Post on 27-Feb-2020
1Philip Poortmans, MD, PhD
Ex-Presidente
Presidente
El Perito Moreno
Parque nacional de los glaciaresEl 4 de abril 2019
3
Debería el perfil molecular influenciar el
tratamiento locoregional?
4
No tengo ningún conflicto de interés.
5
Molecular subtyping & locoregional treatment
1. Introduction
2. Molecular subtyping & & locoregional treatment
3. Discussion
4. Conclusions
6
El manejo de los ganglios axilares: Una
batalla entre la cirugía y la radioterapia?
7https://kanker-actueel.nl/fda-ondersteunt-onderzoek-naar-personalised-medicine-op-basis-van-mutaties-ongeacht-in-welk-lichaamsdeel-de-kanker-zich-het-eerst-openbaart.html
RT RT
RT RT
Molecular subtypes & locoregional ttm: Introduction
8Bertucci F, et al. Cancer research 2005;65:2170-8.
Molecular subtypes & locoregional ttm: Introduction
9Proposed by St Gallen; ASCO; ESMO; …
Molecular subtypes & locoregional ttm: Introduction
10
Molecular subtyping & locoregional treatment
1. Introduction
2. Molecular subtyping & & locoregionaltreatment
3. Discussion
4. Conclusions
11Overgaard M, et al. Radiotherapy & Oncology 2007;82:247-53.
Molecular subtypes & locoregional ttm: Early experience
ABSOLUTELY
IDENTICAL!
Editorial
12Kyndi M, et al. Radiotherapy & Oncology 2009;90:74-79.
Molecular subtypes & locoregional ttm: Early experience
13Kyndi M, et al. Radiotherapy & Oncology 2009;90:74-79.
DBCG 82 b&c
1982 – 1990 n = 3083
Either: pN+
T3-T4
Invasion of the pectoral fascia
Al,l patients received CMF or Tamoxifen
MRM ® ± RT
Molecular subtypes & locoregional ttm: Early experience
14Kyndi M, et al. Radiotherapy & Oncology 2009;90:74-79.
DBCG 82 b&c
5 favourable criteria:
≤ 3 N+ ≤ 2 cm T G1
ER + Her-2-neu –
➔ Low risk = ≥ 4/5 favourable criteria
3 unfavourable criteria:
> 3 N+ > 5 cm T G3
➔ High risk = ≥ 2/3 unfavourable criteria
➔ Intermediate risk = all others
Molecular subtypes & locoregional ttm: Early experience
15Kyndi M, et al. Radiotherapy & Oncology 2009;90:74-79.
Molecular subtypes & locoregional ttm: Early experience
16Kyndi M, et al. Radiotherapy & Oncology 2009;90:74-79.
LRR
Molecular subtypes & locoregional ttm: Early experience
17Kyndi M, et al. Radiotherapy & Oncology 2009;90:74-79.
DSS
Molecular subtypes & locoregional ttm: Early experience
18Kyndi M, et al. Radiotherapy & Oncology 2009;90:74-79.
OS
Molecular subtypes & locoregional ttm: Early experience
19Kyndi M, et al. Radiotherapy & Oncology 2009;90:74-79.
Risk: Low Intermediate High
Treatment: (-) RT (-) RT (-) RT
LR at 5y: 11 → 0 26 → 5 50 → 14
DSS at 15y: 67 → 78 39 → 50 19 → 19
OS at 15y: 53 → 65 30 → 39 12 → 16
-11
+11
+12
-21
+11
+9
-36
+0
+4
➔ ~ 1/1 ~ 1/2 ~ 1/9
Molecular subtypes & locoregional ttm: Early experience
20Kyndi M, et al. JCO 2008;26:1419-14.
Molecular subtypes & locoregional ttm: Molecular based experience
The same DBCG 82 b&c cohort, N=1000
21Kyndi M, et al. JCO 2008;26:1419-14.
