CNS METASTASES FROM

HER2+ METASTATIC BREAST

CANCER: PAST, PRESENT
AND FUTURE

Dr Thomas Bachelot
UCBG, Centre Lèon Bérard, Lyon
DISCLOSURE
Thomas Bachelot
• Has received research funding from Roche, AstraZeneca and
Novartis
• Has served as a consultant for AstraZeneca, Roche, Novartis,
SeattleGenetics and Pfizer
• Received travel expenses from AstraZeneca, Roche, Novartis and
Pfizer
CNS METASTASES FROM HER2+ METASTATIC BREAST
CANCER

Past: Dismal prognosis, WBRT or BSC

Present: “good” prognosis; Surgery ;SRS ; Benefice from HER2

targeted therapy; development of STKI

Future: Better strategies, better local treatment, better molecules,

genomic driven treatment
 Epidemiology: Results from the ESME cohort
% BM at any time during their metastatic
disease
60
50
40
30
49
20 38
34
10 19
0
ER+ HER2 - ER+ HER2 + ER- HER2 + Triple neg

Darlix et al. British Journal of Cancer (2019) 121:991–1000

Pasquier et al. European Journal of Cancer (2020) 125 22e30
Prognosis improvement of BM with HER2 targeted
therapy

New series : > 12 months

Old series : 6 month

Dawood et al. Annals of Oncology 19: 1242–1248, 2008

Prognosis of Brain Mets with current treatment

OS after BM by subtype

ER+ HER2+ => med. 19 months

ER- HER2+ => med. 13 months
ER+ HER2- => med. 7 months
ER- HER2- => med. 4.4 months

Darlix et al. British Journal of Cancer (2019) 121:991–1000

Pasquier et al. European Journal of Cancer (2020) 125 22e30
Current Treatment of Brain Metastases

➢ Surgery
➢ Radiation therapy
➢ Medical treatment
➢ Treatment strategies
 Neurosurgery
➢ Should always be discussed first in case of solitary metastasis
➢ Better than stereotaxic radio surgery (SRS) in case of large (> 3 cm) lesions
➢ Gain more consideration as survival improves
➢ Greatly aided by Neuronavigation tools

Colin Watt, ESMO 2017

 Radiation therapy
➢ Can be used alone for “targeted” treatment
(stereotaxic radio surgery)
➢ Can be used as “adjuvant treatment” after surgery (SRS++)
➢ Can be used for whole brain treatment (WBRT)

Brown et al. J Clin Oncol 2018; 36:483-491; Ramakrishna et al, J Clin Oncol. 2014;32:2100-8
 SRS for up to 10 brain mets !
◆ Non inferiority study : SRS in 3 groups: 1 BM; 2-4 BM and 5-10 BM
◆ 1071 pts, 77% NSCLC, 11% Breast, 11% Others
◆ Neither Mental score maintenance nor post-SRS complication differences

SRS complication

Yamamoto et al. Int J Radiat Oncol Biol Phys. 2017; 99: 31-40
 Chemotherapy/HER2 targeted therapy

Current indication of medical treatment:

▪ When nothing else is possible
▪ When you do not want to use RT and when you plan to use an efficient
medical treatment for systemic disease and the patient has concomitant
asymptomatic brain evolution

ANOCEF, Cancer Radiother. 2015; 19; 66-71; Ramakrishna et al, J Clin Oncol. 2014;32:2100-8
Can medical treatment target BM?

Paclitaxel concentration assessed after tumor resection

=> Blood Brain Barrier # from Tumor-Blood Barrier !!

Fine R L et al. Clin Cancer Res 2006;12:5770-5776

 Can medical treatment target BM?

64Cu-DOTA-trastuzumab PET images of HER2-positive metastatic brain lesions

Kenji Tamura et al. J Nucl Med 2013;54:1869-1875 (c) Copyright 2014 SNMMI; all rights reserved
 Can medical treatment target BM?
Time to BM in the Cleopatra trial
Patients with BM as first recurrence (106/808, 13%)

Sandra Swain, Ann Oncol. 2014;25:1116-21

 Can medical treatment target BM?

