biology of the Disease Sorlie T et al, PNAS 2001, Sotiriou C et al, Proc Natl Acad Sci USA, 100;

ADJUVANT THERAPY Chemotherapy Herceptin Hormonal manipulation Radiotherapy

Falling Death Rates Falling death rates Due to: Tamoxifen Chemotherapy Early detection

Choice of Adjuvant Therapy Risk Factors Axillary Nodes Tumour Grade Size HER-2 Status ER/PR Status Age Menopausal Status Co Morbidities Cultural factors Side Effects Chemotherapy Short Term POF/loss of fertility CCF, 2 nd Ca Hormonal Therapy Hot Flushes Thromboembolism Endometrial Cancer Arthralgia Bone Mineral Loss

Weighing up Risks and Benefits

Patient Choice!

Assessing Risk and Benefit

Adjuvant Chemotherapy

Benefit of Chemotherapy EBCTCG Lancet 2005:365:1687-1717

Evolution of Chemotherapy NSABP ECOG2197 CMFx6 = ACx4 = ATx4 = NSABPB30 TACx4 FASG05 CEF/FECx6 CALGB934 4 CAF/FACx6 ACx4-Pacx4 USON9735 TCx4 PACS01 BCIRG001 ECOG 1199 FEC-T TACx6= ACx4-Tx4 ddacx4-px4 BCIRG005 ACx4-Px12 CALGB934 3 improvement

Anthracyclines Doxorubicin (Adriamycin) and Epirubicin AC = Adriamycin and Cyclophosphamide IV Once every 3 weeks for 4 cycles 3 drug anthracycline containing regimens eg FEC, FEC/T. 6 cycles. 5 months of treatment.

Anthracyclines side effects SHORT TERM Lethargy Nausea and vomiting Hair loss (alopecia) temporary Bone marrow suppression and risk of neutropenic sepsis Chemo-brain LONG TERM Cardiac damage Second malignancy e.g. leukaemia Premature ovarian failure

Anthracyclines Anthracycline therapy is superior to CMF Reduces mortality by additional ~ 3% (absolute)

Breast Cancer Recurrence Additional Benefit of Anthracyclines EBCTCG Lancet 2005:365:1687-1717

Taxanes TC = Taxotere/ Cyclophosphamide IV, q3 weekly, x4 For lower risk disease US Oncology 9735, Stephen E. Jones et al.jco 2006;24:5381-587 FEC/T 5FU, Epirubicin and Cyclophosphamide IV, q3 weekly, x3 Followed by Taxotere IV, q3 weekly, x3 Giving 5 months of treatment For higher risk disease PACS-01, Henri Roche et al, JCO 2006;24:5664-5671

Breast Cancer Recurrence Additional Benefit of Anthracyclines Adapted from EBCTCG Lancet 2005:365:1687-1717

Breast Cancer Recurrence Additional Benefit of Taxanes Adapted from EBCTCG Lancet 2005:365:1687-1717

Disadvantages of Adding Taxanes Increased side-effects Myalgia and arthralgia Febrile neutropenia (TAC vs FAC) Peripheral neuropathy Increased duration of treatment AC vs FEC /Taxotere - 3 vs 5 or 6 months Increased cost $20 25,000

Most Important Point

Febrile Neutropenia May be life threatening. SERIOUS Neutropenia occurs: 10 to 12 days after anthracyclines 7 to 8 days after taxanes Call Oncology if: T> 38.5⁰ x1 T 38⁰ x2 half an hour apart Hot, cold, shaky, crook

Febrile Neutropenia Patients require prompt assessment and empiric broad-spectrum antibiotics Source or infection found only in 20-30% Breakdown of mucosal barriers Prophylactic GCSF can be given with regimens where there is a 20% risk fn

Adjuvant Herceptin

HRG (NRG1) The EGFR/HER Family Ligand binding domain Transmembrane Tyrosine kinase domain erb-b1 EGFR HER1 neu Erb-b2 HER2 Erb-b3 HER3 Erb-b4 HER4 Mendelsohn and Baselga. Oncogene. 2000;19:6550. Olayioye et al. EMBO J. 2000;19:3159. Prigent and Lemoine. Prog Growth Factor Res. 1992;4:1. Harari and Yarden. Oncogene. 2000;19:6102. Earp et al. Breast Cancer Res Treat. 1995;35:115.