ER+ PgR+ HER2-
ER- PgR- HER2+
Molecular subtypes & locoregional ttm: Molecular based experience
22Kyndi M, et al. JCO 2008;26:1419-14.
ER+ PgR+ HER2 -
ER- PgR- HER2+
Molecular subtypes & locoregional ttm: Molecular based experience
23Kyndi M, et al. JCO 2008;26:1419-14.
Rec+, HER2-“Luminal A”
63%
Rec+, HER2+ “Luminal B”
10%
Triple neg “Basal like”
15%
Rec-, HER2+ “HER2 like”
12%
24Kyndi M, et al. JCO 2008;26:1419-14.
Rec+, HER2-“Luminal A”
63%
Rec+, HER2+ “Luminal B”
10%
Triple neg “Basal like”
15%
Rec-, HER2+ “HER2 like”
12%
This study supports the spectrum hypothesis:
• Local disease in Luminal-A
• Mixed in Luminal-B
• With adjuvant endocrine treatment & CMF
• Micrometastases in triple negative and HER-2
• Insufficient systemic treatment in the 80ties
To be explored further:
• Influence of adjuvant systemic treatments
• Role of radioresistance of Rec- and HER-2
25Kyndi M, et al. JCO 2008;26:1419-14.
Rec+, HER2-“Luminal A”
63%
Rec+, HER2+ “Luminal B”
10%
Triple neg “Basal like”
15%
Rec-, HER2+ “HER2 like”
12%
This study supports the spectrum hypothesis:
• Local disease in Luminal-A
• Mixed in Luminal-B
• With adjuvant endocrine treatment & CMF
• Micrometastases in triple negative and HER-2
• Insufficient systemic treatment in the 80ties
To be explored further:
• Influence of adjuvant systemic treatments
• Role of radioresistance of Rec- and HER-2
26Kyndi M, et al. JCO 2008;26:1419-14.
Rec+, HER2-“Luminal A”
63%
Rec+, HER2+ “Luminal B”
10%
Triple neg “Basal like”
15%
Rec-, HER2+ “HER2 like”
12%
This study supports the spectrum hypothesis:
• Local disease in Luminal-A
• Mixed in Luminal-B
• With adjuvant endocrine treatment & CMF
• Micrometastases in triple negative and HER-2
• Insufficient systemic treatment in the 80ties
To be explored further:
• Influence of adjuvant systemic treatments
• Role of radioresistance of Rec- and HER-2
27Nguyen PL, et al. JCO 2008;26:2373-08.
BCS 1998-2001; N=793
FU = 70 months
Systemic therapy:
Chemotherapy 88% of N+ and 29% of N0
Hormonal therapy to 88% of patients with ER+ / PgR+ disease
No trastuzumab
Radiation therapy:
WBI + boost
Supraclavicular / axillary field if N2-disease
N = 18 isolated located recurrences
• Luminal A: ER+ or PgR+ and HER2-
• Luminal B: ER+ or PgR+ and HER2+
• HER2: ER- or PgR- and HER2+
• Basal: triple neg
Molecular subtypes & locoregional ttm: Molecular based experience
28Nguyen PL, et al. JCO 2008;26:2373-08.
Local recurrence
Molecular subtypes & locoregional ttm: Molecular based experience
29Nguyen PL, et al. JCO 2008;26:2373-08.
Local recurrence
Distant metastasis
Molecular subtypes & locoregional ttm: Molecular based experience
30Nguyen PL, et al. JCO 2008;26:2373-08.
Local recurrence
Distant metastasis
Luminal A has a particularly
low recurrence rate
Molecular subtypes & locoregional ttm: Molecular based experience
31Mamounas EP, et al. JCO 2010;28:1677-83.
BCS+RT or MRM 1982-1993; 2 randomised trials:
• B-14 : 5 year Tamoxifem vs placebo, later on Tam 5 vs 10 y
• B-20 : Tamoxifen +/- chemo
✓ The 21-gene OncotypeDX recurrence score (RS) assay can predict distant
recurrence risk in patients with tumors ER+ and N0
? Can the 21-gene assay predict locoregional recurrence risk?
