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)

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Presented By H. Pan at 2016 ASCO Annual Meeting

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

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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

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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

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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

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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