Compiling Data on HER2 Brain Mets
 

Hi,

I've been collecting information about HER2 brain mets and prognosis, not so much for us to think that we are represented by their statistics, but to be able to use the data to communicate with our doctors and press for more aggressive treatment of HER2 brain mets. I will start compiling quotes and references here, feel free to add any that you have that might be useful.

-Ann

Re: Compiling Data on HER2 Brain Mets
 

My neuro-oncologist shared the ASCO 2011 Graded Prognostic Assessment for Brain Metastasis that includes breast cancer and breaks out HER2 positivity (no differentiation between hormonal status though).

The 2011 report used an original dataset spanned 1985-2007, so it predates Perjeta and some other more current treatments, plus some HER2 patients didn't receive Herceptin until it was made publicly available.

ASCO Graded Prognostic Assessment for Brain Metastases [Journal of Clinical Oncology, January 2012]
http://jco.ascopubs.org/content/30/4/419.full
Figure 1 includes the scoring table, midway are the patient characteristics. I scored 90-100 for KPS but you might need to consult with your oncologist about what that is for you; it has to do with functioning level versus impairments. You see which column your diagnosis falls into and then you use the prognositc factor to the right under the patient score (0,.5,1.0,1.5,2.0) to see what your final total and then there is a key at the bottom of the table for median survival.

This recent report on HER2 Brain mets using the above validates this scoring method.
Graded prognostic assessment (GPA) of HER2 positive breast cancer patients with brain metastases. [2015]
http://meetinglibrary.asco.org/content/145612-156

Re: Compiling Data on HER2 Brain Mets
 

The dataset is slightly older but the results are slightly more favorable:

"Overall survival, NS, and RS are improved in patients with HER2+ tumors, relative to those with HER2− lesions, and HER2 amplification is independently associated with increased survival in patients with BM from breast cancer. Our findings suggest that the prognosis of HER2+ patients may be better than that of otherwise similar patients who are HER2− and that stereotactic radiosurgery may be beneficial for some patients with HER2+ lesions."

Relationship Between HER2 Status and Prognosis in Women With Brain Metastases From Breast Cancer
http://www.redjournal.org/article/S0...abstract?cc=y=

Re: Compiling Data on HER2 Brain Mets
 

Leptomeningeal metastases in breast cancer

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3623833

"HER-2 status does not appear to impact overall survival from LM, but treatment with trastuzumab was associated with a significantly longer time to the development of LM (15.2 versus 9.9 months)"

"Individual case reports and case series have shown that IT trastuzumab may have some activity in HER-2 positive breast cancer LM and is potentially well-tolerated"

"In the appropriate clinical context, findings suggestive of LM on MRI are adequate to initiate treatment of LM even in the absence of a positive CSF cytology"

Re: Compiling Data on HER2 Brain Mets
 

Early-onset brain metastases in a breast cancer patient after pathological complete response to neoadjuvant chemotherapy. - PubMed - NCBI
http://www.ncbi.nlm.nih.gov/m/pubmed/24222158

"Physicians should be aware of the possibility of early brain metastases, and consider new treatment strategies to prevent brain metastases in high-risk patients who achieve pCR."

Re: Compiling Data on HER2 Brain Mets
 

Breast cancer metastases to cerebellum.

http://meetinglibrary.asco.org/content/125957-144
[this predates the release of Perjeta]



"approximately 10% of [all] breast cancer (BC) patients develop metastases to cerebellum"


"Her2 over-expression was higher than expected (13/18;72,2%)"


" Majority (11/18; 61%), developed cerebellar metastases as a resectable, first metastatic site, and 73% (8/11) of these patients had Her2 3+ BC, treated with trastuzumab. Our results suggest that Her2 3+ BC has a greater propensity to metastasize to cerebellum than Her2 negative BC."

Re: Compiling Data on HER2 Brain Mets
 

Breast cancer biological subtypes and protein expression predict for the preferential distant metastasis sites: a nationwide cohort study
http://www.breast-cancer-research.co...df/bcr2944.pdf
[2011, Breast Cancer Research] -- this predates Herceptin and Perjeta but the protein links is very interesting and might help with tissue genetic profiling.

