Recenti avanzamenti nel carcinoma della mammella

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Oncologiche e Gastroenterologiche Università di Padova

Università di Padova Dipartimento di Chirurgia,

1 Recenti avanzamenti nel carcinoma della mammella PierFranco Conte Dipartimento di Scienze Chirurgiche, Oncologiche e Gastroenterologiche Università di Padova Pierfranco Conte IOV Istituto Oncologico Veneto I.R.C.C.S. Università di Padova Dipartimento di Chirurgia, Oncologia e Gastroenterologia IOV Istituto Oncologico Veneto I.R.C.C.S.

2 TRENDS IN MORTALITY FROM BREAST CANCER IN SELECTED COUNTRIES: AGE-STANDARDISED RATE (W) PER 100,000 Adj ChemoRx Adj HT Adj trastuzumab Screening For the first time in the history of medicine, MORTALITY due to a lethal, chronic and common disease is declining Availability of effective therapies is the main reason for the reduction in mortality

3 Adjuvant Systemic Therapy for EBC Summary of the Evidence Subgroup Treatment Comparator Risk reduction for recurrence Estimated HR TAM for 5y 1 No therapy 39% 0.61 AI (upfront or sequence) 1 5y TAM 30% 0.43 HR+ Extended adjuvant ET 2,3,4 5y TAM 15-43% Chemo + TAM 5y (age < 50y) 5 TAM 5y 36% 0.40 Chemo + TAM 5y (age 50-69) 5 TAM 5y 15% 0.59 HER2+ Trastuzumab + Chemo 6 Chemo 40% 0.21 Polychemotherapy 7 No chemo 24% 0.76 All Anthra regimens 7 CMF 20% 0.60 Anthra+Taxane regimens 7 Anthra 12% 0.53 Bisphosphonates (postmenopause) 8 ET +/- chemo 14% EBCTCG, Lancet 2015; 2 Goss P, NEJM 2003; 3 Gray RG, ASCO 2008; 4 Davies C, Lancet 2013; 5 EBCTCG Lancet 2005; 6 Cochrane Library 2012; 7 EBCTCG Lancet 2012; 8 EBCTCG Lancet 2015

From ONE Breast Cancer to Breast Cancer Subtypes ONE Size does not fit ALL anymore. Comparison ER+/HER2-ve Breast Cancer Absolute RR in Recurrence % Tamoxifen vs. Nil ^ 11.

4 From ONE Breast Cancer to Breast Cancer Subtypes ONE Size does not fit ALL anymore. Comparison ER+/HER2-ve Breast Cancer Absolute RR in Recurrence % Tamoxifen vs. Nil ^ NNT Aromatase Inhibitors vs TAM* Polychemo vs. Nil ( < 50)^ Polychemo vs. Nil ( 50+)^ Taxanes vs. Anthra 5 20 ChemoRx + Trastuzumab vs ChemoRx HER2+ TN

5 BC: the bright and the dark sides of a successful story - Personalized cancer medicine: reduced treatment burden for patients at lower risk neoadjuvant trials to identify patients with different outcomes - Progress over time: good news for HR+ early breast cancer good news for HR+ advanced breast cancer good news for HER2+ advanced breast cancer TN BC: still an unmet clinical need

6 Recurrence % The quest for precision cancer medicine: the case of HR+ EBC Nil Tam Who can be spared adjuvant chemotherapy? Can chemotherapy benefit be predicted? Tam+CT Which patients are still at risk after adjuvant HT and chemotherapy? Who deserves extended adj HT or HT plus OFS 0 5 years 10

7 Precision Medicine: GEPs PAM50 - ROR Mammaprint Endopredict GGI BCI OncotypeDX Reis-Filho J, Lancet 2011

Trial Assigning IndividuaLized Options for Treatment (Rx), or TAILORx Designed to determine whether HT is not inferior to CT+HT in women whose tumors fall in the Primary Study Group category (RS

Enrolled 10,071 pts (2006-2010) Oncotype DX assay 900 sites, 6 countries Secondary study group Recurrence Score result <11 ~29% of population Primary study group Recurrence Score result 11 25 ~44% of

