Carcinoma della Mammella Novità in tema di Adiuvante

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1 Convegno Nazionale AIOM Giovani, Perugia 8-9 Luglio 2016 Carcinoma della Mammella Novità in tema di Adiuvante Antonella Palazzo, MD, PhD Istituto Europeo Oncologico di Milano

2 The goal in Early Breast Cancer Risk of: Overtreatment Suboptimal treatment Toxicities

3 What s news in 2016 for EBC treatment? Some strategies to improve outcomes and reduce side effects in EBC Endocrine therapy: for how long? Cytotoxic adjuvant chemotherapy: - patient s selection (clinicopathological biomarker versus genomic tests) - which regimens? - which dose? Bone targeting therapy

4 Long Term recurrence risks after use of endocrine therapy for only 5 years Slide 4 Early Breast Cancer Trialists Collaborative Group (EBCTG)

5 EBCTCG - Long Term recurrence risks after use of endocrine therapy for only 5 years Slide 13 Presented By H. Pan at 2016 ASCO Annual Meeting

6 EBCTCG - Long Term recurrence risks after use of endocrine therapy for only 5 years Slide 12 Presented By H. Pan at 2016 ASCO Annual Meeting

7 News in 2016 for EBC treatment Should Extended Endocrine Therapy improves the outcome in Hormone Receptor Positive Early Breast cancer?

Primary Endpoint: DFS from Randomization Secondary Endpoint: OS, All CBC, Safety and QofLife Presented By Paul Goss at

8 MA.17R Trial Schema and Design <br />AI x 5 yrs - Following Prior 5 years of AI - preceded or not by Tamoxifen Stratification Criteria: Node status, previous CT, interval from IA, Tam duration. Primary Endpoint: DFS from Randomization Secondary Endpoint: OS, All CBC, Safety and QofLife Presented By Paul Goss at 2016 ASCO Annual Meeting Stat. Met: 196 events in 1800 pts to achieve a power of 80% to detect an HR 0.67 for DFS Study Emendment : 165 event at 6yrs FUP HR 0.655

9 MA17R Baseline characteristics Slide 10 Presented By Paul Goss at 2016 ASCO Annual Meeting

10 Slide 7 Presented By Paul Goss at 2016 ASCO Annual Meeting

11 <br />MA.17R - DFS by pre-specified subgroups<br /> Presented By Paul Goss at 2016 ASCO Annual Meeting

12 Slide 15 Few women discontinued treatment because of toxic effects (5.4% in the letrozole group vs. 3.7% in the placebo group). Presented By Paul Goss at 2016 ASCO Annual Meeting

13 New strategies to improve outcome in Endocrine positive EBC Waiting for some novel strategy in adjuvant tx Palbobiclib and Everolimus

14 PALLAS Trial of Adjuvant Palbociclib S1207 Trial of Adjuvant Everolimus

15 What s news in 2016 for EBC treatment? Some strategies to improve outcomes and reduce side effects in EBC Endocrine therapy: for how long? Cytotoxic adjuvant chemotherapy: - patient s selection (clinicopathological biomarker versus genomic tests) - which regimens? - which dose? Bone targeting therapy Surgery of axilla

16 Treatment Individualization: why? Outcomes of Adjuvant Chemotherapy in Breast Cancer Walgren et al JCO 2005, 23: 7342

17 The MINDACT Study Presented by M. Piccart at AACR Annual Meeting 2016

Primary Endpoint: Distant metastasis free survival (DMFS) at 5 years Null hypothesis : 5 yrs DMFS in PT population = 92% Power: 80% when tru 5-yrs DMFS rate

18 Primary Endpoint: Distant metastasis free survival (DMFS) at 5 years Null hypothesis : 5 yrs DMFS in PT population = 92% Power: 80% when tru 5-yrs DMFS rate = 95% Primary test: 95% 2-sided CI for the 5-yrs DMFS will be compared to 92%. Significant if exceeds 92% Presented by M. Piccart at AACR Annual Meeting 2016

