Join Dr. Nancy Lin, Director of the Metastatic Breast Cancer Program at Dana-Farber Cancer Institute, as she discusses diagnosis, symptom management, emerging treatments and reasons to be hopeful with Julia Maues, a metastatic breast cancer patient advocate. This one-hour webinar will allow time for questions from participants. In collaboration with Living Beyond Breast Cancer and Young Survival Coalition.

1. Nancy U. Lin, MD
Associate Chief, Division of Breast Oncology, Dana-Farber Cancer Institute (DFCI)
Associate Professor of Medicine, Harvard Medical School
Director, EMBRACE Program for Patients with Metastatic Breast Cancer (DFCI)
Director, Program for Patients with Breast Cancer Brain Metastases (DFCI)
Brain Metastasis:
Emerging Treatments and Reasons to be Hopeful

2. What will we cover today?
• Definitions
• A few comments about prognosis
• Risk factors and symptoms
• Treatment options
• Surgery
• Radiation
• Chemotherapy and targeted therapies
• Clinical trials
• Action items
• Q&A

3. A few comments before we begin
• This is a hard topic – it brings up a lot of emotions
• Even in the best case scenarios, in 2019, we are not able to cure patients
with breast cancer brain metastases – so I share these stories to give hope,
yet fully recognizing we have a LOT of progress left to make – and not in any
way to minimize what patients and their families are going through
• Every patient is different
• I can’t give personalized medical advice during this webinar – but I hope that
you will come away with the knowledge you need to be proactive and
engaged in your health

4. First, some definitions
Brain metastasis = cancer that has spread to the brain
• Appears as “spots”, “tumors”, “lesions” in the brain
• Often retains characteristics of original cancer
Leptomeningeal disease (LMD) = cancer that
has spread to the fluid that surrounds the brain and
spinal cord

5. Who develops brain metastases?
• Not commonly the first place cancer metastasizes – but it can happen
• More common in patients with HER2-positive or triple-negative (TNBC) breast
cancer, but can occur in patients with any breast cancer subtype
• Also seen in patients with lobular breast cancer (usually ER-positive with
more LMD that ductal cancers) and BRCA1/2-associated breast cancer
• More common in younger patients (?is this only because of tumor subtypes?)
• As patients with MBC live longer, we are seeing more patients with brain
metastases

6. A few comments about prognosis

7. A few comments about prognosis
* * * * * **** * * * ** ** * * * * *** *
The “average” is here … but look how different individual
patients will experience this

8. Every patient really is different*
*I’ve changed initials and obscured exact dates and treatment details to protect patient privacy
S.Q.-initial dx HER2+
1998, mets 2001, brain
mets 2003, SRS, NED
T.L.-initial dx
ER+/HER2+ 2013,
mets 2017, brain mets
2018, SRS, WBRT,
clinical trial, now on
HER-targeted tx
M.S.-initial dx ER-
/HER2+ 2014, brain mets
2016, WBRT, SRS,
clinical trials
V.C.-de novo
ER+/HER2-neg MBC
2018, bones, brain,
LMD, focused RT to
spine, endocrine
therapy, chemotherapy
C.T.-initial dx ER-/HER2+
2010, liver and brain mets
2013, SRS (last in 2015)
still on HP
D.P.-initial dx
ER+/HER2-neg 2009,
brain mets 2013,
surgery, SRS,
endocrine therapy
K.E.-ER-/HER2+ IBC
dx 2011, brain mets
2014, SRS, WBRT,
Clinical trials, chemo/H
B.B.-initial dx
ER+/HER2-neg 2014,
brain mets 2016,
endocrine therapy,
trials, chemo, SRS
A.G.-Initial dx TNBC
2013, lung/brain mets
2017, SRS, surgery,
chemo

9. • Many (but unfortunately not all) patients with breast cancer brain
metastases are living longer than ever before
• When asking about prognosis:
• Communicate if, how, and when you want this information
• If you are comfortable, you can ask:
• What is the chance I will be alive in … 3 months? 6 months? 1 year? 2 years? 5 years?
• Have you seen anyone get out XXX (fill in the blank) years?
• Is it realistic to hope for (fill in the blank)
• How do you know? Why do you think so?
A few comments about prognosis

10. Symptoms
• Headaches
• Nausea, vomiting
• Seizures
• Weakness or numbness
• Imbalance, falls, loss of coordination
• Changes in vision (double vision, difficulty seeing one side of the
world)
• Confusion, back pain, problems with bladder or bowel function