Her2 Receptor HER2 receptor found on 15 20% of breast cancers Associated with More aggressive disease

Trastuzumab: Humanized Anti-HER2 Antibody HER2 epitopes recognized by hypervariable murine antibody fragment Human IgG-1 Targets HER2 protein High affinity (K d = 0.1 nm) and specificity 95% human, 5% murine Decreases potential for immunogenicity Increases potential for recruiting immune effector mechanisms

Global Herceptin Adjuvant Programme HERA (ex-us) (n=5090) NSABP B-31 (US) (n=1960) NCCTG N9831 (US) (n=3046) 4 Trials >13,000 patients BCIRG 006 (global) (n=3222)

August 2009

Adjuvant trastuzumab in EBC: reported OS Median follow-up, years HERA H 1 year B-31 / N9831 AC PH BCIRG 006 AC DH BCIRG 006 DCarboH 2 3 3 3 0 1 2 Favours Favours no trastuzumab trastuzumab HR Slamon et al 2006; Perez et al 2007; Smith et al 2007

Adjuvant Herceptin Improves Survival HERA : Absolute overall survival benefit at 3 years of 2.7% NSABP/NCCTG : Absolute overall survival benefit at 4 years of 3.2%, HR = 0.65, and 8.8% 10 years from randomisation BCIRG: AC/T vs AC/TH arms os ꜛ 6% at 4 years

SUMMARY: Cardiac Safety in EBC Trial Arm Baseline LVEF, % CHF, n (%) Cardiac death, n HERA Nil H 1 year >55 0 9 (0.5) 1 0 NSABP B-31 AC P AC PH >50 4 (0.8) a 31 (4.1) a 1 0 NCCTG N9831 AC P AC PH >50 0 a 20 (2.9) a 0 1 BCIRG 006 AC D AC DH DCarboH >50 3 (0.3) 17 (1.6) 4 (0.4) 0 0 0 FinHER a Cumulative percent H No H 0 (0) 1 (1) Piccart-Gebhart et al 2005; Romond et al 2005; Slamon 2005; Tan-Chiu et al 2005 0 0

Trastuzumab Controversies Duration Gold standard = 1 year HERA 2 years no better than 1 PHARE? 1 year better than 6 months Await SOLD 6 weeks concurrent vs 1 year Size Trials have established benefit for T>1cm NCCN guidelines treat 5mm. Higher risk of recurrence compared with Her2 neg

Adjuvant Hormonal Manipulation

Mechanism of Action of Tamoxifen and AIs

Effect of 5 yrs of Tamoxifen vs Placebo/No Treatment

Adjuvant Hormonal Manipulation ONLY if ER+ and/or PR+, new cut off = 1% More likely to respond if strongly ER+ PREMENOPAUSAL Tamoxifen 20mg od for 5 to 10 years Ovarian ablation Goserelin, Triptorelin - Surgery - Radiation ablation

Adjuvant Hormonal Manipulation POSTMENOPAUSAL Tamoxifen Aromatase Inhibitor (Anastrazole or Letrozole) Switch policy with Tamoxifen and AI Aromatase Inhibitors Upfront Switch policy @2-3y (as per BIG1-98, TEAM) After 5 years of tamoxifen (MA17) If intolerant of Tamoxifen If Tamoxifen CI (eg PH PE) NB Monitor bone density

Case Study Mrs BC, 45yo 01/05/2010 Bilateral mastectomies and ALND Histology = Left: 40mm IDC, Grade 2, ER+ PR+ Her2 neg Right: >60mm IDC/ILC, Grade 2, ER+ PR+ Her2 neg LN + (3/17) 15/10/2010 Completed adjuvant FEC/Taxol chemotherapy and commenced adjuvant tamoxifen. 12/2010 Completed adjuvant RT 10/2015 Will complete 5 years of adjuvant tamoxifen. What then?

[TITLE] Presented By Ruth O'Regan at 2014 Breast Cancer Symposium

ATLAS n= 6846 women ER positive 10 vs 5 years tamoxifen Lancet 2013;381:805-16

Do Premenopausal Women Benefit from OFS?

