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
The goal in Early Breast Cancer
Risk of: Overtreatment Suboptimal treatment Toxicities
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
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 <br />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
<br />MA.17R - DFS by pre-specified subgroups<br />
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
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
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
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
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<0.01
FinXX° (N=1495) 10 yrs FUP
0.88 p=0.22
0.54 p=0.02 N=202
0.84 P= 0.15
0.55 p=0.0037
Are we undertreating in Adjuvant Tx? Adding Capecitabine in Adjvant regimens: Results
*S-J Lee, SABCS 2015 °H. Joensuu, ASCO 2016
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: what’s news
Qualità dell’evidenza 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: what’s 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
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
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: What’s news for EBC Treatment
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)
Have we improved outcomes and efficacy ?
Grazie
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