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Lani
07-06-2006, 03:58 PM
1: J Neurooncol. 2006 Jul 5; [Epub ahead of print] Related Articles, Links

HER2-positive Breast Cancer Brain Metastases: Multiple Responses to Systemic Chemotherapy and Trastuzumab-a Case Report.

Church DN, Bahl A, Jones A, Price CG.

Department of Medical Oncology, Bristol Haematology and Oncology Centre, Horfield Road, BS2 8ED, Bristol, UK, chris.price@ubht.swest.nhs.uk.

Brain metastases from metastatic breast cancer typically occur in 10-15% of patients and are associated with survival of 3-6 months. Recent series have shown that women with HER2-postive metastatic breast cancer receiving the drug trastuzumab develop brain metastases more frequently than this, but also that continuation of trastuzumab after diagnosis of brain metastases in such patients is associated with extended survival. Authors have speculated that this is due to improved systemic control of disease; however, a possibility is that trastuzumab may have a beneficial effect on cerebral metastases themselves. We report the case of a woman with HER2-positive metastatic breast cancer who developed multiple brain metastases while on trastuzumab, in whom the addition of systemic chemotherapy to continued trastuzumab has produced multiple treatment responses associated with prolonged survival. This is the first report of its kind.

PMID: 16821088 [PubMed - as supplied by publisher]

...Well the stories of many of the participants on this site could add a thing or two to the medical literature!

StephN
07-06-2006, 06:13 PM
"continuation of trastuzumab after diagnosis of brain metastases in such patients is associated with extended survival. Authors have speculated that this is due to improved systemic control of disease; however, a possibility is that trastuzumab may have a beneficial effect on cerebral metastases themselves"

Thanks, Lani. This has been on my mind.
Last Friday when I had my consult with my rad onc after my followup brain MRI, we were talking along the same vein.
I have another area that was Gamma Knifed 18 months ago that is showing some increased enhancement. He wants to follow this one rather than do any intervention now, since we proved radiation necrosis in the larger tumor with the surgery in Jan.

He said normally they are quicker to want to investigate the area of concern as some 42% of these spots (in general population) turn out to be tumor regrowth and another large percentage test out as a mix of tumor and necrosis. It is a minority that turn out to be necrosis alone.
We talked about the number of what "looked like brain tumor regrowth" in HER2 positive women from this board and he says that they have no studies on whether the Herceptin DOES penetrate the BBB or some breakdown in the circulating blood could have a positive effect.
I also asked about those of us who have also had an open surgery and are still on Herceptin and he does not know how this would matter either.
Sure would be nice if some researcher would take up this subject.

He also said that TAXOL is a radiosensitizer and that would probably hold true for Abraxane as well. I wonder what else we take that is radiosensitizing??

Chelee
07-06-2006, 07:32 PM
So now we have herceptin for us Her2/neu women...and they find that it increases our chances of getting brain mets. (Gee...what next.)

I have a brain mri schedule as we speak due to a constant headache I have had since June 23rd. I thought it was a bit soon for me to have brain mets since I was DX in Dec 2005...and surgery 1-3-06....just finished chemo in mid June. Now after reading this I am more concerned.

I wish they were wrong about this report. Its always something it seems.

Chelee

Sherryg683
07-06-2006, 08:27 PM
The way it was explained to me by my Oncologist is that Herceptin itself doesn't increase or cause the chance of brain mets, it's that HER2+ women are living longer on Herceptin and therefore giving the Cancer more time to find the brain. I guess before Herceptin many of of HER2+ gals with mets would die before it had a chance to get into the brain. That's why I am waiting for them to OK the use of Tykerb along with HErceptin. Tykerb supposedly does enter the BBB...sherryg683

Lani
07-07-2006, 01:31 AM
Many many compounds radiosensitize in different forms of cancer. For head and neck cancers even cox2 inhibitors radiosensitize. I am off in Denmark without a lot of time to do research, but remind me and I will try to scrounge around a partial list for you. The radiation oncologists tend to be very practical people and feel that what they do already has been shown to work (and the are not even REALLY sure why!) so it is hard to get them to do a study (it would be hard to interpret the results anyway) as to what works better...hence the very slow uptake of new techniques such as APBI. I can't move from this to other screen without losing my post, so I will post a couple of articles from yesterday's search showing how little is known about radiation therapy for breast cancer...and how they are only now starting to entertain thoughts of doing studies to remedy that and try to answer very basic questions.

