Compiling Data on HER2 Brain Mets

[agness]

This article is very much about the central nervous system as the first site of mets for HER2.


Incidence of central nervous system metastases in patients with HER2-positive metastatic breast cancer treated with pertuzumab, trastuzumab, and docetaxel: results from the randomized phase III study CLEOPATRA (2014)

http://m.annonc.oxfordjournals.org/c...25/6/1116.full

"Results from CLEOPATRA have demonstrated that the combination of pertuzumab with trastuzumab and docetaxel further improves systemic disease control by trastuzumab plus docetaxel, resulting in a significant and clinically meaningful prolongation of median progression-free [median time 15 months vs 11.9 months placebo group] and overall survival [median time34.4 months vs 26.3 months with placebo]. Our results presented here suggest that this improvement in systemic disease control with pertuzumab-based treatment delays the onset of CNS disease. Advances in systemic disease control and overall survival may result in an increase in the number of patients who will eventually develop CNS metastases; therefore, better treatment options for CNS disease are needed to increase quality of life and prolong survival of these patients. Based on results from CLEOPATRA, further investigation into the activity of HER2-targeted antibodies in patients with CNS disease from HER2-positive breast cancer is warranted"

[thinkpositive]

Agness

I believe that the people in this study were already metastatic. This would mean that the CNS wasn't the first area where mets appeared. Perhaps I got this wrong. What do you think?

[agness]

I noticed that as well. It seemed to state both though we know they didn't study below stage 4 before introducing it for locally advance disease and now for earlier stage disease as well. The earliest the stage 3 patient group reports are due back is Summer 2016 from what I have read. So, it must have to do with stage 4 patients who then developed CNS but anti-HER2 therapy controlled systemic disease.

[agness]

Here are some studies out of MD Anderson some of which target HER2 and all brain mets

Clinical Trials Explore Systemic Treatments for Brain Metastases from Breast Cancer (may 2015)
http://www.mdanderson.org/publicatio...st-cancer.html

[agness]

"Taking samples from brain tumors resulting from breast cancer, Jandial and his team found that the breast cancer cells were exploiting the brain's most abundant chemical as a fuel source. This chemical, GABA, is a neurotransmitter used for communication between neurons.

When compared to cells from nonmetastatic breast cancer, the metastasized cells expressed a receptor for GABA, as well as for a protein that draws the transmitter into cells. This allowed the cancer cells to essentially masquerade as neurons."Breast cancer cells can be cellular chameleons (or masquerade as neurons) and spread to the brain," Jandial said."

BREAST CANCER SPREADS TO BRAIN BY MASQUERADING AS NEURONS, STUDY FINDS
http://www.cityofhope.org/blog/breas...s-brain-tumors

[agness]

Before doing surgery patients should demand SRS to the tumor to reduce the risk of spread during surgery. Even with my large tumor, as I had a good response to dexamethasone to reduce swelling, SRS can be completed in one session if needed and it reduces the chance of spread.

NaSRS = neoadjuvant SRS, before surgery

"CONCLUSIONS: NaSRS can be performed safely and effectively with excellent results without documented radiation necrosis. Local control was excellent even in the setting of large (>3 cm) lesions. The strong majority of patients were able to avoid WBRT. NaSRS merits consideration in a multi-institution trial."

A new treatment paradigm: neoadjuvant radiosurgery before surgical resection of brain metastases with analysis of local tumor recurrence.
http://www.ncbi.nlm.nih.gov/m/pubmed/24606851/

[agness]

"Patients with BM may be at increased risk of developing LM, especially if the BM are located in the posterior fossa (BMPF). Among patients undergoing craniotomy for BMPF, estimates of the risk of developing LM are reported as high as 67%. Recent reports have begun to dissect out the details on the risk of CSF seeding after craniotomy. In a review of 379 patients with BMPF who were treated with either surgical resection or stereotactic radiation, 8.7% developed LM. But, there was a significantly higher risk of LM (14%; rate ratio, 2.45; P = .02) in those patients having a piecemeal resection of their BMPF when compared with either stereotactic radiation or en bloc resection. A follow-up study of 827 patients undergoing craniotomy for supratentorial BM found a similar result, with a hazard ratio of 5.8 (P = .002) comparing piecemeal resection vs stereotactic radiation and a hazard ratio of 2.7 (P = .009) comparing piecemeal resection vs en bloc resection. Patients with BM who undergo piecemeal tumor resection may be a good population in which to test biomarker-based or prophylactic interventions against LM."