" Luminal A cancers had a propensity to give rise first to bone metastases, HER2-enriched cancers to liver and lung metastases, and basal type cancers to liver and brain metastases. Primary tumors that gave first rise to bone metastases expressed frequently estrogen receptor (ER) and SNAI1 (SNAIL) and rarely COX2 and HER2, tumors with first metastases in the liver expressed infrequently SNAI1, those with lung metastases expressed frequently the epidermal growth factor receptor (EGFR), cytokeratin-5 (CK5) and HER2, and infrequently progesterone receptor (PgR), tumors with early skin metastases expressed infrequently E-cadherin, and breast tumors with first metastases in the brain expressed nestin, prominin-1 and CK5 and
infrequently ER and PgR."


Breast cancer molecular subtype: HER2+/HR-
No. of patients: 36
No. of metastatic sites: 48
Bone: 14 (29.2)
Liver: 13 (27.1)
Lung: 11 (22.9)
Non-regional lymph nodes: 4 (8.3)
Skin: 4 (8.3)
Pleura: 0 (0.0)
Brain: 1 (2.1)
Other 1 (2.1

Re: Compiling Data on HER2 Brain Mets
 

IRSA - Stereotactic Radiosurgery for Patients with Metastatic Brain Cancer
http://www.irsa.org/metastatic%20guideline.pdf

[May 2008, the latest version I could find]

"Lesions of the brain and leptomeninges account for 80% of intracranial metastases. The majority of brain metastases (approximately 80%) are located in the cerebral hemispheres. The cerebellum (10–15%) and brainstem (2– 3%) are less frequently involved."

"Patients treated with conventional open surgical resection without WBRT had a 46% risk of failure at the site of the resection in a randomized trial evaluating the role of WBRT after surgical resection. In subsequent studies patients were treated with SRS alone (without WBRT). These studies found excellent local control (70–80% at one year). Other published series of patients treated with SRS have demonstrated a risk of distant brain failure at one year, ranging from 43% to 57%. In general, the risk of new metastasis in patients with solitary tumors is approximately 37% (crude), but the actuarial risk is 50% at one year"

Re: Compiling Data on HER2 Brain Mets
 

Note that they are studying switching the order of treatment to radiation therapy first (SRS) and surgery second to see if they can help limit LM mets

"This Phase II trial will investigate the safety, tolerability, and effectiveness of changing the order of receiving radiation therapy for treating brain cancer and brain metastases. Normal procedure is to follow surgical removal of a brain metastases with stereotactic radio surgery. This trial reverses the order of these treatments in the hope that doing the radiation first will lower the risk of cancer spreading throughout the spinal fluid which covers the brain and spinal cord, causing leptomeningeal metastases. Patients with smaller brain metastases will start at a lower dose of radiation than those with larger brain metastases. To qualify for the trial patients must have brain metastases that can be removed by surgery. The metastases must be between 2 and 6 cm in size and no more than four in number."
Dose Escalation/De-escalation Study of Pre-operative Stereotactic Radiosurgery for Brain Metastases(RAD 1002)

https://clinicaltrials.gov/show/NCT01252797

Re: Compiling Data on HER2 Brain Mets
 

The Effect of Tumor Subtype on Survival and the Graded Prognostic Assessment for Patients with Breast Cancer and Brain Metastasis
[Poster from the 2011 ASCO Breast Cancer Symposium, similar to the first link but just about brain mets in BC]
http://meetinglibrary.asco.org/conte...erImg&poster=1

Re: Compiling Data on HER2 Brain Mets
 

ASCO Clinical Practice Guideline: Disease Management in Advanced HER2-Positive Breast Cancer With Brain Metastases

http://www.ascopost.com/issues/july-...etastases.aspx

"On review of the available evidence, the ASCO expert panel concluded that the majority of the evidence was insufficient to inform evidence-based recommendations for a traditional ASCO clinical practice guideline.

Thus, the recommendations were developed by a multidisciplinary group of experts and reviewed by a consensus ratings panel including radiation oncologists, neurosurgeons, members of the ASCO Breast Cancer Guidelines Advisory Group, and others using a formal consensus process based on the best available evidence and clinical experience."

Re: Compiling Data on HER2 Brain Mets
 

ASCO Guideline for Management of Brain Metastases From HER2-Positive Breast Cancer: An Important Framework

http://www.ascopost.com/issues/july-...framework.aspx
[2014]


"In the Breast Cancer Graded Prognostic Assessment, a prognostic scoring metric derived from a multi-institutional database of 400 breast cancer patients, the median overall survival was 17 months (95% confidence interval [CI] = 13–23) in HER2-positive patients with brain metastases3; significant prognostic factors were Karnofsky performance status, age, HER2 status, and the interaction between estrogen receptor and progesterone receptor status and HER2. Other large retrospective series have reported median survival as high as 23 months in these patients."

