Compiling Data on HER2 Brain Mets

[agness]

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

[agness]

“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/

[agness]

"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

[agness]

"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

[agness]

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

[agness]

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/

[agness]

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."

[agness]

"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/

[agness]

"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

[agness]

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

[Jackie07]

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

[agness]

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."

[agness]

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

[agness]

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."

[Rolepaul]

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.

[agness]

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

[agness]

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.

[agness]

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)

[agness]

"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

[Joan M]

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).