New Strategies in the Management of Leptomeningeal Metastases (2010)
http://archneur.jamanetwork.com/mobi...ticleid=799479

[agness]

Summary Report on the Graded Prognostic Assessment: An Accurate and Facile Diagnosis-Specific Tool to Estimate Survival for Patients With Brain Metastases

http://jco.ascopubs.org/content/30/4/419.full



"Prognostic factors for patients with brain metastases vary by diagnosis, and for each diagnosis, a robust separation into different GPA scores was discerned, implying considerable heterogeneity in outcome, even within a single tumor type. In summary, these indices and related worksheet provide an accurate and facile diagnosis-specific tool to estimate survival, potentially select appropriate treatment, and stratify clinical trials for patients with brain metastases."

[agness]

"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."

Breast cancer metastases to cerebellum. ASCO 2014
http://meetinglibrary.asco.org/content/125957-144

[agness]

The risk of developing LM in breast cancer is actually quite high comparatively and yet the authors claim no increased risk across the patient population of cancer patients with brain mets. Compare the number of breast cancer patients in the study with the number of breast cancer patients who developed LM. Infratentorium refers to the posterior fossa region of the brain, where the cerebellum resides, and HER2 already has a demonstrated proclivity to. When you compare the number of breast cancer patients in the study to how many developed LM it is very high but the authors claim across all study groups that it was low, which isn't the case in what I can see -- and for us HER2 gals is deadly wrong.

"Leptomeningeal carcinomatosis developed in 12 cases (14%) and was associated with breast histology and infratentorial cavities (p = 0.024 and 0.012, respectively)"

http://www.ncbi.nlm.nih.gov/pubmed/25434940

[agness]

Understanding the brain a bit, with an emphasis on the cerebellum. Please add if you can.

The brain is divided up by the dura mater into three regions: the left and right hemispheres (supratentorial) and the posterior fossa region also referred to as infratentorial. The dura mater has lots or nerve endings and can feel pain, in contrast the brain does not have such nerve endings so unless determined by brain scans, many brain mets, lesions and tumors won't be found until symptoms manifest.

The tentorium cerebelli (https://en.m.wikipedia.org/wiki/Tentorium_cerebelli) is the structure that isolates the cerebellum from the rest of the brain. This is the rigid membrane that they refer to tumor being above (supratentorial) or below (infratentorial). Surgeries should take place in either compartment but not to the tentorium as its structure can't be repaired or replaced.

The cerebellum is responsible for movement coordination though people who have done a lot of movement study will find that cerebellar coordination activities are distributed across the brain and the cerebellum is more resistant to showing issues.

The cerebellum has a large surface area, plus a greater risk of developing LM after a craniotomy. Hesitation about treating the cerebellum increases the risk of spread and decreases the patient's chance of rapid treatment to stop LM spread.

https://en.m.wikipedia.org/wiki/Anat...the_cerebellum

Much more detailed information about the cerebellum and its structures:

http://nba.uth.tmc.edu/neuroscience/m/s3/chapter05.html

Overview and good diagram showing the different areas of the whole brain
http://www.brainwaves.com

[agness]

Another phase III study tested RSR13 (efaproxiral) in combination with WBRT. RSR13 binds to hemoglobin and reduces its affinity for oxygen thus increasing tissue pO2. In this study of WBRT plus supplemental oxygen with or without RSR13, overall survival increased from 4.6 months to 8.7 months in the subset of breast cancer patients. The role of RSR13 is currently being evaluated for patients with brain metastases from breast cancer.110


http://www.irsa.org/metastatic%20guideline.pdf

[agness]