Molecular subtypes & locoregional ttm: Molecular based experience
32Mamounas EP, et al. JCO 2010;28:1677-83.
N=895
Molecular subtypes & locoregional ttm: Molecular based experience
33Mamounas EP, et al. JCO 2010;28:1677-83.
N=895
N=355
Molecular subtypes & locoregional ttm: Molecular based experience
34Mamounas EP, et al. JCO 2010;28:1677-83.
N=895
N=355
N=424
Molecular subtypes & locoregional ttm: Molecular based experience
35Mamounas EP, et al. JCO 2010;28:1677-83.
N=895
N=355
N=424
Conclusion:
The 21-gene assay locoregional recurrence risk
• In this group of ER+ and N0 patients
• With this adjuvant systemic treatment
Further studies required:
• To confirm the low LRR risk group ➔ without RT
• To define the high LRR risk group ➔ new RT indications
Molecular subtypes & locoregional ttm: Molecular based experience
36Chen J, et al. WJSO 2014;12:212.
N = 21.654
Molecular subtypes & locoregional ttm: Molecular based experience
37Chen J, et al. WJSO 2014;12:212.
Molecular subtypes & locoregional ttm: Molecular based experience
38Chen J, et al. WJSO 2014;12:212.
Molecular subtypes & locoregional ttm: Molecular based experience
39Abdulkarin BS, et al. JCO 2011;29:2852-8.
Single institution; N = 768
Molecular subtypes & locoregional ttm: Molecular based experience
40Abdulkarin BS, et al. JCO 2011;29:2852-8.
Molecular subtypes & locoregional ttm: Molecular based experience
41Abdulkarin BS, et al. JCO 2011;29:2852-8.
Molecular subtypes & locoregional ttm: Molecular based experience
42Rezai M, et al. The Breast 2015;24:380-94.
Molecular subtypes & locoregional ttm: Molecular based experience
43Rezai M, et al. The Breast 2015;24:380-94.
0
100
200
300
400
500
600
700
Lum A Lum B (Her 2 Neg) TNP Her 2 + Other
Number Local recurrence
LRR: 2.2% 2.7% 11.3% 9.3%Lum B HER-2 +: 3.8%
Molecular subtypes & locoregional ttm: Molecular based experience
44
1. Introduction
2. Molecular subtyping & locoregional treatment
3. Discussion
4. Conclusions
Molecular subtyping & locoregional treatment
45
Molecular subtypes & locoregional ttm: Discussion
Risk factors for local recurrence:
• After mastectomy
• After lumpectomy +/- WBRT
• After lumpectomy +/- WBRT +/- boost
• After APBI
46Poortmans P. Lancet. 2014 Jun 21;383(9935):2104-6.
1/4
1/2-3
1/1.5
1/
1/4
Interaction systemic and locoregional treatments
Molecular subtypes & locoregional ttm: Discussion
47Poortmans P. Lancet. 2014 Jun 21;383(9935):2104-6.
Triple -/Her2 type Lum B type Lum A type
NC/PD PR CR
Molecular subtypes & locoregional ttm: Discussion
48Poortmans P. Lancet. 2014 Jun 21;383(9935):2104-6.
Triple -/Her2 type Lum B type Lum A type
NC/PD PR CR
Lum A; minor R
Molecular subtypes & locoregional ttm: Discussion
49Poortmans P. Lancet. 2014 Jun 21;383(9935):2104-6.
Triple -/Her2 type Lum B type Lum A type
NC/PD PR CR
---; ypCR
Molecular subtypes & locoregional ttm: Discussion
50Poortmans P. Lancet. 2014 Jun 21;383(9935):2104-6.
Triple -/Her2 type Lum B type Lum A type
NC/PD PR CR---; NC
Molecular subtypes & locoregional ttm: Discussion
20th century21st centuryL. van ‘t Veer et al Nature 415, p530-536, 2002 M. vd Vijver et al, NEJM 347; 1999-2009, 2002
The « omics" are here!