"These recommendations also highlight the areas of need for randomized trials of systemic agents in both newly diagnosed and recurrent brain metastases. Indeed, interpreting results from clinical trials and their applicability to patients has been a challenge, given the heterogeneous patient populations and variable endpoints across trials. Traditional cytotoxic agents have some activity in the brain,5 but have often required coordination with radiation and/or surgical interventions to obtain durable control. As systemic therapies improve and begin to include combinations of agents with penetration across the blood-brain barrier, the guidelines will also likely evolve to include more frequent use of chemotherapeutic regimens as a primary treatment modality for HER2-positive breast cancer brain metastases."

Re: Compiling Data on HER2 Brain Mets
 

The use of sterotactic radiosurgery for brain metastases from breast cancer: who benefits most?
http://sharedresources.fredhutch.org...-benefits-most

"In all subtypes other than TNBC, SRS can provide meaningful control of BM even in the setting of multiple lesions and may be worth repeating for new lesions that develop metachronously."

Re: Compiling Data on HER2 Brain Mets
 

May we all live long and NED that something like this might be considered a possibility for those of us treated for brain mets:

SMART syndrome: a late reversible complication after radiation therapy for brain tumours

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3101343/

"We report on four patients with reversible clinical and radiological features occurring years after radiation for brain tumours, suggestive for the so called SMART syndrome (stroke-like migraine attacks after radiation therapy)."

Re: Compiling Data on HER2 Brain Mets
 

My wife is part of the Intrathecal Herceptin study and I am one of the point people in getting this method of treatment at least looked at by physicians. I think the compilation of the studies would be worthwhile. They started at Northwestern, but were done in a few other locations in parallel. There were some individuals that contacted me to get information on how to progress in getting treatment. The overall information that I have on this is very promising. There are still less than 20 patients that have been treated.

Re: Compiling Data on HER2 Brain Mets
 

" surgical resection of parenchymal cerebellar metastases has purportedly resulted in subsequent development of LM. Resection of a supratentorial brain metastasis that violates the ventricular system also appears to increase the risks of developing LM"

"isolated meningeal involvement is no longer an exceptional site of relapse after chemotherapy for breast cancer, particularly when taxanes or trastuzumab are used, both of which penetrate poorly into the CSF"

"LM involvement is remains a relatively rare manifestation of HER2/neu positive tumors (3-5%) notwithstanding the observed increased incidence of parenchymal 2].[37,73,157,160,227] In breast cancer, the most common solid tumor to cause LM, risk factors of LM include an infiltrating lobular carcinoma and cancers negative for estrogen receptor (ER) and progesterone receptor (PR).[4,169–171,177,108,181] Triple negative status of breast cancer (HER2/neu negative; ER negative; PR negative) has been reported to be a risk factor of LM.[230] LM involvement is remains a relatively rare manifestation of HER2/neu positive tumors (3-5%) notwithstanding the observed increased incidence of parenchymal brain metastasis."

"the incidence of undiagnosed or asymptomatic LM may be 20% or more with many solid tumors as illustrated in autopsy series."

"An early diagnosis of LM, before fixed neurologic deficits are manifest, permits earlier and potentially more effective treatment, thus leading to a better quality of life in patients so affected"

Carcinomatous meningitis: Leptomeningeal metastases in solid tumors
http://www.ncbi.nlm.nih.gov/pmc/arti...tid836011title

Re: Compiling Data on HER2 Brain Mets
 

"Studies have consistently demonstrated that the risk of CNS involvement is high in patients with HER2-positive metastatic breast cancer. Incidence ranges from 15% to 55%, depending on length of follow-up and stringency of screening. Within the HER2-positive cohort, estrogen receptor (ER)-negative disease confers a greater risk than ER-positive disease. In a 3,000-plus patient cohort from a National Comprehensive Cancer Network database, women with ER-negative disease had a 63% increased risk over ER-positive patients, he said."