Hope this helps rather than makes people uncomfortable...
Lani

Lani
07-07-2006, 01:36 AM
ABSTRACT: Cardiac Risks of Breast-cancer Radiotherapy: A Contemporary View [Clinical Oncology]
For some time, there has been compelling evidence both from randomised-controlled trials and from observational studies, that some of the breast-cancer radiotherapy regimens used in the past have led to increased risk of mortality from heart disease. There is also some evidence that the more recent regimens used in the USA are associated with lower risks than previous ones, but it is not clear whether current regimens are free from cardiac risk, especially in the light of recent evidence from the survivors of the bombings of Hiroshima and Nagasaki, in whom a clear relationship was observed between the risk of mortality from heart disease and radiation dose for doses in the range 0-4 Gy. Mortality from radiation-induced heart disease usually occurs at least a decade after irradiation. Symptomatic heart disease might have a much shorter induction period, but little information about it is available at present. Subclinical vascular abnormalities have been observed within months of irradiation, via myocardial perfusion imaging studies, but little is known about the relationship between these and later overt heart disease. At present, few data relate heart dose and other specific characteristics of breast radiotherapy to cardiac outcome. Further information on these topics is needed to enable estimation of the cardiac risk, that is likely to arise from radiotherapy regimens in current use and from those being considered for future use. Such knowledge would facilitate radiotherapy treatment planning and enable a reduction in cardiac risk while maintaining the known benefit in terms of breast cancer mortality.


ABSTRACT: Radiotherapy and Genetic Predisposition to Breast Cancer [Clinical Oncology]
Cancer genetics is becoming increasingly integrated into oncological care; particularly in breast cancer management. The recognition of monogenic breast cancer predisposition syndromes, such as BRCA, is critical as there is also a risk of other cancers in addition to a markedly elevated risk of contralateral breast cancer.

In individuals with breast cancer due to some predisposition genes, radiation should be avoided, e.g. the ATM and TP53 genes, but there is still controversy as to whether radiation should be used in BRCA1/2 mutation carriers and more follow-up is needed.

There are some radiation-sensitive genetic conditions where, if breast cancer occurs (as it may occur in any individual, not necessarily due to an increased risk associated with the condition), radiation should be avoided. These conditions are often associated with dysmorphic features. If such features are noticed then the advice of a geneticist should be sought urgently prior to giving radiation.


ABSTRACT: Moving to a High-tech Approach to the Irradiation of Early Breast Cancer: Is It Possible to Balance Efficacy, Morbidity and Resource Use? [Clinical Oncology]
There is substantial evidence documenting the potential morbidity associated with radiotherapy in early breast cancer. An appraisal of current standard radiation practice is therefore necessary, given that women are surviving longer, have an improved quality of life, and are overcoming subsequent side-effects caused by postoperative irradiation. New technology allows the application of more complex approaches. This discussion paper considers some of the benefits of the widespread use of new complex approaches, such as intensity-modulated radiotherapy (IMRT) in the light of staffing and equipment shortfalls, and possible consequences on waiting times for treatment. The discussion is considered under the following themes: (1) which women with breast cancer benefit from complex treatment approaches? (2) What is the role of treatment accuracy in limiting morbidity? And (3) what is the potential effect of complex breast irradiation approaches on service delivery? In the UK, and globally, many departments are struggling to meet waiting-time guidelines. The use of more complex approaches for breast irradiation may increase this difficulty. However, a number of simple technical changes can be used to enhance efficacy and reduce levels of normal tissue morbidity. A sub-set of women who are at greatest risk from normal tissue morbidity or reduced cosmesis should be accurately defined in order to allow departments to plan their treatment strategies with optimal use of resources.


and two more:
Boost radiotherapy helps early breast cancer: study [Reuters News Service]
LONDON (Reuters) - A booster dose of radiotherapy may help stop young women with very early breast cancer from progressing to a more serious form of the disease, researchers said on Thursday.

Ductal carcinoma in situ (DCIS) is a pre-cancer that occurs in cells lining the breast milk ducts. It is contained within the ducts and has not yet spread to the surrounding breast tissue.

Surgery is usually performed to remove the cells and stop the cancer returning. If the DCIS is extensive, a mastectomy may be necessary. Radiotherapy can also be used to kill any remaining cancer cells.

But scientists who compared different treatments for DCIS said their findings show radiotherapy and a boost dose improves the patients' chances.