11. Symptoms
• Headaches
• Nausea, vomiting
• Seizures
• Weakness or numbness
• Imbalance, falls, loss of coordination
• Changes in vision (double vision, difficulty seeing one side of the
world)
• Confusion, back pain, problems with bladder or bowel function
If you have these symptoms, let your medical team know

12. Many ways to treat patients with brain metastases
Surgery
Radiation
Systemic therapy
-Chemotherapy
-Targeted therapy
-Endocrine therapy

13. At every decision point, we weigh:
-surgical options
-radiation options
-systemic therapy options
-clinical trials
-patient preferences and values
A well-functioning team approach is critical!
Many ways to treat patients with brain metastases

14. When/why do we consider neurosurgery?
• In patients who present with a single brain
metastasis –survival benefit
• When the diagnosis is in question
• Initial presentation
• Radiation necrosis vs progressive tumor
• ?subtype switch
• If there is a large, symptomatic brain
metastasis
• In patients who have controlled (or
controllable) disease outside of the brain
• In patients healthy enough to tolerate
surgery

15. Advances in Neurosurgery
• Functional MRI
• Intraoperative MRI
• 3D navigation system
• Intraoperative
monitoring
• “Awake” surgery
• Interstitial laser ablation
(LITT)

16. “Tess”*: ER+ Brain Mets since 2013
• 2011: Stage II ER+, HER2- BC
• 2013: Headaches led to brain MRI, which showed brain met
• 2013: surgical resection of brain met and SRS to area where tumor
was removed
• 2014: Gamma Knife (SRS) to spot near surgical site
• 2017: New enhancement on MRI treated with laser ablation (LITT). It
was radiation necrosis.
• NED since then
*Name changed to protect privacy

17. Radiation-based approaches
Whole brain radiation therapy
WBRT
Stereotactic radiosurgery
SRS

18. • Treats entire brain
• Can treat many
lesions
• Lowers chance of
new brain mets
• But … we worry
about fatigue and
effects on cognition
• Focused treatment
of visible lesions
• Can be done in 1
day
• Faster recovery
• But…we worry more
about new brain
mets
WBRT versus SRS

19. Advances in Whole Brain Radiation Therapy
Memantine
Hippocampal-avoidant WBRT

20. Advances in Whole Brain Radiation Therapy
Memantine
Hippocampal-avoidant WBRT
• Phase III trial has shown that starting memantine
during WBRT and continuing for 6 months reduces
the impact of WBRT on neurocognitive function ,
without compromising effectiveness of the WBRT

21. Advances in Whole Brain Radiation Therapy
Memantine
Hippocampal-avoidant WBRT
• Phase III trial has shown this to preserve
neurocognitive function and reduce patient-reported
symptom burden, without compromising effectiveness
in controlling brain mets or in overall survival
• Phase III trial has shown that starting memantine
during WBRT and continuing for 6 months reduces
the impact of WBRT on neurocognitive function ,
without compromising effectiveness of the WBRT

22. Focused radiation approaches
• Stereotactic radiosurgery (SRS)
• Gamma knife
• Cyber knife
• Stereotactic radiotherapy (SRT)

23. Advances in Focused radiation approaches
• “Frameless” SRS
• Single-isocenter treatment
• Improved monitoring systems

24. ”Tania*”: HER2+ brain mets since 2003
• 1998: Stage III HER2+ BC while 34 weeks pregnant
• 2001: HER2+ MBC, mets to lung, bones and liver
• 2003: mets to brain, treated with Gamma Knife (stereotactic
radiosurgery)
• NED since SRS
*Name changed to protect privacy

25. ”Tania”: HER2+ brain mets since 2003
• 1998: Stage III HER2+ BC while 34 weeks pregnant
• 2001: Stage IV HER2+ BC, mets to lung, bones and liver
• 2003: mets to brain, treated with Gamma Knife (stereotactic
radiosurgery)
• NED since SRS

26. ”Tania”: HER2+ brain mets since 2003
• 1998: Stage III HER2+ BC while 34 weeks pregnant
• 2001: Stage IV HER2+ BC, mets to lung, bones and liver
• 2003: mets to brain, treated with Gamma Knife (stereotactic
radiosurgery)
• NED since SRS
Photos used with permission (and appreciation)