"compared to patients with triple-negative breast cancer, those with HER2-positive disease have a longer time from metastatic diagnosis to CNS relapse (approximately 1 year vs < 6 months), greater control of extracranial disease at the time of CNS relapse (50% vs rarely), and longer median overall survival from the time of CNS relapse (1–2 years vs 3–5 months). However, patients with triple-negative disease rarely die as a result of CNS progression alone, whereas up to 50% of those with HER2-positive disease do, he pointed out."

"Patients with HER2-positive disease who receive local therapy as the primary approach to CNS metastasis often develop progression over the ensuing months and years."

“Our treatment goals are to prolong survival, palliate neurologic symptoms, and prevent symptom progression. And we have to balance treatment-related toxicities with overall brain control and minimize the risk of ‘neurologic’ death—that is, death from the progression of the CNS metastases,” Dr. Winer said.

How to Approach the Problem of CNS Metastasis in HER2-Positive Patients
http://www.ascopost.com/issues/march...-patients.aspx

Re: Compiling Data on HER2 Brain Mets
 

"With improved systemic control and prolonged survival, the incidence of brain metastases has increased, and CNS disease, often in the setting of well-controlled extracranial disease, is proving to be an increasingly important and clinically challenging cause of morbidity and mortality in patients"

"finding new treatments that target BM has not been prioritized, and nearly all clinical trials have excluded these patients. However, as patients live longer due to advances in human epidermal growth factor receptor-2 (HER2)-targeted and systemic therapy, it appears that the incidence of BM is increasing"

"Because trastuzumab does not cross the blood–brain barrier (BBB), the CNS serves as a sanctuary for metastatic disease in the setting of sustained extracranial control and improved survival."

"treatments for HER2-positive BM are a growing unmet clinical need deserving of dedicated clinical trials evaluating novel therapeutics and strategies"

"observational data suggest that HER2-positive cells may exhibit tissue tropism that cannot be explained by circulatory patterns"

"In trastuzumab-treated patients, median survival from diagnosis of CNS metastases has varied across studies, ranging from 12 to 25 months"

"Historically, BM trials have included patients with various solid tumors. There are few trials testing novel therapies specifically in breast cancer BM, and even fewer solely in patients with HER2-positive disease "

Emerging treatment options for the management of brain metastases in patients with HER2-positive metastatic breast cancer
http://www.ncbi.nlm.nih.gov/pmc/arti...960/#Abs1title

Re: Compiling Data on HER2 Brain Mets
 

"We show that CED of TP-38 is well tolerated at effective doses and provides some encouraging radiographic responses. However, we also show that the potential efficacy of agents delivered by CED may be severely constrained by inconsistent and ineffective infusion in many patients."

Intracerebral infusion of an EGFR-targeted toxin in recurrent malignant brain tumors (2007)
http://m.neuro-oncology.oxfordjourna.../10/3/320.full

Re: Compiling Data on HER2 Brain Mets
 

http://m.neuro-oncology.oxfordjourna...7-0beacc753dc7

CNS Anticancer Drug Discovery and Development Conference White Paper (2015)

Abstract

Following the first CNS Anticancer Drug Discovery and Development Conference, the speakers from the first 4 sessions and organizers of the conference created this White Paper hoping to stimulate more and better CNS anticancer drug discovery and development. The first part of the White Paper reviews, comments, and, in some cases, expands on the 4 session areas critical to new drug development: pharmacological challenges, recent drug approaches, drug targets and discovery, and clinical paths. Following this concise review of the science and clinical aspects of new CNS anticancer drug discovery and development, we discuss, under the rubric “Accelerating Drug Discovery and Development for Brain Tumors,” further reasons why the pharmaceutical industry and academia have failed to develop new anticancer drugs for CNS malignancies and what it will take to change the current status quo and develop the drugs so desperately needed by our patients with malignant CNS tumors. While this White Paper is not a formal roadmap to that end, it should be an educational guide to clinicians and scientists to help move a stagnant field forward.

Re: Compiling Data on HER2 Brain Mets
 

In the overall population (n = 186), median PFS was 18.7 weeks in patients with BM and 19.4 weeks in patients without BM (HR 0.98 [95% CI: 0.71-1.35], P = 0.88). Among patients with BM, median overall PFS was significantly prolonged in patients who did not use prior capecitabine (28.3 weeks vs 14.0 weeks, P = 0.009), but brain PFS was not statistically significantly different between these two subsets (31.4 weeks vs 25.6 weeks, P = 0.54; Figure 1).

