NOVITA’ DAGLI STUDI DI TERAPIA ADIUVANTE PER IL CARCINOMA MAMMARIO HER2+: RILEVANZA CLINICA
Mirco Pistelli
Clinica di Oncologia Medica A. O. Ospedali Riuniti Ancona
Perugia, 6 luglio 2018
Anti-HER2 adjuvant therapy:
CHALLENGES WITH EVIDENCE
• Less chemotherapy (de-escalation)
• Duration of Trastuzumab: longer versus shorter
• Addition of other agents (escalation)
• ER+ HER2+
Impact of adjuvant trastuzumab on long-term outcome in early-stage HER2-positive breast cancer
1986-1992 2004-2008
Cossetti RJ et al JCO 2015 7178 pazienti- stadio I-III
Adjuvant Trastuzumab Trials: >13,000 Patients 2005 Was a Good Year
Anti-HER2 adjuvant therapy:
CHALLENGES WITH EVIDENCE
• Less chemotherapy (de-escalation)
• Duration of Trastuzumab: longer versus shorter
• Addition of other agents (escalation)
• ER+ HER2+
Less chemotherapy: anthracyclines, yes or not?
Less chemotherapy: anthracyclines, yes or not?
Less chemotherapy: anthracyclines, yes or not?
Less chemotherapy: anthracyclines, yes or not?
Less chemotherapy: anthracyclines, yes or not?
Tolaney et al, NEJM 2015 & ASCO 2017
Less chemotherapy: anthracyclines, yes or not?
Less chemotherapy: anthracyclines, yes or not?
Tolaney et al, NEJM 2015 & ASCO 2017
Less chemotherapy: anthracyclines, yes or not?
Tolaney et al, NEJM 2015 & ASCO 2017
Less chemotherapy: anthracyclines, yes or not?
Tolaney et al, NEJM 2015 & ASCO 2017
Less chemotherapy: anthracyclines, yes or not?
Tolaney et al, NEJM 2015 & ASCO 2017
Adjuvant chemotherapy: yes or not?
Adjuvant chemotherapy is standard of care
Anti-HER2 adjuvant therapy:
CHALLENGES WITH EVIDENCE
• Less chemotherapy (de-escalation)
• Duration of Trastuzumab: longer versus shorter
• Addition of other agents (escalation)
• ER+ HER2+
Just one year ago…
Just 7 months ago…
Just 1 month ago…
6 vs 12 months (DFS)
9 weeks vs 12 months (DFS)
HORG=481 pz
p=ns p=ns
PHARE=3380 pz
p=0.01
PERSEPHONE=4089 pz
Short-HER=1253 pz
p=ns
SOLD=2176 pz
p=ns
Short-HER=1253 pz PHARE=3380 pz PERSEPHONE=4089 pz
Subgroup analysis (DFS)
Slide 31
Presented By Martine Piccart-Gebhart at 2018 ASCO Annual Meeting
Anti-HER2 adjuvant therapy:
CHALLENGES WITH EVIDENCE
• Less chemotherapy (de-escalation)
• Duration of Trastuzumab: longer versus shorter
• Addition of other agents (escalation)
• ER+ HER2+
Addition of other agents: Lapatinib
Martine Piccart, JCO 2016
Addition of other agents: Lapatinib
DFS L+T vs T=+2% (4y) p=ns OS L+T vs T=+1% (4y) p=ns
Addition of other agents: Neratinib
Martin M, Lancet Oncology 2017
Addition of other agents: Neratinib
DFS N+T vs T=+2.5% (5y) p=0.008
Martin M, Lancet Oncology 2017
Martin M, Lancet Oncology 2017
Addition of other agents: Neratinib
DFS N+T vs T=+4.4% (5y) p=0.002 DFS N+T vs T=+0.1% (5y) p=ns
Addition of other agents: Pertuzumab
(expected 89.2%)
Addition of other agents: Pertuzumab
* statistically signicant
ALTTO (N=8381) ExteNET (N=2840) APHINITY (N=4805) T >2 cm 4199 (50.1%) 1401 (49.3%) 2879 (59.9%)
N+ (%) 4323 (51.6%) 2169 (76.4%) 3007 (62.6%)
DFS (control group) 86% (4y) 87.7% (5y) 90.6% (4y)
OS (control group) 94% (4y) nr nr
HR 0.84 0.73 0.81
in favour of «more» (ALL) +2% +2.5%* +1.7%*
in favour of «more» (ER+) +2% +4.4% * +1.4%
in favour of «more» (ER-) +3% +0.1% +2.3%
in favour of «more» (N0) nr Nr +0.5%
in favour of «more» (N+) nr nr** +3.2%*
** HR=0.67 (0.46-0.96) N>4
Addition of other agents: does it really benefit?
• Lapatinib: not approved for adjuvant treatment
• Neratinib: approved by FDA, rejected by EMA
• Pertuzumab: approved by FDA and EMA, waiting for AIFA.
Addition of other agents: where are we now?
Anti-HER2 adjuvant therapy:
CHALLENGES WITH EVIDENCE
• Less chemotherapy (de-escalation)
• Duration of Trastuzumab: longer versus shorter
• Addition of other agents (escalation)
• ER+ HER2+
• We may (and probably are) over-treating a subgroup of ER+
HER2+ BC in the (neo-) adjuvant setting.
• Inhibition of HER2 without inhibition of ER may increase ER signaling allowing ER to act as an escape mechanism. This could contribute to the lower pCR seen in ER+HER2+ BC. Crosstalk could explain worse outcome in the ExteNET.
• There may be a subset of ER+HER2+ BC where ER inhibition is critical and more important than chemotherapy.
Why is this important?
• The use of Trastuzumab-based chemotherapy has dramatically improved outcome for patients with early stage HER2+ BC; patients in more recent trials have lower recurrence rates than in earlier trials.
• For the present, chemotherapy is a key component and standard of care for the treatment of early stage HER2+ BC.
• Further follow-up from APT trial demonstrates very favorable outcome with low rates of distant recurrence; thus can be considered for stage I HER2+ BC.
• A short duration of adjuvant Trastuzumab (< 12-mo) should be considered (especially if cardiac risk factors) and patients who cannot complete 12-mo can be reassured.
• Addition of pertuzumab to adjuvant regimens improves DFS but restricted to high risk patients (especially N+). However, don’t forget to select N+ HER2+ BC for neo-adjuvant treatment (pCR= ↑OS).
• ER+ HER2+ BC are heterogeneous and further therapeutic de-escalation could be evalueted.
