CNS Metastases

Dr Yoon-Sim YAP Division of Medical Oncology,National Cancer Centre Singapore

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DISCLOSURE SLIDE

Personal COI:Consultancy/Honoraria/Travel/Research Support• Astra Zeneca, Eisai, Lilly, Novartis, Pfizer, Roche

Outline

• Incidence and Risk Factors

• Prognosis

• Management

• Multidisciplinary

• Systemic Therapies

• (Leptomeningeal Metastases)

• Conclusion(s)

Incidence of Brain Metastases(BM)

• Autopsy Study : advanced breast cancer (all subtypes)

735

193

116

Patients

No CNSinvolvementBraininvolvementMeninges orspinal cord only

• 30% (309/1044) showed CNS

involvement.

• 31% of 309 cases clinically

suspected or diagnosed before

death.

• 14% of 309 patients died from

CNS failure.

Tsukada et al, Cancer 1983

Risk Factors

•Disease Stage- Risk ↑ with ↑ stage

•Age- Risk ↑ with ↓ age

•Grade- Risk ↑ with ↑ grade

•Subtype- Risk ↑ with HER2+ or triple negative

Barnholtz-Sloan et al, JCO 2004; Tsukada et al, Cancer 1983; Arvold et al, BCRT 2012; Slimane et al, Ann Oncol 2004; Pestalozzi

et al, Ann Oncol 2006; Kennecke et al, JCO 2010

Metastatic Behaviour of BC Subtypes: early -stage BC diagnosed 1986 -1992

Kennecke et al, JCO 2010

Metastatic Behaviour of Breast Cancer Subtypes: Patients with early-stage breast cancer diagnosed between 1986 and 1992

Kennecke et al, JCO 2010Kennecke et al, JCO 2010

Does Trastuzumab increase risk of developing brain metastases(BM)?HER2+ metastatic cases 1999-2006 (n=251) @ Samsung Medical Centre• Higher rate of brain metastases probably related to increased

survival of patients and inability of trastuzumab to cross intact BBB• Trastuzumab treatment improves brain metastasis outcomes

through control and durable prolongation of systemic extracranial disease in HER2-overexpressing breast cancer patients.

Post-Trastuzumab Pre- Trastuzumab P-value

Development of BM 37.8% 25% 0.028

Time to BM 15 mths 10 mths 0.035

Time to Death from BM 14.9mths 4.0mths 0.0005

Park et al, BJC 2009

Prognosis according to subtypesBreast cancer patients with brain metastases diagnosed 2001-2006 (n=126) at National Cancer Centre, Korea

Nam et al, BrCaRes 2008

Brain Metastases in Newly Diagnosed BC: A Population -Based Study (SEER, 2010-2013)

Martin et al, JAMA Oncology 2017

Graded Prognostic Assessment (GPA ) to estimate survival from brain metastases by diagnosis.

Sperduto JCO 2012

What about treatment factors?

Association of Treatment with survival after HER2+ Brain Metastasis (BM)

Yap et al, BJC 2012

280 HER2+ brain met patients from 6 countries in Asia (2006-2008).But patients may receive more systemic treatments if they live longer anyway!

Factors Associated with survival post-BM

•Factors associated with better survival after brain metastasis

– - Solitary brain metastasis (vs multiple)

• - Treatment (chemotherapy/endocrine therapy/anti-HER2 Tx)

•Patients with better prognosis are also more likely to receive more treatments by virtue of living longer!

Yap et al, BJC 2012

Management of Brain Metastases- Often MULTIDISCIPLINARY• Local Therapy

- Surgical Resection

- Stereotactic Radiosurgery (SRS)

- Whole brain radiotherapy

• Systemic Therapy

–- For CNS disease +/- extracranial disease

• Symptomatic Management

• May retreat with local therapy as appropriate or consider systemic therapy options upon disease progression.

Algorithm for Management of Newly Diagnosed Breast Cancer Brain Metastases

Zagar, Oncology 2016

Surgery• Three randomized clinical trials have compared surgery plus WBRT

with WBRT alone in patients with single brain metastases (various solid tumors).

• Two of these demonstrated a survival benefit – eg 48 pts with single brain met; majority lung cancer; OS 40weeks with

surgery vs 15wks with RT(p<0.01), significantly fewer local recurrences (20 versus 52 percent), better QOL (Patchell et al, NEJM 2006)

– eg 63 patients with a single brain metastasis, OS with surgery + WBRT was significantly longer than WBRT alone (10 versus 6 months), and patients remained functionally independent for a longer period (Vecht et al, Ann Neurol 1993)

Factors that correlated significantly with increased survival in addition to surgical treatment were the absence of extracranial disease, longer time to the development of the brain metastasis, and younger age.

• Third trial did not show improved outcomes; a lower Karnofskyperformance score at baseline were included and a higher proportion of cases had extracranial disease (Mintz et al, Cancer 1996)

Stereotactic Radiosurgery (SRS)

• Alternative to surgery or WBRT for small tumors that are not surgically accessible.

• Neurotoxicity and local failure after SRS increase with increasing lesion size, thus consideration of SRS rather than surgery should generally be limited to lesions with a diameter of 3 cm or less.

• No adequately powered randomized trials have been completed comparing SRS alone with surgery plus postoperative radiation .