Clinical outcomes of HER2-positive metastatic breast cancer patients with brain metastasis treated with lapatinib and capecitabine: an open-label expanded access study in Korea
http://www.biomedcentral.com/1471-2407/12/322

Re: Compiling Data on HER2 Brain Mets
 

“More than a decade ago, we devised a genetic approach to generate immune cells, called T cells, that are specific for HER2, an antigen (or protein) present on a broad range of cancers including breast cancer, sarcomas and brain tumors,” said Dr. Nabil Ahmed in a news release. Dr. Ahmed added that the strategy involves the isolation and culture of T cells from cancer patients, while genetically modifying them with human epidermal growth factor receptor 2 (HER2)-specific chimeric antigen receptors (HER2-CARs). The cells can then be infused back into patients and target HER2-positive tumor cells


HER2-specific T cells As An Immunotherapy In HER2-Positive Sarcoma (2015)
http://immuno-oncologynews.com/2015/...itive-sarcoma/

Re: Compiling Data on HER2 Brain Mets
 

"A recent trial presented in the ASCO 2015 meeting has shown that whole brain radiation therapy did not improve the overall survival for those patients with a limited number of brain metastases, besides the fact it is related to a neurocognitive impairment."

"Although we tend to think of cerebral metastases as being multiple, approximately 50% are seemingly solitary at diagnosis and in a minority of cases no known or identifiable malignancy is present.4 They often occur at the grey-white matter junction or in the arterial watershed areas."

"Typically metastases are relatively well demarcated from the surrounding parenchyma and usually there is a zone of peritumoural oedema out of proportion with the tumour size."

"Parenchymal blood flow is an important determinant of the distribution of metastases: 80% of metastases localize to the cerebral hemispheres, 15% localize to the cerebellum and 3% localize to the basal ganglia.8 Often these tumours can be found at the gray/white matter junction."

Cerebral metastases [Radiopaedia]
http://radiopaedia.org/articles/cerebral-metastases

Re: Compiling Data on HER2 Brain Mets
 

"there is initial evidence that penetration of trastuzumab into CSF may be facilitated under conditions of an impaired BBB, as is known for meningeal carcinomatosis. We demonstrate further that high levels of trastuzumab can also be achieved by direct application of trastuzumab into the brain using an Ommaya reservoir. Given the increasing use of trastuzumab to treat HER2-overexpressing breast cancer patients in the metastatic and the adjuvant setting, more patients are expected to benefit from this therapy and may experience a considerable survival advantage."

Application of intrathecal trastuzumab (HerceptinTM) for treatment of meningeal carcinomatosis in HER2-overexpressing metastatic breast cancer (2005)
http://www.spandidos-publications.co.../1373/download

Re: Compiling Data on HER2 Brain Mets
 

A combination HER-2+ targeted approach achieved clinical remission with stable disease in our patient 46 months after she was diagnosed with LM metastases. However, spinal cord C-1 metastasis was not fully controlled with IT trastuzumab, ultimately leading to the patient’s respiratory compromise. In our patient, IT trastuzumab immunotherapy improved prognosis and was an effective strategy to manage HER-2+ LM disease. Given alone or alongside other anti-HER-2+ therapeutics with sufficient CNS penetration, IT trastuzumab could extend the lifespan of patients with leptomeningeal and CNS metastasis.

Intrathecal trastuzumab: immunotherapy improves the prognosis of leptomeningeal metastases in HER-2+ breast cancer patient [2015]
Nu T. Lu1,2, Jeffrey Raizer3, Erwin P. Gabor5, Natalie M. Liu2, James Q. Vu2, Dennis J. Slamon1,4 and John L. Barstis1,4*

http://www.immunotherapyofcancer.org...015-0084-y.pdf

Re: Compiling Data on HER2 Brain Mets
 

Also, opposing the classical view that drugs injected into the CSF space will be washed out within short time without targeting the brain [5], recent findings demonstrate that drugs, following intrathecal application, may very well be transported throughout the entire brain.

A new look at cerebrospinal circulation [2015]
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4016637/

Re: Compiling Data on HER2 Brain Mets
 

From the book: Natural Strategies for Cancer Patients

"Some tissues are particularly resistant to invasion by cancers. For instance, the brain and cartilage are both highly resistant to tumor invasion. At first this seems strange, when you consider that one of the first places in which lung cancer appear to produce symptoms is the brain. Yet, while the cancers end up in the brain arterioles and capillaries, they do not invace the brain itself. As they enlarge, and grow, they push the brain tissue aside but they do not invade it -- that is, in the brain, they act like benign tumors in terms of their invasiveness."