27. WBRT vs SRS for patients with 5-20 brain mets
• Traditionally, the more mets in the brain, the more we lean towards WBRT
• We don’t know which is better (disease control, side effects)– treating many
brainmets with SRS or starting right away with WBRT
• Clinical trial ongoing comparing WBRT vs SRS
• Dana-Farber/Brigham & Women’s
• South Shore Hospital (MA)
• Milford (MA)
• Lifespan (Rhode Island Hospital)
• Clinicaltrials.gov: NCT03075072 (PI: Dr. Ayal Aizer)

28. Advances in Systemic therapy
• Old (incorrect) assumptions:
• Systemic treatments don’t work in the brain
• New approach:
• Systemic therapies can be effective—but we need to invest more in
developing and testing them, specifically in patients with active brain
metastases
• Consider systemic therapy as an option – but it is not always the
“right” option and local therapies (e.g. surgery, radiation) should also
be considered

29. Chemotherapy or endocrine therapy can be
effective in some patients
• Capecitabine (Xeloda)
• Carboplatin or cisplatin
• Anthracyclines (Adriamycin, Doxil)
• Irinotecan
• Aromatase inhibitors
• Tamoxifen
Baseline ~8 months later

30. “Lauren*”: TNBC brain mets since 2014
• 2014: diagnosed with de novo MBC involving brain, breast, nodes
• Because of rapidly worsening disease outside of brain, started on
carboplatin
• After 2 cycles, all disease (including in brain) improved
• Held off on radiation and finished 6 cycles of chemotherapy
• Later had surgery to breast and lymph nodes when it grew again
• Has not had any treatment in 3-4 years (!)
*Name changed to protect privacy

31. Some chemo drugs of note in clinical trials
• NKTR 102
• Nal-IRI
• ANG1005
• Tesetaxel
~80,000
Irinotecan
Salt
Molecules
PEG-DSPE
~110 nm
Interna
l
Aqueou
s Space
Lipid
Membra
ne

32. HER2 targeted options with CNS Activity
• Lapatinib (Tykerb) + Capecitabine (Xeloda)
• Neratinib (Nerlynx) + Capecitabine (Xeloda)
• Ado-trastuzumab emtansine (TDM1, Kadcyla)
• Tucatinib + Capecitabine + trastuzumab (Herceptin)*
* Awaiting results of HER2CLIMB clinical trial

33. Study # pts Prior RT CNS ORR
Lin et al
CCR 2009
50 100% 20%
Sutherland et al,
Br J Ca 2010
(LEAP)
34 94% 21%
Metro et al, Ann
Oncol 2011
22 86% 32%
Bachelot et al,
Lancet Oncol
2013
45 0% 66%
Lapatinib +Capecitabine for
HER2+ Breast Cancer Brain Metastases
As a single agent, CNS
ORR to lapatinib in only
~ 6%*
In pre-treated patients,
lap-cape results in CNS
ORR 20-30%
In the upfront setting,
lap-cape results in CNS
ORR 66%
*Lin et al CCR 2009

34. TDM1 (Kadcyla)
• We had assumed that since TDM1 is
a large monoclonal antibody (with
chemotherapy attached), that it
would not work against brain
metastases
• Several reports in the literature of
activity of TDM1 in the brain
Keith et al, Cancer Treat Comm 2016

35. TBCRC 022: Neratinib + capecitabine
%reductioninvolumeofCNSlesions
* 6 patients did not reach first re-staging evaluation and are categorized as ‘0’
-100
-80
-60
-40
-20
0
20
40
60
80
100
Best Volumetric CNS response (n=31evaluablepts)
CNS ORR = 49% (95% CI 32-66%)
Slide adapted from
Freedman et al, ASCO 2017

36. Neratinib for HER2+ Brain Mets
%reductioninvolumeofCNSlesions
* 6 patients did not reach first re-staging evaluation and are categorized as ‘0’
• Neratinib-capecitabine now listed in 2018 NCCN Neuro-Oncology
practice guidelines
• TBCRC 022 has opened several additional cohorts to test the
combination of TDM1 + neratinib*
• 4 cohorts, including TDM1 pre-treated patients as well as patients with and
without prior radiotherapy for brain metastases
*study sites: DFCI, MGH, UNC, Penn, UMich, Mayo, UPMC, Baylor, Hopkins, UCSF

37. Phase 1 Tucatinib + Capecitabine + Trastuzumab
Hamilton et al, SABCS 2016
ORR 61%
N=23
CNS ORR 42%
(N=12)

38. HER2Climb
• HER2+ MBC
• Prior trastuzumab,
• pertuzumab, and TDM1 required
• Active brain mets allowed
(but not required)
Trastuzumab + capecitabine
+ placebo
Trastuzumab + capecitabine
+ tucatinib
2:1
Recruitment completed—awaiting results!!