19 MINDACT Trial: Patient demographic and compliance with assigned therapy Presented by M. Piccart at AACR Annual Meeting 2016

20 MINDACT population at 5y median follow up Discordant Risk group: primary test DMFS in all 4 Risk groups Discordant group Presented by M. Piccart at AACR Annual Meeting 2016

21 MINDACT Trial Efficacy: CT vs no CT in discordant risk group Intent to treat analysis Presented by M. Piccart at AACR Annual Meeting 2016

22 MINDACT Population: CT assignment according to a Clinical vs a Genomic strategy Slide 35 14% reduction Presented by M. Piccart at AACR Annual Meeting 2016

23 Proposed future clinica use of MammaPrint Presented by M. Piccart at AACR Annual Meeting 2016

24 What s news in 2016 for EBC treatment? Some strategies to improve outcomes and reduce side effects in EBC Endocrine therapy: for how long? Cytotoxic adjuvant chemotherapy: - patient s selection (clinicopathological biomarker versus genomic tests) - which regimens? - which dose? Bone targeting therapy

25 The bridge to a cure Dose dense schedule Anthra-taxane based regimens? Slide 3 Adding Capecitabine in Adjv regimens. CMF Anthracyclines Taxanes CREATE-X SABCS2015 Tiffany Traina at 2016 ASCO Annual Meeting

26 Are we undertreating in Adjuvant? Adding Capecitabine in Adjvant regimens. Capecitabine (X): 2500 mg/mq/day po day 1-14 q3wk for 8 cycles Primary Epoint: DFS SABCS 2015, LEE S-J et al Primary E.point Recurence Free Survival (RFS) Heikki Joensuu at 2016 ASCO Annual Meeting

27 Are we undertreating in Adjuvant Tx? Adding Capecitabine in Adjvant regimens: Results DFS/RFS OS All pts ERneg All pts ERneg CREATE-X* (N= 910) 5 yrs FUP 0.70 p= ( ) N= P<0.01 FinXX (N=1495) 10 yrs FUP 0.88 p= p=0.02 N= P= p= *S-J Lee, SABCS 2015 H. Joensuu, ASCO 2016

28 Are we overtreating or giving right in Adjuvant Tx? Anthra-taxane based vs taxane based regimens Dose dense schedules ABC Joint Analysis PANTHER Trial Primary Epoint: IDFS Inferiority of TC to TaxAC pre-defined as HR Secondary Epoint: RFI, OS, Toxicity Joanne Blum at 2016 ASCO Annual Meeting Primary E.point: Breast cancer relapse free survival Jonas Bergh at 2016 ASCO Annual Meeting

29 Anthra-taxane based vs taxane based regimens and Dose dense schedules: Results ABC Joint Analysis* mfup 3,2 yrs TC vs TaxAC (N=4242) IDFS All pts 1.23 p=0.004 HRneg HER2 neg pts 1.46 p< 0.05 PANTHER Trial mfup 5.3 yrs tddec->tddd vs FEC100 -> D100 (N =2003) BCRFS All pts 0.79 p= HRneg HER2neg 0.89 p= 0.6 EFS 0.79 p=0.042 OS 1.08 * Joanne Blum, ASCO 2016 Jonas Bergh, ASCO2016 p= p=0.093

30 The bridge to a cure Adjuvant chemotherapy: what s news From FinXX and CREATE-X trials: Integration of capecitabine into the taxane-anthracycline regimens did not prolong RFS or overall survival Findings for TNBC need to be interpreted with caution (small sample size) Asian population for favourable results of CREATE-X From ABC trials: IDFS was significant for superiority of TaxAC relative to TC; high 4 yrs OS in both groups. Minimal if any benefit in ER+/node negative cohorts Small benefit in ER+/1-3 node pos and ER-/node neg cohorts (2,0-2,5%) Large benefit in ER+/ 4 node pos and ER-/node pos cohorts (5,8-11,0%) From PANTHER trial: Higher doses of anthracycline and taxane are not necessarily better Difficult translation in daily practice Metanalysis support that dose dense delivery improves OS