8 Trial Assigning IndividuaLized Options for Treatment (Rx), or TAILORx Designed to determine whether HT is not inferior to CT+HT in women whose tumors fall in the Primary Study Group category (RS 11-25). The primary study endpoint is disease-free survival. Other co-primary endpoints include distant recurrence-free interval, recurrence-free interval, and overall survival. Enrolled 10,071 pts ( ) Oncotype DX assay 900 sites, 6 countries Secondary study group Recurrence Score result <11 ~29% of population Primary study group Recurrence Score result ~44% of population Secondary study group Recurrence Score result >25 ~27% of population ARM A: endocrine therapy alone N=1626 (15.9%) RANDOMISE N=6897 (67.3%) ARM D: chemotherapy plus endocrine therapy N=1730 (16.9%) ARM B: endocrine therapy alone ARM C: chemotherapy plus endocrine therapy Recurrence Score = % distant recurrence rate at 10 years 95% CI 5%, 10% Study arms for primary analysis To be reported at a later date (2017) Recurrence Score = % distant recurrence rate at 10 years 95% CI 13%, 20% Sparano JA et al. N Engl J Med 2015

9 TailorX: prognosis of RS low patients 5yrs rate 93.8% (95% CI, 92.4 to 94.9) 5yrs rate 99.3% (95% CI, 98.7 to 99.6) 5yrs rate 98.7% (95% CI, 97.9 to 99.2) 5 yrs rate 98.0% (95% CI, 97.1 to 98.6) Sparano, NEJM 2015

10 5-year BCFI (%) STEPP of 5-year BCFI according to Composite Risk Score: Overall HER2-negative yr N0 T 2cm Grade 1 Ki67<14% ER 50% PgR 50% yr N 1-3 T 2cm Grade 2 Ki % ER Overall 50% PgR 50% yr N0 T>2cm Grade 3 Ki67 >26% ER 50% PgR 50% <35 yr N 4+ T>2cm Grade 3 Ki67 >26% ER <50% PgR <20% Median CPRS in Subpopulations M. Regan et al, BCRT 2015

11 5-year BCFI (%) 5-year BCFI (%) STEPP of 5-year BCFI according to Composite Risk Score: 100 SOFT No Chemo Exemestane E+OFS + OFS Tamoxifen T+OFS + OFS Tamoxifen T E+OFS 1.50 T+OFS T posite Risk 0 Score in Subpopulations (SOFT No Chemo) Composite Risk Score Median in Subpopulations Composite Risk (SOFT Score in No Subpopulations Chemo) M. Regan et al, BCRT 2015

12 BC: the bright and the dark sides of a successful story - Personalized cancer medicine: reduced treatment burden for patients at lower risk OncoTypeDx identifies very low risk HR+ patients not requiring chemotherapy A composite risk score (age,t,n,g,er,pgr,ki67) identifies pts not requiring OFS neoadjuvant trials to identify patients with different outcomes - Progress over time: good news for HR+ early breast cancer good news for HR+ advanced breast cancer good news for HER2+ advanced breast cancer TN BC: still an unmet clinical need

13 The quest for precision cancer medicine: the case of HER2+ EBC Patients(%) year trastuzumab 19.4% Necessary but not effective 80 Observation 6.6% Necessary & effective NNT=15 3-year Events DFS HR 95% CI p value 74% Not necessary , 0.75 < Months from randomisation No at risk

14 HERA: Precision Cancer Medicine or Over-treatment? Patients(%) year trastuzumab Observation 3-year Events DFS HR 95% CI p value Same efficacy with reduced toxicity&costs Spare unnecessary treatments Reduce treatment burden , 0.75 <

15 Less Chemo for «low risk» HER2+ EBC Phase II trials APT 1 12wks wpac+ 1y T DocCtx x 4 + 1y T 2 Patient # Age median (range) 55 (24-85) 55 (24-75) T < 2cm % Node Neg % HR + % DFS % 98.7 (3y DFS) 97.8 (2y DFS) Cardiac events all G n (%) Cardiac events G ¾ n (%) 15 (3.7%) 29 (6 %) 2 (0.5%) 2 (0.4%) 1 Tolaney S et al, NEJM 2015; 2 Jones SE et al, Lancet Oncol 2013

