Novità in tema di terapia 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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The goal in Early Breast Cancer

Risk of:

Overtreatment

Suboptimal treatment

Toxicities

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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

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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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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

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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

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

News in 2016 for EBC treatment

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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.

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Slide 10

MA17R Baseline characteristics

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Slide 7

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<br />MA.17R - DFS by pre-specified subgroups<br />

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Slide 15

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

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Waiting for some novel strategy in adjuvant tx…

 Palbobiclib and Everolimus

New strategies to improve outcome

in Endocrine positive EBC

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S1207 Trial of Adjuvant Everolimus

PALLAS Trial of Adjuvant Palbociclib

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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

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Outcomes of Adjuvant Chemotherapy in Breast Cancer

Treatment Individualization: why?

Walgren et al JCO 2005, 23: 7342

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The MINDACT Study

Presented by M. Piccart at AACR Annual Meeting 2016

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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%

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MINDACT Trial: Patient demographic and compliance with assigned therapy

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MINDACT population at 5y median follow up

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

Discordant group

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MINDACT Trial Efficacy: CT vs no CT

in discordant risk group Intent to treat analysis

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Slide 35

14% reduction

MINDACT Population: CT assignment according to a

Clinical vs a Genomic strategy

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Proposed future clinica use of MammaPrint

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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

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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

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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….

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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

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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

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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

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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

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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

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A. Chan et al Lancet Oncology 2016

ExteNET Trial

Adjuvant chemotherapy: what’s news HER2+ EBC

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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

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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

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ABCSG-18 Trial: The Impact of Adjuvant Denosumab

in breast cancer

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ABCSG-18 Primary Endpoint Results (ASCO 2015)

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Sensitivity Analysis DFS (cross-over censored)

ABCSG-18: DSF Analysis

ITT Analysis

Presented M.Gnant at SABCS 2015

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Indirect comparison with bisphosphonates: Metanalyses

Lancet Oncology 2015 Oct, 386

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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 ?

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