"It is estimated that 10-35% of patients diagnosed with breast cancer will develop metastasis to the brain. Although patients with localized disease have a low probability of initial brain metastasis (BM), those with regional and metastatic disease have a 7.6% and 13.5% risk of BM at diagnosis, respectively, while those with HER-2 positive disease or ER-negative disease may be at an even higher risk, especially in the context of other visceral metastases, such as the liver. Current international guidelines for the evaluation of a new patient with breast cancer recommend screening for BM only if there are suspicious clinical symptoms, and not as a routine test. For patients with neurological symptoms, such as progressive headache, motor dysfunction, or sensation changes, there should be a low threshold for ordering an MRI of the brain. Treatment options for breast cancer brain metastases (BCBM) include surgery with/without adjuvant radiotherapy (whole brain or tumor-bed alone), whole-brain radiotherapy (with or without a focal boost, such as radiosurgery), radiosurgery alone, and potentially, systemic or targeted therapy, either used singly or in conjunction with other localized therapeutic approaches."

Management of solitary and multiple brain metastases from breast cancer (2015)
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4477383/

[agness]

Long-term Survival after Cerebellar Metastasis Resection from Her2 3+ Locally Advanced Breast Cancer (2015)
http://www.touchoncology.com/article...dvanced-breast

We present a patient who first developed a distant metastatic site in the cerebellum during treatment for Her2 3+ locally advanced breast cancer (LABC). LABC was in complete remission at that time and isolated cerebellar metastasis was resected. The patient is still alive more than 135 months after LABC diagnosis, and more than 99 months after neurosurgery, and is still receiving trastuzumab without further progression or any toxicity. To the best of our knowledge, this is first report of such exceptional disease course for a patient with a predicted grave prognosis according to all prognostic parameters.

[agness]

"Cramps, or rather complaints of cramps, were the presenting symptom of recognizable and previously unsuspected neurologic dysfunction in 64% (27 of 42) of the identified causes. Therefore, we conclude that muscle cramps in cancer patients may not be a benign complaint and that they usually mark the presence of an identifiable neurologic disorder"

Muscle cramps in cancer patients
http://onlinelibrary.wiley.com/doi/1...O;2-L/abstract

[agness]

A compilation of brain radiation treatment options and review of side effects.

This is something I am experiencing, starting about 5-6 weeks out from partial brain rads. I've not seen it discussed in brain mets patient forums:

"Weeks or months after treatment: So-called “early delayed” or sub-acute reactions commonly occur between one and three months after treatment. Symptoms include loss of appetite, sleepiness, lack of energy, and an increase in pre-existing neurological symptoms. Sub-acute reactions are thought to be due to temporary disruption to the nerve coverings. These symptoms are usually temporary, lasting about six weeks, the length of time it takes for myelin to repair itself. In some cases, however, recovery may take several months.

Another reaction that can occur weeks or months after treatment is swelling as a result of the build-up of dead tumor cells. The brain lacks an effective lymph system, the clean-up system of the body. Therefore, dead tumor cells are cleared away very slowly and radiation-induced cell death may cause rapid build-up of dead cells. The swelling that occurs as a result of the dead cells may cause an increase in neurological symptoms similar to the symptoms of the brain tumor."

Radiation Therapy for Brain Tumors
http://www.texasoncology.com/types-o...-brain-tumors/

[agness]

I've read about gliadel wafers being used for breast cancer brain mets successfully before. Given that adjuvant chemo is not standard of care for the brain as the first site of metastases and due to my own observations that a) they wait until lesions are large before recognizing them, b) resectioned tumors via craniotomy increases the risk of the spread of BC brain mets and c) the expectation is not "if" the lesions come back but more a matter of when then adding in chemo agents directly into the tumor bed makes sense. We know that targeted therapies work best against HER2+, especially in combo with a cytotoxic agent, perhaps lumber puncture administration of IT Herceptin into the spinal fluid would be a good companion.