16 Trials exploring different durations of trastuzumab administration Trial Sponsor Duration months CT regimen Start Accrual Status HERA BIG 12 vs 24 Center s choice PHARE INCA 6 vs 12 Center s choice 12/2001 3,387 completed 06/2005 5/2006 3,400 completed 05/2011 Hellenic Oncology Heraklion University 6 vs 12 ddfec/d 10/ completed 12/2011 Short-HER Modena&Padova Universities 2 vs.12 A+T vs T+FEC 12/2007 1,250 completed 09/2013 SOLD Finnish BCG 2 vs 12 T+FEC 1/2008 2,168 completed 11/2014 Persephone Warwick University 6 vs. 12 Center s choice 10/2007 4,000 ongoing total # > 15,000

DFS Probability Disease Free Survival 1.00 0.75 3y Δ 2.9 % 0.50 HR (95% CI): 1.28 (1.05-1.56) 0.25 395 events/1040 required 0.

17 DFS Probability Disease Free Survival y Δ 2.9 % 0.50 HR (95% CI): 1.28 ( ) events/1040 required 0.00 T-12m T-6m Months Trastuzumab T-12m T-6m Pivot X et al, Lancet Oncol 2013

18 Phare: Subgroup analysis Pts # 1,104 3y MFS % T 12 = 98.3 T 6 = 98.3 Pts # 702 3y MFS % T 12 = 90.4 T 6 = 85.7 Pts # 1,211 3y MFS % T 12 = 95.8 T 6 = 94.2 Pts # 322 3y MFS % T 12 = 78.4 T 6 = 74.8 Kramar A et al, Ann Oncol 2014

19 Duration of Trastuzumab and cardiac dysfunctions NSABP-B31 1 Phare 2 HERA 3 Age (median) concomitant T 100% 57.8% 0 Duration of T 0 1 yr 6 m 1 yr 0 1 yr 2 yr Cardiac events % P value p<0.001 p< Not reported 1 EH Romond et al, JCO 2012; 2 X Pivot et al, Lancet Oncol De Azambuja E et al, JCO 2014

20 BC: the bright and the dark sides of a successful story - Personalized cancer medicine: reduced treatment burden for patients at lower risk OncoTypeDx identifies very low risk HR+ patients not requiring chemotherapy A composite risk score (age,t,n,g,er,pgr,ki67) identifies pts not requiring OFS Good outcome for low risk HER2+ pts with reduced chemo burden or trastuzumab duration neoadjuvant trials to identify patients with different outcomes - Progress over time: good news for HR+ early breast cancer good news for HR+ advanced breast cancer good news for HER2+ advanced breast cancer TN BC: still an unmet clinical need

21 Meta-analysis Results from the Collaborative Trials in Neoadjuvant Breast Cancer (CTNeoBC): pcr correlates with long-term outcome Cortazar P et al, The Lancet 2014

22 Dual HER2 inhibition for HER2+ EBC TRIAL Treatment tpcr % P value NeoALLTO 1 # 455 NeoSphere 2 # 417 wpac + T 27.6 wpac + L 20 wpac +TL Doc+ T 21.5 Doc+ TP HP 11.2 T = Trastuzumab; L = Lapatinib; P = Pertuzumab Doc + P 17.7 CherLob 3 # 121 wpac/fec+ T 25.7 wpac/fec+ L 27.8 wpac/fec+ TL NSABP-B41 4 # 518 AC/wPac + T 49.4 AC/wPac + L 47.4 AC/wPac + TL Baselga J et al, Lancet 2012; 2 Gianni L et al, Lancet Oncol 2012; 3 Guarneri V et al, JCO 2012; 4 Robidoux A, JCO 2012; 5 Carey L, ASCO 2013 CALGB # 299 wpac + T 43 wpac + L 29 wpac +TL 52 NS

Food and Drug Administration today granted accelerated approval to Perjeta (pertuzumab) as part of a

23 FDA approves Perjeta for neoadjuvant breast cancer treatment First drug approved for use in preoperative breast cancer The U.S. Food and Drug Administration today granted accelerated approval to Perjeta (pertuzumab) as part of a complete treatment regimen for patients with early stage breast cancer before surgery (neoadjuvant setting). Perjeta is the first FDA-approved drug for the neoadjuvant treatment of breast cancer.

Loser in NeoALLTO = Loser in ALLTO TRIAL Treatment tpcr % P value NeoALLTO 1 # 455 wpac + T 27.6 wpac + L 20 wpac +TL 46.8 0.