39. Other Interesting Targets and Drugs
Target Drugs
Angiogenesis (blood vessels) Bevacizumab (Avastin)
CDK4/6 Abemaciclib, palbociclib
PI3K/mTOR GDC0084, alpelisib, etc.
Immune system Pembrolizumab, atezolizumab, etc.
PARP Olaparib, talazoparib, veliparib

40. Clinical Trials
• Clinical trials are how we learn about side effects and possible anti-
tumor activity of new treatments
• Increasing number of clinical trials for patients with brain metastases
• Many national efforts to increase inclusion of patients with brain
metastases into clinical trials
• Trials testing new surgical, radiation, chemotherapy, targeted therapy
approaches

41. “Jenna*”: HER2+ Brain Mets since 2013
• 1998: Diagnosed with early stage breast cancer
• 2013: Diagnosed with brain mets
• Has been treated with WBRT, SRS, and HER2-targeted agents
including 2 clinical trials
*Name changed to protect privacy

42. SWOG1416
TNBC and/or BRCA mutation-associated HER 2 negative Breast cancer
0 /1 prior lines of chemotherapy (N=235)
Cisplatin 75 mg/m2 Day 1 Cisplatin 75 mg/m2 Day 1
ABT-888 300 mg PO BID (D1-14) Placebo PO BID (D1-14)
CNS cohort N = 98 from Alliance collaboration
• New / progress. (≥10 mm) brain mets AFTER prior
intracranial RT (WBRT, SRS, etc)
TNBC or BRCA1/2-associated MBC
NCT02595905

43. HER2+ LMD
NCT03501979
TBCRC 049

44. HER2+ Brain Metastases
NCT01494662
TBCRC 022

45. ER+ or TNBC Brain Metastases

46. How to find a clinical trial?
• Talk to your doctor
• Seek a second opinion
• Talk to other patients or patient advocates
• Websites
• www.brainmetsbc.org
• www.clinicaltrials.gov
• www.sharecancersupport.org
• www.breastcancertrials.org
• www.mbcalliance.org
• Many others

47. What gives me hope?
• I see (some) people living longer and better with brain metastases in a
way I used to hardly ever see
• It is still not “enough”, but it gives me hope that we are making progress
• The pace of scientific/technological advances keeps getting faster
• More people are focused on this problem – in the lab and in the clinic
• There is greater inclusion in clinical trials and change in culture (though
still much progress to be made)

48. ”Action Items”
• Educate yourself
• Put together a strong multidisciplinary team for your care
• Consider a second opinion
• Ask about clinical trials
• Advocate for inclusion of patients with brain metastases in clinical trials
• If you are comfortable with it -- be visible

49. Thank you!

51. Backup slides

52. Why don’t we routinely screen patients for brain
metastases??
• “Early” treatment could be beneficial – but could also cause short- and long-term
side effects
• Develop treatments with fewer side effects
• If brain scans are not timed with body scans, the meaning can hard to interpret
• Time brain scans with regular restaging scans
• Presence of brain metastases can affect clinical trial eligibility
• Advocate for inclusion of patients with brain metastases in clinical trials
• No study has definitively shown a benefit
• Conduct studies to test the impact of brain MRI screening on neurological quality of life,
neurological symptoms, use of whole brain radiation therapy, and survival

53. Why don’t we routinely screen patients for brain
metastases??
• “Early” treatment could be beneficial – but could also cause short- and long-term
side effects
• Develop treatments with fewer side effects
• If brain scans are not timed with body scans, the meaning can hard to interpret
• Time brain scans with regular restaging scans
• Presence of brain metastases can affect clinical trial eligibility
• Advocate for inclusion of patients with brain metastases in clinical trials
• No study has definitively shown a benefit
• Conduct studies to test the impact of brain MRI screening on neurological quality of life,
neurological symptoms, use of whole brain radiation therapy, and survival

54. Ongoing Brain Met Screening Trials
• Toronto: https://clinicaltrials.gov/ct2/show/NCT03881605
• Boston: https://clinicaltrials.gov/ct2/show/NCT04030507