Qualità dell evidenza SIGN A Raccomandazione clinica Nelle pazienti con carcinoma mammario operato candidate a trattamento chemioterapico adiuvante, dovrebbe essere presa in considerazione una

31 Qualità dell evidenza SIGN A Raccomandazione clinica Nelle pazienti con carcinoma mammario operato candidate a trattamento chemioterapico adiuvante, dovrebbe essere presa in considerazione una polichemioterapia 197. Forza della raccomandazione clinica Positiva forte A Nelle pazienti con carcinoma mammario operato candidate a chemioterapia adiuvante, dovrebbe essere preso in considerazione in prima intenzione un regime contenente antracicline e taxani in quanto superiore in DFS e in OS rispetto ai regimi senza taxani e contenenti dosi di antracicline simili o moderatamente maggiori 198. Positiva forte Moderata (GRADE) Nelle donne con carcinoma mammario operato linfonodi positivi, HER2- negative candidate a chemioterapia gli schemi a base di antracicline e taxani dose dense dovrebbero essere presi in considerazione in prima intenzione Positiva forte AIOM Breast Guidelines 2015

32 Adjuvant chemotherapy: what s news HER2+ EBC ExteNET Trial A. Chan et al Lancet Oncology 2016

New strategies to improve outcome in TNBC and HER+ EBC Waiting for some novel strategy in adjuvant tx NRG-BR003 Trial APHINITY TRIAL N=4800 Operable HER2+ breast cancer Primary endpoint: IDFS

33 New strategies to improve outcome in TNBC and HER+ EBC Waiting for some novel strategy in adjuvant tx NRG-BR003 Trial APHINITY TRIAL N=4800 Operable HER2+ breast cancer Primary endpoint: IDFS R Standard chemotherapy (6-8 cycles) + Trastuzumab q3 wks x 52 weeks + Pertuzumab q3 wks x 52 weeks Standard chemotherapy (6-8 cycles) + Trastuzumab q3 wks x 52 weeks + Placebo q3 wks x 52 weeks

34 What s news in 2016 for EBC treatment? Some strategies to improve outcomes and reduce side effects in EBC Endocrine therapy: for how long? Cytotoxic adjuvant chemotherapy: - patient s selection (clinicopathological biomarker versus genomic tests) - which regimens? - which dose? Bone targeting therapy

35 ABCSG-18 Trial: The Impact of Adjuvant Denosumab in breast cancer

36 ABCSG-18 Primary Endpoint Results (ASCO 2015)

37 ABCSG-18: DSF Analysis ITT Analysis Sensitivity Analysis DFS (cross-over censored) Presented M.Gnant at SABCS 2015

38 Indirect comparison with bisphosphonates: Metanalyses Lancet Oncology 2015 Oct, 386

39 Conclusion: What s news for EBC Treatment Have we improved outcomes and efficacy? Extended Endocrine therapy: yes / changing practice in high risk patients Cytotoxic adjuvant chemotherapy: - patient s selection (clinicopathological biomarker versus genomic tests) not yet - which regimens? Adjv CT must include anthracyclines. Anthra-free in special population (HER2 small tumors, low risk pts, cardiac comorbidities) - which dose? Dose dense should be considered in high risk patient Bone targeting therapy: Denosumab and bisphosphonates should be considered in postmenopausal pts as adjuvant tx (19% RR in DFS and 18% RR in OS respectively)

40 Grazie

Advances in Breast Cancer Therapeutics in the Adjuvant and Metastatic Settings. Eve Rodler, MD University of California at Davis October 2016

Advances in Breast Cancer Therapeutics in the Adjuvant and Metastatic Settings Eve Rodler, MD University of California at Davis October 2016 17th Annual Advances in Oncology September 30-October 1, 2016