24 Loser in NeoALLTO = Loser in ALLTO TRIAL Treatment tpcr % P value NeoALLTO 1 # 455 wpac + T 27.6 wpac + L 20 wpac +TL Following an interim analysis in September 2011 the lapatinib arm was discontinued and patients were offered trastuzumab. Piccart M, ASCO 2014; Perez E ESMO 2014

25 NeoAdjuvant Trials: a smart tool should be used for smart purposes. Neo-adjuvant trials to drop the loser Neo-adjuvant trials to identify biomarkers of resistance Neo-adjuvant trials to reduce treatment burden Neo-adjuvant trials to select high-risk patients for post neoadj trials

26 PER ELISA: HR+/HER2+ operable breast cancer Letrozole 2.5 mg CDD Diagnostic biopsy/ki67 Ki67 for molecular response Letrozole 2.5 mg CDD X 2 wks Molecular responders Non-Molecular responders S U R G E R Y Sample size 65 pts Biomarker analysis LVEF measurement Pertuzumab 840 mg loading dose -> 420 mg Trastuzumab 8 mg/kg loading dose -> 6 mg/kg Paclitaxel 80 mg/mq

27 Adjuvant post-neoadjuvant trials in patients with < than pcr HR+ PENELOPE: ER + CDK4/6 or placebo after PCT HER2+ KATHERINE: TDM1 vs Trastuzumab after PCT+T TNBC BRE09-146: Cisplatin vs Cisplatin + Rucaparib BRCAm OLYMPIA: Olaparib vs Placebo

28 BC: the bright and the dark sides of a successful story - Personalized cancer medicine: reduced treatment burden for patients at lower risk OncoTypeDx identifies very low risk HR+ patients not requiring chemotherapy A composite risk score (age,t,n,g,er,pgr,ki67) identifies pts not requiring OFS Good outcome for low risk HER2+ pts with reduced chemo burden or trastuzumab duration neoadjuvant trials to identify patients with different outcomes pcr identifies patients with a good prognosis PST allows to modulate treatment according to the observed clinical or biological outcome Patients with residual disease after PST are good candidates for post-neoadjuvant trials - Progress over time: good news for HR+ early breast cancer good news for HR+ advanced breast cancer good news for HER2+ advanced breast cancer TN BC: still an unmet clinical need

29 TEXT and SOFT joint analysis: results TEXT trial (n=2672) R Tamoxifen + OFS x 5y Exemestane + OFS x 5y Joint Analysis (n=4690) R SOFT trial (n=3066) Tamoxifen x 5y Tamoxifen + OFS x 5y Exemestane + OFS x 5y Tamoxifen + OFS x 5y Exemestane + OFS x 5y Primary endpoint: DFS Secondary endpoints: BCFI, DRFI, OS Pagani O, NEJM 2014

30 5-year BCFI (%) 5-year BCFI (%) 100 STEPP of 5-year BCFI according to Composite Risk Score: SOFT Prior Chemo Exemestane E+OFS + OFS Tamoxifen T+OFS + OFS Tamoxifen T E+OFS T+OFS T posite Risk 0 Score in Subpopulations (SOFT No Chemo) Median Composite CPRS in Subpopulations Risk Score in (SOFT Subpopulations Prior Chemo) M. Regan et al, BCRT 2015

31 HR+ EBC: extended Endocrine Therapy YEARS 0-4 YEARS 5-9 YEARS 10+ Recurrence (% per year) Recurrence (% per year) Recurrence (% per year) ER+ PR ys TAM in POSTMENOPAUSE ER-, PR Trial Experimental arm # DFS Δ HR MA17 1 5y Let 5, % 0.57 B33 2 5y Exe 1, % 0.44 ABCSG6a 3 3y Ana % 0.62 Trial Experimental arm # DFS Δ HR ATLAS 4 10y TAM 6, % 0.75 attom 5 10y TAM 6,953 4% Goss et al. NEJM 2003; 2 Mamounas et al, JCO 2008; 3 Jakesz et al JNCI 2007; 4 Davies et al, Lancet 2013; 5 Gray et al, ASCO 2013