Ovarian Function Suppression SOFT and TEXT trials evaluated ofs + exemestane or tamoxifen vs tamoxifen alone EBC, premenopausal, ER+. OFS plus exemestane resulted in improved 5y dfs. No os difference. More toxicity and more patients stopped with ofs. Exploratory analysis suggests those with higher risk derive most benefit: most benefit if had chemo or 35yo. Francis PA et al NEJM 2015;372:436 Pagani O et al NEJM 2014;371:107

Adjuvant Radiotherapy

Adjuvant Radiotherapy All patients following Wide Local Excision Mastectomy If 1 LN positive If margins positive If Tumour > 5cm Relative indications = Grade III, LVI, multifocal Reduces the risk of loco-regional relapse Small increase in overall survival

Advances in RT Hypofractionation 3 weeks Equivalent outcomes, more tolerable, maybe better cosmesis All except reconstructed breasts Intra-beam Low risk cases ( 3cm, Grade 1, postmenopausal). At time of surgery Only in private at present Requires co-ordination of team

THE FUTURE

Problems with adjuvant chemotherapy Not everyone needs treatment Not everyone benefits from standard treatment which translates to a modest benefit overall Treatment is toxic: nausea, hair loss, menopause, infection risk

cdna expression profiling Transcriptional Profiling on MicroArrays DNA clones Test Reference laser 1 laser 2 excitation Reverse transcription Label with fluor dyes Scan PCR Amplification and purification Robotic Printing cdna microarray Computer Analysis combine outputs Hybridize Target to microarray

Prospects for the Future Microarray will become routine Id those whose prognosis is so good, don t need chemo Predict those most likely to respond to treatment Tailor treatment to patient more precisely Microarray in prospective clinical trials Identify new therapeutic targets

TAILORx and MINDACT Node-negative B.C. population High risk 21-gene R.S. OR High risk 70-gene signature + High risk adjuvant on line Medium risk 21-gene R.S. OR Discordant risk group (mostly low risk 70-gene signature but high risk adjuvant on line) Low risk 21-gene R.S. OR Low risk 70-gene signature + Low risk adjuvant on line CHEMOTHERAPY RANDOMIZE CHEMO YES or NO (TailorX) RANDOMIZE FOR the decision-making tool (Mindact) ENDOCRINE THERAPY

New Drugs

Pertuzumab CLEOPATRA (SwainSM et al, NEJM. 2015;372(8):724) Trastuzumab + pertuzumab (anti-her2 monoclonal AB)+ docetaxel chemo, n=808, Her2+ MBC Improved os = 16 months, HR = 0.68 Additional SE = diarr, neutropenia, rash, mucositis, fn. No increase in LV dysfunction. Not yet funded in NZ Adjuvant trials are ongoing

Survivorship Survivorship care plan Follow up Psychological support Annual mammogram Fertility Genetics referral

Genetics Referrals Br ca 35yo Bilateral br ca if premenopausal Male br ca 2 cases 55yo 3 cases in 3 generations Ovarian cancer and br ca (TNBC)

Relapse

Patterns of relapse - Local 15-40% involve chest wall and axillary or SCFLN Treatment options are potentially curative = surgery, chemo (CALOR trial, esp if ER neg), endocrine therapy, RT (if no previous RT). If 2yrs from 1, risk distant mets = 25-30%, so staging CT and bone scan

Patterns of relapse - Distant Br ca can metastasise to almost any organ Incurable Most commonly: bone, liver, lung Brain in 5% as first presentation ILC peritoneal surfaces, leptomeninges, may relapse late. Average = 2 years from primary TNBC faster ER + - later, up to 15 years or more

Second primaries 0.5 1%pa Annual screening for 10years after diagnosis BRCA1 lifetime risk 65% BRCA2 lifetime risk 50% Consider prophylactic surgery

Conclusion Not all patients need adjuvant therapy Adjuvant therapy improves survival Risk vs benefit We need ways to better define who will derive benefit from treatment And better adjuvant treatments (especially in TNBC)

Thank you for listening!

FINHER Trial Design 1010 pts. EBC pn+ or pn0 (tumour >2 cm, PR-) R 507 pts. Vinorelbine 502 pts. Docetaxel 392 pts. HER2-115 pts. HER2 + 116 pts. HER2 + 386 pts. HER2 - R R 392 pts. HER2-57 pts. + Herceptin 58 pts. 58 pts. + Herceptin 58 pts. 386 pts. HER2-1010 patients were recruited and after 2 randomisations allocated to 6 treatment arms (1 patient excluded from efficacy analyses)

Benefit of Herceptin in FinHER

Do Premenopausal Women Benefit from OFS?

POEMS Zoladex and chemo vs chemo alone. ER/PR - Ov failure 8% in zoladex group vs 22%in chemo alone group. Pregnancy in 21% vs 11%. dfs and os superior on zoladex group. Consider ovarian function suppression with Zoladex 3.6mg sc every 4 weeks in patients about to receive adjuvant chemo, who wish to retain fertility, ER/PR neg. Fertility Specialist Moore HCF et al. NEJM 2015;372:923-32.