52Iyer et al Science 1999 83-7; Chang et al PLoS Biology 2004 Feb 2 2 1- 9
In vitro Wound Model – 516 genes
Prognostic Significance in
• Breast
• Lung
• Gastric cancer
Wound Response Signature
Molecular subtypes & locoregional ttm: Discussion
53Nuyten DS et al, Breast Cancer Res. 2006;8(5):R62.
Predict of Local Recurrence in Early Breast Cancer
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0 2 4 6 8 10 12
Activated
Quiescent
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0 2 4 6 8 10 12
Activated
Quiescent P=0.0005P=0.00014
Training Validation
0
0.2
0.4
0.6
0.8
1
1.2
0 5 10 15 20
timelokr_1
Pro
bab
ilit
y
High Risk
Low Risk0
0.2
0.4
0.6
0.8
1
1.2
0 5 10 15 20
High Risk
Low Risk
Molecular subtypes & locoregional ttm: Discussion
54
1. Introduction
2. Molecular subtyping & locoregional treatment
3. Discussion
4. Conclusions
Molecular subtyping & locoregional treatment
55
✓ Validated risk factors are known
• After mastectomy
• After BCS +/- WBRT +/- boost
• After APBI
✓ Risk factors change over time ➔ role of
systemic treatment
Molecular subtypes & locoregional ttm: Conclusions
56Bouganim N, et al. Breast Cancer Res Treat 2013;139:603–6.
Advances in treatment have differentially reduced the proportion
of LRR compared with DR ➔ down to 10-15% of all recurrences
➔ influence design new clinical trials.
Evolution of sites of recurrence after EBC over the last 20 years
Molecular subtypes & locoregional ttm: Conclusions
57
Still a lot of work to be done!• Predictive molecular and genetic testing of normal tissue
and tumour responsiveness.
• The role of the immune system and host response.
• Test general hypotheses relating to radiation genomics and normal tissue responses.
• Large databases incl radionomics
• Nanoparticles as radiosensitisers.
• Sequential/serial biopsies.
• Overall treatment time.
Molecular subtypes & locoregional ttm: Conclusions
58
Molecular subtypes & locoregional ttm: Conclusions
59
• The molecular subtype influences the recurrence risk ...
• ... as well as the relative distribution of recurrences!
• Systemic treatments modify the recurrence risks and distribution ...
• ... and thereby modify the contribution of optimising locoregionalcontrol!
• Probably most benefit of locoregional ttm on OS for patients with low-risk tumours (Lum-A) and those treated with effective systemic treatment (Her2; TN)
Take home messages
Molecular subtypes & locoregional ttm: THM
60
• The molecular subtype influences the recurrence risk ...
• ... as well as the relative distribution of recurrences!
• Systemic treatments modify the recurrence risks and distribution ...
• ... and thereby modify the contribution of optimising locoregional control!
• Probably most benefit of locoregional ttm on OS for patients with low-risk tumours (Lum-A) and those treated with effective systemic treatment (Her2; TN)
Take home messages
Molecular subtypes & locoregional ttm: THM
61
• The molecular subtype influences the recurrence risk ...
• ... as well as the relative distribution of recurrences!
• Systemic treatments modify the recurrence risks and distribution ...
• ... and thereby modify the contribution of optimising locoregionalcontrol!
• Probably most benefit of locoregional ttm on OS for patients with low-risk tumours (Lum-A) and those treated with effective systemic treatment (Her2; TN)
Take home messages
Molecular subtypes & locoregional ttm: THM
62
- Jens Overgaard
- Harry Bartelink
- Birgitte Offersen
- Orit Kaidar-Person
- Paul Span
- Charlotte Coles
- Liesbeth Boersma
- Sandra Hol
- Icro Meattini
- And many others!
Molecular subtypes & locoregional ttm: Acknowledgements
El Perito Moreno
El GlaciariumEl 5 de abril 2019
64