Re: Compiling Data on HER2 Brain Mets
 

"Also, opposing the classical view that drugs injected into the CSF space will be washed out within short time without targeting the brain [5], recent findings demonstrate that drugs, following intrathecal application, may very well be transported throughout the entire brain."



A new look at cerebrospinal circulation [2015]
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4016637/

Re: Compiling Data on HER2 Brain Mets
 

"Brain metastases usually are more encapsulated and easily removed than primary glial tumors"

Bottom of page 13

http://www.phys.mcw.edu/documents/PD...rs/Lassman.pdf

Re: Compiling Data on HER2 Brain Mets
 

I'm linking to the section about leptomeningeal disease as that is what I am most interested in right now. The whole article is pretty interesting about understanding symptoms, types of disruptions and some treatments commonly used to treat brain mets.

Neurologic Complications of Systemic Cancer : Leptomeningeal Metastases
http://www.aafp.org/afp/1999/0215/p878.html#sec-4

Re: Compiling Data on HER2 Brain Mets
 

Found three abstracts of recent research articles on the subject (Leptomeningeal metastasis (LM) in breast cancer patients) via PubMed database http://www.ncbi.nlm.nih.gov/pubmed:

Neurol Sci. 2015 Sep;36(9):1691-3. doi: 10.1007/s10072-015-2259-1. Epub 2015 May 20.
Intravenous thiotepa for treatment of breast cancer-related leptomeningeal carcinomatosis: case series.
Chahal J1, Stopeck A, Clarke K, Livingston RB, Chalasani P.
Author information
Abstract
Leptomeningeal carcinomatosis (LMC) secondary to metastatic breast cancer (MBC) has increased in incidence with improved systemic disease control. Current treatment options include radiation therapy (to symptomatic sites) and systemic treatment [intrathecal (IT) or intravenous (IV) chemotherapy]. Methotrexate (MTX), thiotepa and cytarabine are the most commonly used IT agents, while high-dose MTX is the most common IV regimen. While IT treatments are generally well tolerated, complications like chemical meningitis, leukoencephalopathy, etc. occur. LMC may cause a breakdown in the blood-brain barrier and thus allow systemic agents to penetrate; however, efficacy is reported only for agents administered at high doses (MTX). We report our institution's experience in using IV thiotepa as treatment for LMC secondary to MBC. We conducted a retrospective chart review of 13 patients with MBC who developed LMC and treated with IV thiotepa at our institution. It was administered at 40 mg/m(2) every 21 days; median number of thiotepa cycles administered was 5 with the major dose-limiting toxicity being myelosuppression. Four had partial response, 3 had stable disease and 6 had progressive disease. The 6-month survival rate was 69 % and 1-year survival rate was 31 %. Despite retrospective nature of our case series, we found the use of IV thiotepa as sole treatment for LMC in patients with MBC to be well tolerated, easily administered in the ambulatory setting, and with efficacy comparable to the other chemotherapeutic agents commonly used in the treatment of LMC. This regimen warrants further investigation in prospective studies.

BMC Cancer. 2015 Apr 17;15:299. doi: 10.1186/s12885-015-1290-1.
A pilot study of bevacizumab combined with etoposide and cisplatin in breast cancer patients withleptomeningeal carcinomatosis.
Wu PF1, Lin CH2, Kuo CH3, Chen WW4, Yeh DC5, Liao HW6, Huang SM7, Cheng AL8,9,10, Lu YS11,12.
Author information
Abstract
BACKGROUND:
Elevated vascular endothelial growth factor (VEGF) was associated with poor prognosis in leptomeningeal carcinomatosis and anti-angiogenic therapy was found to prolong the survival of mice in preclinical studies. This prospective pilot study investigated the efficacy of anti-VEGF therapy plus chemotherapy in patients with leptomeningeal carcinomatosis originating from breast cancer.
METHODS:
Eligible patients were scheduled to receive bevacizumab combined with etoposide and cisplatin (BEEP) every 3 weeks for a maximum of 6 cycles or until unacceptable toxicity. The primary objective was the central nervous system (CNS)-specific response rate, which was defined as disappearance of cancer cells in the cerebrospinal fluid (CSF) and an improved or stabilized neurologic status. The impact of VEGF inhibition on etoposide penetration into the CSF was analyzed.
RESULTS:
Eight patients were enrolled. The CNS-specific response rate was 60% in 5 evaluable patients. According to intent-to-treat analysis, the median overall survival of the eight patients was 4.7 months (95% confidence interval, CI, 0.3-9.0) and the neurologic progression-free survival was 4.7 months (95% CI 0-10.5). The most common grade 3/4 adverse events were neutropenia (23.1%), leukopenia (23.1%), and hyponatremia (23.1%). The etoposide concentrations in the CSF were much lower than those in plasma, and bevacizumab did not increase etoposide delivery to the CSF.
CONCLUSIONS:
BEEP exhibited promising efficacy in breast cancer patients with leptomeningeal carcinomatosis. Additional studies are warranted to verify its efficacy and clarify the role of anti-angiogenic therapy in this disease.

