Carcinoma della Mammella Novità in tema di Adiuvante

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

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  • Carcinoma della Mammella Novit in tema di Adiuvante

    Antonella Palazzo, MD, PhD

    Istituto Europeo Oncologico di Milano

    Convegno Nazionale AIOM Giovani, Perugia 8-9 Luglio 2016

  • The goal in Early Breast Cancer

    Risk of: Overtreatment Suboptimal treatment Toxicities

  • Whats 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: - patients selection (clinicopathological biomarker versus genomic tests) - which regimens ? - which dose? Bone targeting therapy

  • Slide 4

    Long Term recurrence risks after use of endocrine therapy for only 5 years

    Early Breast Cancer Trialists Collaborative Group (EBCTG)

  • Slide 13

    Presented By H. Pan at 2016 ASCO Annual Meeting

    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

    EBCTCG - Long Term recurrence risks after use of endocrine therapy for only 5 years

  • Should Extended Endocrine Therapy improves the outcome in Hormone Receptor Positive Early Breast cancer ?

    News in 2016 for EBC treatment

  • MA.17R Trial Schema and Design AI x 5 yrs - Following Prior 5 years of AI - preceded or not by Tamoxifen

    Presented By Paul Goss at 2016 ASCO Annual Meeting

    Primary Endpoint: DFS from Randomization Secondary Endpoint: OS, All CBC, Safety and QofLife

    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

    Stratification Criteria: Node status, previous CT, interval from IA, Tam duration.

  • Slide 10

    Presented By Paul Goss at 2016 ASCO Annual Meeting

    MA17R Baseline characteristics

  • Slide 7

    Presented By Paul Goss at 2016 ASCO Annual Meeting

  • MA.17R - DFS by pre-specified subgroups

    Presented By Paul Goss at 2016 ASCO Annual Meeting

  • Slide 15

    Presented By Paul Goss at 2016 ASCO Annual Meeting

    Few women discontinued treatment because of toxic effects (5.4% in the letrozole group vs. 3.7% in

    the placebo group).

  • Waiting for some novel strategy in adjuvant tx

    Palbobiclib and Everolimus

    New strategies to improve outcome in Endocrine positive EBC

  • S1207 Trial of Adjuvant Everolimus

    PALLAS Trial of Adjuvant Palbociclib

  • Whats 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: - patients selection (clinicopathological biomarker versus genomic tests) - which regimens ? - which dose? Bone targeting therapy Surgery of axilla

  • Outcomes of Adjuvant Chemotherapy in Breast Cancer

    Treatment Individualization: why?

    Walgren et al JCO 2005, 23: 7342

  • The MINDACT Study

    Presented by M. Piccart at AACR Annual Meeting 2016

  • 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 = 95% Primary test: 95% 2-sided CI for the 5-yrs DMFS will be compared to 92% . Significant if exceeds 92%

  • MINDACT Trial: Patient demographic and compliance with assigned therapy

    Presented by M. Piccart at AACR Annual Meeting 2016

  • Presented by M. Piccart at AACR Annual Meeting 2016

    MINDACT population at 5y median follow up

    Discordant Risk group: primary test DMFS in all 4 Risk groups

    Discordant group

  • MINDACT Trial Efficacy: CT vs no CT in discordant risk group Intent to treat analysis

    Presented by M. Piccart at AACR Annual Meeting 2016

  • Slide 35

    14% reduction

    Presented by M. Piccart at AACR Annual Meeting 2016

    MINDACT Population: CT assignment according to a Clinical vs a Genomic strategy

  • Presented by M. Piccart at AACR Annual Meeting 2016

    Proposed future clinica use of MammaPrint

  • Whats 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: - patients selection (clinicopathological biomarker versus genomic tests) - which regimens ? - which dose? Bone targeting therapy

  • Slide 3

    Tiffany Traina at 2016 ASCO Annual Meeting

    The bridge to a cure

    CMF Anthracyclines Taxanes

    Adding Capecitabine in Adjv regimens.

    Anthra-taxane based regimens?

    Dose dense schedule

    CREATE-X SABCS2015

  • SABCS 2015, LEE S-J et al

    Capecitabine (X): 2500 mg/mq/day po day 1-14 q3wk for 8 cycles

    Primary Epoint: DFS Primary E.point Recurence Free Survival (RFS)

    Heikki Joensuu at 2016 ASCO Annual Meeting

    Are we undertreating in Adjuvant? Adding Capecitabine in Adjvant regimens.

  • DFS/RFS OS

    All pts ERneg All pts ERneg

    CREATE-X* (N= 910) 5 yrs FUP

    0.70 p=0.0052

    0.58 (0.39 0.87)

    N=296

    0.60 P

  • Anthra-taxane based vs taxane based regimens Dose dense schedules

    Primary Epoint: IDFS Inferiority of TC to TaxAC pre-defined as HR 1.18. Secondary Epoint: RFI, OS, Toxicity

    Joanne Blum at 2016 ASCO Annual Meeting

    Are we overtreating or giving right in Adjuvant Tx?

    ABC Joint Analysis PANTHER Trial

    Primary E.point: Breast cancer relapse free survival

    Jonas Bergh at 2016 ASCO Annual Meeting

  • ABC Joint Analysis* mFUP 3,2 yrs

    PANTHER Trial mFUP 5.3 yrs

    TC vs TaxAC (N=4242)

    tddEC->tddD vs FEC100 -> D100 (N =2003)

    IDFS All pts 1.23 p=0.004

    HRneg HER2 neg pts 1.46 p< 0.05

    BCRFS All pts 0.79 p= 0.062

    HRneg HER2neg 0.89 p= 0.6

    EFS 0.79 p=0.042

    OS 1.08 p=0.6

    0.77 p=0.093

    Anthra-taxane based vs taxane based regimens and Dose dense schedules: Results

    * Joanne Blum, ASCO 2016 Jonas Bergh, ASCO2016

  • 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

    The bridge to a cure Adjuvant chemotherapy: whats news

  • Qualit dellevidenza SIGN

    Raccomandazione clinica Forza della raccomandazione clinica

    A Nelle pazienti con carcinoma mammario operato candidate a trattamento chemioterapico adiuvante, dovrebbe essere presa in considerazione una polichemioterapia197.

    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 maggiori198.

    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

  • A. Chan et al Lancet Oncology 2016

    ExteNET Trial

    Adjuvant chemotherapy: whats news HER2+ EBC

  • Waiting for some novel strategy in adjuvant tx

    New strategies to improve outcome in TNBC and HER+ EBC

    N=4800

    Operable HER2+ breast cancer

    Primary endpoint: IDFS

    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

    R

    NRG-BR003 Trial APHINITY TRIAL

  • Whats 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: - patients selection (clinicopathological biomarker versus genomic tests) - which regimens ? - which dose? Bone targeting therapy

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

  • ABCSG-18 Primary Endpoint Results (ASCO 2015)

  • Sensitivity Analysis DFS (cross-over censored)

    ABCSG-18: DSF Analysis

    ITT Analysis

    Presented M.Gnant at SABCS 2015

  • Indirect comparison with bisphosphonates: Metanalyses

    Lancet Oncology 2015 Oct, 386

  • Conclusion: Whats news for EBC Treatment

    Extended Endocrine therapy: yes / changing practice in high risk patients Cytotoxic adjuvant chemotherapy: - patients 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)

    Have we improved outcomes and efficacy ?

  • Grazie