32 BC: the bright and the dark sides of a successful story - Personalized cancer medicine: reduced treatment burden for patients at lower risk OncoTypeDx identifies very low risk HR+ patients not requiring chemotherapy A composite risk score (age,t,n,g,er,pgr,ki67) identifies pts not requiring OFS Good outcome for low risk HER2+ pts with reduced chemo burden or trastuzumab duration neoadjuvant trials to identify patients with different outcomes pcr identifies patients with a good prognosis PST allows to modulate treatment according to the observed clinical or biological outcome Patients with residual disease after PST are good candidates for post-neoadjuvant trials - Progress over time: good news for HR+ early breast cancer OFS (premenopause) and 10y ET for high risk patients good news for HR+ advanced breast cancer good news for HER2+ advanced breast cancer TN BC: still an unmet clinical need

33 BOLERO-2 and PALOMA-3: cross trials comparison Everolimus + Exemestane (n=485), % Placebo + Exemestane (n=239), % Palbociclib + Fulvestrant (n=347), % Placebo + Fulvestrant (n=174), % Sensitivity to prior hormonal therapy Prior AI Prior tamoxifen Prior fulvestrant Prior chemotherapy for metastatic BC Number of prior therapies for MBC > Median PFS mo CBR % (HR 0.44) 50.5 (p<0.0001) 25.5 (HR 0.42) 34 (p<0.0004) 19

34 Algorithm for Management of Post-menopausal ER+/HER2 MBC Determine sites and extent of disease & symptoms; ER status; HER2 status; disease free & treatment-free intervals; performance status No life-threatening disease Hormone-responsive Hormone-unresponsive, or Life-threatening disease 1 st line hormonal therapy 1 st line chemotherapy Response Median PFS mo Progression 2nd-line hormonal therapy Median Response PFS mo Progression 3rd-line hormonal therapy No Response No Response No Response Progression 2nd-line chemotherapy Progression 3rd-line chemotherapy Supportive care National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. V3.2012

35 BC: the bright and the dark sides of a successful story - Personalized cancer medicine: reduced treatment burden for patients at lower risk OncoTypeDx identifies very low risk HR+ patients not requiring chemotherapy A composite risk score (age,t,n,g,er,pgr,ki67) identifies pts not requiring OFS Good outcome for low risk HER2+ pts with reduced chemo burden or trastuzumab duration neoadjuvant trials to identify patients with different outcomes pcr identifies patients with a good prognosis PST allows to modulate treatment according to the observed clinical or biological outcome Patients with residual disease after PST are good candidates for post-neoadjuvant trials - Progress over time: good news for HR+ early breast cancer OFS (premenopause) and 10y ET for high risk patients good news for HR+ advanced breast cancer STIs can overcome/delay secondary endocrine resistance good news for HER2+ advanced breast cancer TN BC: still an unmet clinical need

OS 1 st line Treatment of HER2+ ABC: progress over time CT CT + H D + H D + H + P 20.3 m 25.1 m 40.8 m 56.5 m 2001 2014 2 nd line Cape Cape-Lap 16.2 m 18.8 m 2010 Cape-Lap T-DM1 25.1 m 30.

36 OS 1 st line Treatment of HER2+ ABC: progress over time CT CT + H D + H D + H + P 20.3 m 25.1 m 40.8 m 56.5 m nd line Cape Cape-Lap 16.2 m 18.8 m 2010 Cape-Lap T-DM m 30.9 m rd line Lap Lap + H 9.5 m 14 m 2010 Slamon, NEJM 2001 Swain ESMO 2014 TPC 14.9 m T-DM1 ++ NR Cameron, Oncologist 2010 Verma, NEJM Blackwell, JCO 2010 Krop, Lancet Oncol 2014

37 BC: the bright and the dark sides of a successful story - Personalized cancer medicine: reduced treatment burden for patients at lower risk OncoTypeDx identifies very low risk HR+ patients not requiring chemotherapy A composite risk score (age,t,n,g,er,pgr,ki67) identifies pts not requiring OFS Good outcome for low risk HER2+ pts with reduced chemo burden or trastuzumab duration neoadjuvant trials to identify patients with different outcomes pcr identifies patients with a good prognosis PST allows to modulate treatment according to the observed clinical or biological outcome Patients with residual disease after PST are good candidates for post-neoadjuvant trials - Progress over time: good news for HR+ early breast cancer OFS (premenopause) and 10y ET for high risk patients good news for HR+ advanced breast cancer STIs can overcome/delay secondary endocrine resistance good news for HER2+ advanced breast cancer dual antiher2 antibodies and ADC significantly prolong survival TN BC: still an unmet clinical need