This is a good read:

Gliadel for brain metastasis
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3656564/

[agness]

"Molecular factors implicated in CNS metastases and LM include E-cadherin–catenin complexes, plasmin, urokinase-type plasminogen activator, metalloproteinases, tissue inhibitors of metalloproteinases (associated with brain invasion), and activated integrin αvβ3. Metalloproteinases can degrade endothelial tight junction proteins at the BBB. Along with vascular endothelial growth factor (VEGF) and stromal-derived factor metalloproteinases may allow for transendothelial migration of tumor cells.


New Strategies in the Management of Leptomeningeal Metastases
http://archneur.jamanetwork.com/mobi...ticleid=799479

[FilY]

Hello,
I’m a HER2 patient originally diagnosed in 2013 at Stage 4. I’m also a 68 year old male. I’m posting here because I’m currently being treated by a neuro-oncologist (at a major cancer center) with what is essentially an experimental regimen - pulsed dosing of Tykerb - intended to prevent occurrence of brain mets in Her2 cancer that is otherwise being controlled by Herceptin.

The theory behind the treatment (and it’s not much more than a theory) is that Tykerb, unlike Herceptin, is a small enough molecule to get through the blood brain barrrier (BBB). However in normal doses (1000-1250mg/day) it doesn’t penetrate the BBB well enough to have a clinical effect. The hope/guess is that by pulsing a week’s dose over 2 days, the high concentration of lapatinib will overwhelm the BBB and act on any cancer in the central nervous system. I want to stress that, so far, there is NO solid evidence (e.g., a clinical trial) that this treatment is effective. There is some evidence (a Phase I trial) that the therapy is safe. There are significant side effects but the bottom line is if it prevents another brain met, it’s worth it.

In addition to providing information about this treatment to readers of this forum (I don’t see any other mention), I’d love to connect with any other patients on this regimen (there’s a lot of variability in how to do it) and/or get feedback from other Her2 patients who might talk to their oncologists about it.

Thanks in advance for any response and thanks to providers of this forum.
----------------------------------------------------------

1/2013: CT scan looking for source of distributed pain turns up Stage 4 adenocarcinoma of unknown primary metastasized to a wide range of sites in my bones, including sacrum, sternum, multiple ribs, iliac bones, thoracic spine. After significant searching, no primary tumor found then or since.
3/2013: Biopsy of inflamed lymph node provided a sample which was sent to Biotheranistics for Gene Expression Profiling and to Foundation Medicine for oncogene sequencing. These identified the following molecular characteristics of the cancer

• Her2/neu positive
• ER & PR negative
• BRCA1 positive (both in my germline and the cancer)
• Characteristics consistent with either breast or salivary gland cancer
• Above led to treatment as breast cancer[/INDENT]

3/2013 - 10/2013: Eight courses of Carboplatin + Taxol. Well tolerated.
8/2013: Began Herceptin (transtuzumab) “maintenance” infusions every 3 weeks. Scans show stable disease; no progression.
1/2014: Began supplementing Herceptin with Tykerb (lapatinib) 1250mg (5 tablets) daily. Well tolerated. Scans continue stable; no progression.
9/2015: Scans show apparent brain met growing in my dura
11/2015: Successful craniotomy removes 2.5cm tumor with same molecular characteristics as cancer above. 3 courses of conventional radiotherapy to clean up margins.
2/2016: Resumed Herceptin after surgery. Add pulsed dosing of Tykerb as an experimental treatment intended to overwhelm blood-brain-barrier and thereby prevent another brain met. Pulsed dosing = approx. 4000mg Tykerb (16 tablets/day) for 2 days out of 7. Difficult side effects.
Present status: Stable whole body bone scans every 3 mos. MRI brain scans every 3 mos. - clean so far. Feel good.