philip poortmans, md, phd 1 · triple neg “basal like” 15% rec-, her2+ “her2 like” 12% this...

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.


9Proposed by St Gallen; ASCO; ESMO; …


10


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.



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



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



LRR



DSS



OS



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


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+


22Kyndi M, et al. JCO 2008;26:1419-14.

ER+ PgR+ HER2 -

ER- PgR- HER2+


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.


63%


10%


15%


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.


63%


10%


15%


12%










26Kyndi M, et al. JCO 2008;26:1419-14.


63%


10%


15%


12%










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



Local recurrence



Local recurrence

Distant metastasis



Local recurrence

Distant metastasis

Luminal A has a particularly

low recurrence rate


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?



N=895



N=895

N=355



N=895

N=355

N=424



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


36Chen J, et al. WJSO 2014;12:212.

N = 21.654


37Chen J, et al. WJSO 2014;12:212.


38Chen J, et al. WJSO 2014;12:212.


39Abdulkarin BS, et al. JCO 2011;29:2852-8.

Single institution; N = 768


42Rezai M, et al. The Breast 2015;24:380-94.


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%


44

1. Introduction

2. Molecular subtyping & locoregional treatment

3. Discussion

4. Conclusions


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



Triple -/Her2 type Lum B type Lum A type

NC/PD PR CR




NC/PD PR CR

Lum A; minor R




NC/PD PR CR

---; ypCR




NC/PD PR CR---; NC


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


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


54

1. Introduction

2. Molecular subtyping & locoregional treatment

3. Discussion

4. Conclusions


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


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.


58


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




• ... and thereby modify the contribution of optimising locoregional control!


Take home messages


61




• ... and thereby modify the contribution of optimising locoregionalcontrol!


Take home messages


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

philip poortmans, md, phd 1 · triple neg “basal like” 15% rec-, her2+ “her2 like” 12% this...

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