Trastuzumab + Pertuzumab + taxanes T- DM1

Platinum salts Olaparib Chemotherapy mos

capecitabine mos for HER+ ABC Lapatinib +

38 Palliative treatments of ABC molecular subtypes MBC HR + HR HER2 HER2+ HER2+ HER2 BRCA mutated AI SERD AI + mtori Trastuzumab+Ana Lapatinib + Let Trastuzumab + Pertuzumab + taxanes T- DM1 Chemotherapy mos for TN ABC months Platinum salts Olaparib Chemotherapy mos for HR+ ABC months Lapatinib + capecitabine mos for HER+ ABC Lapatinib + Trastuzumab months Metastatic Bone Disease: Bisphosphonates, Denosumab

TNBC: Some Research Strategies Basal-like 1: Cell cycle, DNA repair and proliferation genes Basal-like 2: Growth factor signaling (EGFR, MET, Wnt, IGF1R) IM: Immune cell processes (medullary breast

39 TNBC: Some Research Strategies Basal-like 1: Cell cycle, DNA repair and proliferation genes Basal-like 2: Growth factor signaling (EGFR, MET, Wnt, IGF1R) IM: Immune cell processes (medullary breast cancer) M: Cell motility and differentiation, EMT processes MSL: Similar to M but growth factor signaling, low levels of proliferation genes (metaplastic cancers) LAR: Androgen receptor and downstream genes, luminal features PARPi, ± DNA damaging agents homologous recombination deficiency assay (BRCA-1 ness) EGFR (cetuximab, lapatinib) Self-renewal pathways (stem cell) Wnt Notch (PF ) Immune check point PD1/PDL1, CTLA4 Vaccines: MUC1, NYO-ESO1 Plus PI3Ki, RAS/MEK/Erk, MET, PTEN etc, etc Agents targeting androgen receptor (enzalutamide, bicalutamide, etc)

40 TNBC - Single Gene Targets gbrca 1/2m Platinum PARPi TBCRC009 Platinum mtnbc Androgen Receptor Bicalutamide (n=43, ORR: 0%, CBR-24 weeks: 19%, A. Gucalp et al, CCR 19: , 2013) Enzalutamide (n=75, ORR: 10%, CBR-24weeks: 29%; Traina et al ASCO 2015)

42 Immune checkpoint inhibitors that are being tested in ongoing phase II/III trials including MBC patients only. Nivolumab (BMS) Human IgG4 anti-pd-1 antibody Pembrolizumab (Merck) Humanized IgG4 anti- PD-1 antibody MPDL3280 (Genentech) engineered human IgG1 anti-pd-l1 antibody MEDI4736 (AZ) Human IgG1 anti-pd-l1 antibody Tremelimumab (AZ) Human IgG2 Anti-CTLA-4 antibody

43 Pembrolizumab in TNBC: Keynote-12 trial Characteristics n = 32 N. Prior therapies for MBC 0 5 (15.6%) Confirmed complete response Confirmed partial response Stable disease Progressive disease 1 6 (18.8%) 2 6 (18.8%) 3 5 (15.6%) 4 3 (9.4%) >=5 7 (21.9%) Objective response rate: 18.5% Stable disases: 25.9 % Nanda, SABCS 2015

44 Tailored Management of Breast Cancer Prognosis of Breast Cancer Patients has improved as the result of earlier diagnosis, molecular classification and more efficacious adjuvant treatments In early disease, molecular subtypes contribute to define risk categories and are major drivers of treatment selection In advanced disease, a prolonged survival and a meaningful QoL can be provided to the majority of the patients Important drivers of treatment choices include molecular subtypes, prior adjuvant treatments, tumor extent and burden, patient desires Targeted agents and new cytotoxics should be developped in specific subtypes of breast cancer A multimodality approach can be potentially curative for some patients TN disease still represents an unmet need, however, identification of specific genetic alterations and the high mutational load are promising therapeutic targets

What is new in HR+ Breast Cancer? Olivia Pagani Breast Unit and Institute of oncology of Southern Switzerland

What is new in HR+ Breast Cancer? Olivia Pagani Breast Unit and Institute of oncology of Southern Switzerland Outline Early breast cancer Advanced breast cancer Open questions Outline Early breast cancer