Landmark Radiation Oncology Studies for Breast Cancer Brain Metastases

Zagar, Oncology 2016

Summary of findings from Local Therapy Randomised Trials

(various solid tumors)

Addition of WBRT to surgery or SRS to reduces local recurrence, but no OS benefit demonstrated.

Addition of SRS to surgery reduces local recurrence but no OS benefit demonstrated (Mahajan et al, Lancet Oncol 2017).

Brown et al Lancet oncology 2017

WBRT versus SRS following Surgery?• WBRT – better time to intracranial tumor progression

• SRS = 6.4m vs WBRT = 27.5m• 6 month surgical bed control control

• SRS = 80.4% vs WBRT = 87.1%

• Better preservation of cognitive function with SRS• No overall survival differences.

Systemic Therapy –When to consider?

• Newly diagnosed patient with limited extent of CNS disease in presence of reasonable systemic option and plans for close monitoring with view to local therapy when necessary..

• Recurrent or progressive CNS disease after surgery and/or RT

• Minimal and/or asymptomatic CNS disease in setting of significant systemic disease burden

• As part of a clinical trial.

• ? As maintenance treatment after local therapy

Systemic Treatment Options for Breast Cancer Brain Metastases (BCBMs)

Lin et al, ASCO 2017

There are currently no U.S. Food and Drug Administr ation (FDA)-approved treatments specifically for BCBMs.

Effectiveness of Systemic Therapy

Cellular constituents of the blood–brain barrier.

Abbott et al, Nature Reviews Neuroscience, 2006

•Ability of drug to reach therapeutic concentrations in the brain.

BBB; small, lipophilic, not substrate of efflux pumps BBB may be disrupted with brain metastases and radiotherapy

•Intrinsic sensitivity of tumour cells to the drug (intracranial + extracranial)•Favourable toxicity profile

CNS penetration by 89Zr-trastuzumab –18-fold higher uptake in brain tumours than in normal brain tissue

Dijkers et al, Clin Pharm and Ther 2010

Summary of Case Reports, Case Series, and Prospective Studies Testing Cytotoxic Agents in Patients With Breast Ca Brain Mets

Lin et al, ASCO 2017

Endocrine therapy +/- Targeted therapy

Case reports• Tamoxifen• Megestrol acetate• Aromatase inhibitors

• Everolimus – no published data in ER+ brain mets; only in HER2+ - with vinorelbine and trastuzumab(Van Swearingen et al, BCRT 2018)

• CDK inhibitors – trials in progress

Lin et al, ASCO 2017

Trials of Capecitabine + Lapatinib for Brain Metastases in HER2+ Breast Cancer

Lin et al, ASCO 2017

TDM-1 in HER2+ breast cancer brain metastases

• Jacot et al, BCRT 2016, Retrospective study (n=39)

–CNS ORR 44%, median PFS 6.1months

• Fabi et al, Breast 2018, Retrospective study (n=53)

–Overall response rate 24.5%; with 3.8% complete response.

Selected clinical trials for HER2+ breast cancer brain metastases

Brosnan et al, Annals Trans Med 2018

Selected clinical trials for HR + breast cancer brain metastases

Brosnan et al, Annals Trans Med 2018

Selected clinical trials for triple negative breast cancer brain metastases

Brosnan et al, Annals Trans Med 2018

Challenges of Clinical Trials on Brain Metastases

• Exclusion of patients with brain metastases (stable/unstable)from most clinical trials

• Unfit or poor prognosis

• Small Numbers

• Response assessment criteria

– need for standardisation of criteria used.

• Evaluation of efficacy may be confounded by effect of radiotherapy in some instances.

Leptomeningeal Metstases

Morikawa et al, Clin Br Ca 2017;

Lin ASCO 2017

• Incidence of leptomeningeal metastases varies from 2% to 40%, either alone or associated with parenchymal brain metastases.

• MSKCC series : breast cancer diagnosed with leptomeningeal metastasis 1998-2013 (n=318), 44% were HR+HER2-, 18% were HR+HER2+, 8.5% were HR-HER2+, 25.5% were triple-negative; and 4% had missing information. The median survival was 3.5 months (95% confidence interval, 3.0-4.0) with 63 patients (20%) surviving >1 year.

• Favorable prognostic factors include HER2+ subtype, preserved performance status, and CNS-only involvement.

• Unfavorable prognostic factors include poor performance status, progressive/treatment-refractory extracranial disease, and major neurological deficits.

Management of Leptomeningeal Metastases

• RT to sites of bulky disease followed by consideration of intrathecal and/or systemic therapy.

• Methotrexate, liposomal cytarabine, and thiotepa are the intrathecal drugs of choice (NB: intrathecal trastuzumabis still experimental).

• Systemic therapy has been used off-label to treat patients with leptomeningeal disease based on observed efficacy in case reports and small case series. Regimens with reported efficacy (with caveats given the very limited data) include tamoxifen, aromatase inhibitors, high-dose intravenous methotrexate, capecitabine, lapatinib + capecitabine, and platinum salts.

Lin ASCO 2017

Take Home Message(s)

• Risk of Brain Metastases is increased in HER2+ and triple negative subtypes.

• Prognosis after diagnosis of brain metastases(es) has improved with better treatment options, eg HER2+

• Multidisciplinary Approach• Relatively limited data on efficacy of optimal systemic

therapy for brain metastases.• Area of unmet need which requires further research and

clinical trials – with associated challenges.

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Thank you for your attention !

Pink Ribbon Walk, October 2016