J Clin Neurosci. 2015 Apr;22(4):632-7. doi: 10.1016/j.jocn.2014.10.022. Epub 2015 Feb 9.
Treatment of leptomeningeal carcinomatosis: current challenges and future opportunities.
Kak M1, Nanda R2, Ramsdale EE3, Lukas RV4.
Author information
Abstract
Leptomeningeal metastasis (LM) in breast cancer patients confers a uniformly poor prognosis and decreased quality of life. Treatment options are limited and often ineffective, due in large part to limitations imposed by the blood-brain barrier and the very aggressive nature of this disease. The majority of studies investigating the treatment of LM are not specific to site of origin. Conducting randomized, disease-specific clinical trials in LM is challenging, and much clinical outcomes data are based on case reports or retrospective case series. Multiple studies have suggested that chemo-radiotherapy is superior to either chemotherapy or radiation therapy alone. Attempts to overcome current obstacles in the treatment of breast cancer LM hold promise for the future. We review the epidemiology, diagnosis, and prognosis of LM in breast cancer, and discuss the treatment options currently available as well as those under investigation.

PS. Lani posts regularly new findings/researches about Her2 breast cancer. We can use the 'Search' button on the top bar to locate new articles by typing in 'Lani' and/or specific subject (eg. Lani and 'brain mets'). Sort of a short cut. http://her2support.org/vbulletin/sea...archid=1884595

Re: Compiling Data on HER2 Brain Mets
 

I had a PCR to neoadjuvant TCHP and no regrowth post surgical resection and LINAC SRS but they are struggling to diagnose me with leptomeningeal disease since my presentation and pattern of orogression are atypical. I'm going to post more LM related links since it seem quite dire if it is the diagnosis and patients should understand the symptoms more.

Medscape: Leptomeningeal Carcinomatosis
http://emedicine.medscape.com/articl...38-clinical#b1

"Meningeal symptoms are the first manifestations in some patients; however, most patients already have widespread and progressive cancer with few therapeutic options left."

It looks like there are three main pathways of symptom progression:

"Involvement of the CNS is divided into the following 3 broad anatomical groups:

Cerebral involvement results in headache, lethargy, papilledema, behavior changes, and gait disturbance (the latter can be due to either cerebellar or cauda equina involvement). Major dysfunction, such as hemiparesis and hemisensory loss or visual field defects, is rare and more indicative of parenchymal metastasis.

Cranial-nerve involvement presents with impaired vision, diplopia (most common), hearing loss, and sensory deficits, including vertigo. Palsies of cranial nerves III, V, and VI are most common; palsy of nerve VII is less common. Solid tumor-derived LC has a higher affinity for the optic and extraocular nerves, while leukemic meningitis preferentially affects the facial nerve. Involvement of multiple cranial nerves is the rule rather than the exception.

Spinal-root involvement is caused by either meningeal irritation, presenting with nuchal rigidity (15%) and neck and back pain (rare), or invasion of the spinal roots. The latter can cause leg weakness, radiculopathy (usually lumbar, mimicking a herniated disk), reflex asymmetry or loss (most common, noted in 70% of patients), sphincter incontinence (less common), positive Babinski reflexes, paresthesias, and numbness. Asymptomatic bladder enlargement can occur from spinal cord compression. Spinal-root symptoms are usually followed by cranial-nerve symptoms. Nuchal rigidity, positive results on the straight-leg raising test, and decreased rectal tone are rare."