=> TDM1

Dec 2013 Mai 2014

- ORR 60%; TTP: 6 months (retrospective)

- Ongoing prospective studies

Jacot et al. Breast Cancer Res Treat. 2016;157:307-318

 The best medical treatment is the best for BM!!
PFS and OS in the EMILIA trial for Pts with BM at inclusion (95/991, 9.5%)

Krop, Annals of Oncology 26: 113–119, 2015

 Specific trials for BM: data from small TKI
➢ First generation TKI Lapatinib in combination with capecitabine has been the
cornerstone of medical treatment of HER2+ disease for the last 10 years

- After RT : ORR 20%; PFS: 3.6 months

- Before RT : ORR 66%; PFS: 5.6 months

Nancy U. Lin et al. Clin Cancer Res 2009;15:1452-59 ; Bachelot et al. Lancet oncol 2013; 14: 64-71
 Specific trials for BM: data from small TKI
Lapa + Capecitabine as front line treatment before WBRT (phase II, n=44)

CNS Volumetric change n %

CNS objective response 29 66% (95% CI: 50.1-79.5)

≥ 80% Reduction 9 20%
50- <80% Reduction 20 46%
20- <50% Reduction 6 14%
> 0- <20% Reduction 2 5%
Progression* 7 16%

*2 patients had extra-CNS disease progression

Bachelot et al. Lancet oncol 2013; 14: 64-71

 Specific trials for BM: data from small TKI
➢ Second generation TKI Neratinib (irreversible pan-HER TK inhibitor) in combination with
capecitabine for pretreated BM of HER2+ MBC

ORR 49%; PFS: 5.5 months

Freedman et al. J Clin Oncol. 2019; 37:1081-1089
 Specific trials for BM: data from small TKI
➢ Second generation TKI Neratinib (irreversible pan-HER TK inhibitor) in combination with
capecitabine fro pretreated BM of HER2+ MBC

ORR 49%; PFS: 5.5 months

Freedman et al. J Clin Oncol. 2019; 37:1081-1089
 Specific trials for BM: data from small TKI
➢ Third generation TKI Tucatinib (specific HER2 inhibitor) in combination with capecitabine and
trastuzumab in second line HER2+ MBC

Murthy et al. N Engl J Med 2020;382:597-609

 Specific trials for BM: data from small TKI
➢ Third generation TKI Tucatinib (specific HER2 inhibitor) in combination with capecitabine and
trastuzumab in second line HER2+ MBC

Murthy et al. N Engl J Med 2020;382:597-609

 Specific trials for BM: data from small TKI
➢ Third generation TKI Tucatinib (specific HER2 inhibitor) in combination with capecitabine and
trastuzumab in second line HER2+ MBC

PFS: 7.6 months

Murthy et al. N Engl J Med 2020;382:597-609
 Specific trials for BM: data from small TKI
➢ Third generation TKI Tucatinib (specific HER2 inhibitor) in combination with capecitabine and
trastuzumab in second line HER2+ MBC

Murthy et al. N Engl J Med 2020;382:597-609

 New / future development

➢ Intrathecal trastuzumab for patients with leptomeningeal metastases

 Definitive interest for some patients

 Numerous case reports /

retrospective cohorts

 One phase I clinical trial

already published, ongoing phase II

Fugura et al. Breast Cancer Res Treat. 2019;177:277-294.

New / future development

➢ New molecules / New strategies

 New ADC => DS8201, SYD985

 Better combination => Anti cdk 4/6, Pi3Ki, other targeted treatment

 Immunotherapy

 Biology driven treatment => ctDNA

 “Screening strategies”? => systematic brain MRI

 “Prevention strategies” ? => Tucatinib in the post neo-adjuvant setting

Conclusion

➢ BM in HER2+ MBC is common

➢ Favorable evolution can be obtained following local treatment and standard
systemic therapy
➢ Prognostic is good, WBRT should be delayed as much as possible
➢ Medical treatment with ADC (T-DM1) and small TKI are efficient
➢ Progress will come with progress for this disease in general, nevertheless,
research on specific biology and targeted therapy are warranted