Re: Compiling Data on HER2 Brain Mets
 

This is not about brain mets but about radiation-induced changes in primary brain cancer and notes that arteriol venous malformations (slightly different blood vessels than normal) seems to increase the risk of this developing post SRS. Since I am having adjacent swelling in my cerebellum with no symptoms we are doing watchful waiting for a few weeks as its either atypical swelling or atypical leptomeningeal disease -- nice options, eh?




"Radiation effects have generally been divided into acute, subacute, and chronic phases [16]. The acute phase is first 2 months following irradiation, the subacute occurs from 2 to 6 months, and the chronic is after 6 months."

"20 Gy or more for the targeted lesion. One possible explanation is that hemodynamic changes result from changes to AVM vessels [9]. Two patients with AVM in the present study exhibited new lesions when shrinkage of AVMs was seen following STI. Generally, complete obliteration of cerebral AVM can occur from 4 months to 5 years after SRS"

Radiation-induced changes in the brain following stereotactic irradiation evaluated by sequential MRI (2004)
http://www.sciencedirect.com/science...72349604000198

Re: Compiling Data on HER2 Brain Mets
 

Canadian Doctors Perform Breakthrough Blood-Brain Barrier Surgery Using Focused Ultrasound (11/9/2015)
http://www.techtimes.com/articles/10...ultrasound.htm

"The breakthrough procedure makes use of focused ultrasound and microbubbles to bypass the protective layer around the brain's blood vessels, and according to the researchers, it has already produced positive results in their clinical trials on animals."

Re: Compiling Data on HER2 Brain Mets
 

Duke is starting a new Intrathecal Study using Pertuzumab and Trautuzumab for Brain mets starting in February 2016. The dosing is about what I think is going to be very therapeutic. Only enrolling limited number of patients and only for 36 weeks of treatment. It might be worth asking doctor to investigate if you have brain mets. Ask to run similar treatment under compassionate care protocol.

Re: Compiling Data on HER2 Brain Mets
 

Thanks Paul.

I heard yesterday that Seattle Cancer Care Alliance should be starting an intrathecal anti-HER2 (pertuzumab maybe) in 2016. It will be with Dr Mrugula. It isn't listed or recruiting yet but this is where I think it will be listed when available:

http://www.sccaclinicaltrials.org/breast-trials.html

Re: Compiling Data on HER2 Brain Mets
 

Updates on the Management of Breast Cancer Brain Metastases (2014)

http://www.cancernetwork.com/oncolog...ain-metastases

Some good stuff about the risk of brain mets for HER2+ BC, risks of progressive mets to the brain, brain as first site of mets, lack of approved systemic therapies for treatment of brain mets, and more.

I was able to read page 1 and then catch glimpses of page 2 before their server tried to get me to login. It might be possible to email or grab from HTML the content of those internal pages but I'm not sure.

Re: Compiling Data on HER2 Brain Mets
 

Breast cancer brain metastases responding to lapatinib plus capecitabine as second-line primary systemic therapy. (2015)

http://www.ncbi.nlm.nih.gov/m/pubmed/25714248/

About durable responses of HER2 brain mets with systemic therapy using Herceptin, Tykerb (lapatinib)and Xeloda (capatacibine)

Re: Compiling Data on HER2 Brain Mets
 

"treatment of subsequent progression is based mainly on expert opinion rather than the results of well controlled trials.3 Although median survival after a diagnosis of brain metastasis now exceeds 2 years in patients with good performance status and HER2-positive disease,4 this outcome has resulted in patients who live long enough to have substantial morbidity from additional CNS progression and long-term effects of radiation."

Better treatments needed for breast cancer brain metastases - The Lancet, 2015
http://www.thelancet.com/journals/la...477-5/abstract

Re: Compiling Data on HER2 Brain Mets
 

Thanks, Agness for compiling the data. I only had time to look at some of it. Thank you for the 2015 piece on Canadian doctors using vibration? to break the BBB. That's been in the news lately.

Here's something to know about brain mets (and I can't put my finger on the source at the moment, and I'm not sure whether Agness reported on it here). Although, brain mets usually develop after spread to other organs or the bones, survivors who develop a brain met first often do better than those who didn't. Sounds backwards, right? Women are usually in disbelief when I tell them that, but then they do a happy dance (if such a dance is possible with metastatic disease).