"First, not using radiotherapy in young patients with DCIS resulted in an unacceptable number of women having their cancer return and second, these patients benefit from an additional boost dose," said Guenther Gruber of the Kantonsspital in Aarau, Switzerland.

He and a team of researchers analyzed the outcomes of 373 women of 45 years old or younger who had been treated in 18 different institutions throughout the world for DCIS.

One sixth had surgery to remove the DCIS. Nearly half had surgery plus radiotherapy and the remainder had surgery, radiotherapy and a boost dose.

The risk of a recurrence of DCIS or invasive breast cancer decreased with each additional treatment.

"Our findings clearly suggest that the radiation dose is very important for local tumor control for patients with DCIS aged 45 years or younger," Gruber said in a report in The Lancet Oncology journal.

[NOTE: For the full article, please follow the supplied link.]


ABSTRACT: Boost radiotherapy in young women with ductal carcinoma in situ: a multicentre, retrospective study of the Rare Cancer Network [Lancet Oncology; Subscribe; Sample]
Background: Outcome data in young women with ductal carcinoma in situ (DCIS) are rare. The benefits of boost radiotherapy in this group are also unknown. We aimed to assess the effect of boost radiotherapy in young patients with DCIS.

Methods: We included 373 women from 18 institutions who met the following inclusion criteria: having tumour status Tis and nodal status (N)0, age 45 years or younger at diagnosis, and having had breast-conserving surgery. 57 (15%) patients had no radiotherapy after surgery, 166 (45%) had radiotherapy without boost (median dose 50 Gy [range 40-60]), and 150 (40%) had radiotherapy with boost (60 Gy [53-76]). The primary outcome was local relapse-free survival.

Findings: Median follow-up was 72 months (range 1-281). 55 (15%) patients had local relapse. Local relapse-free survival at 10 years was 46% (95% CI 24-67) for patients given no radiotherapy, 72% (61-83) for those given radiotherapy without boost, and 86% (78-93) for those given radiotherapy and boost (difference between all three groups, p<00001). Age, margin status, and radiotherapy dose were significant predictors of local relapse-free survival. Compared with patients who had no radiotherapy, those who had radiotherapy had a decreased risk of local relapse (without boost, hazard ratio 033 [95% CI 016-071], p=0004; with boost, 015 [006-036], p<00001).

Interpretation: In the absence of randomised trials, boost radiotherapy should be considered in addition to surgery for breast-conserving treatment for DCIS.

Good thing they are NOW trying to look at these things critically. Hopefully with our ever increasing knowledge of the genetics of breast cancer things will become clearer...

PS Perhaps herceptin's effect on the brain is indirect via the immune system!?

R.B.
07-07-2006, 04:10 AM
I posted this as part of the thread on the Greek diet as it relates to Omega threes.

"Taken together, these results indicate that omega-3 PUFA regulate COX-2-mediated invasion in brain-metastatic melanoma."

I have also posted the question on a number of occasions does Herceptin which is reported as intervening in the fat pathways block the making of DHA and EPA.

IF it does it would be a least in part a possible explanation as to a potential for increase of brain tumours.

It has been suggested that the balance of fats in the brain and risk of tumours are linked.

Smart Fats by A Schmidt ia an exellent book which gives an insight into the power and importance of fats. I do not know or have any connection with the persons involved in the book I have simply read it.

I repost this in the hoping of tempting those of you who have not looked at the issue of balancing the omega threes and sixes, and wider dietary issues to do so.

RB



http://www.ncbi.nlm.nih.gov/entrez/...l=pubmed_docsum

Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA. ydenkins@vetmed.lsu.edu

Cyclooxygenase-2 (COX-2) is important in the progression of epithelial tumors. Evidence indicates that omega-6 PUFAs such as arachidonic acid (AA) promote the growth of tumor cells; however, omega-3 fatty acids [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] inhibit tumor cell proliferation. We investigated the effects of omega-3 PUFA on the expression and function of COX-2 in 70W, a human melanoma cell line that metastasizes to the brain in nude mice. We show that 1) tumor necrosis factor-alpha upregulates the expression of both COX-2 mRNA and prostaglandin E2 (PGE2) production, and 2) omega-3 and omega-6 PUFA regulate COX-2 mRNA expression and PGE2 production. AA increased COX-2 mRNA expression and prostaglandin production in omega-6-stimulated 70W cells. Conversely, COX-2 mRNA expression decreased in cells incubated with EPA or DHA. AA increased Matrigel invasion 2.4-fold, whereas EPA or DHA did not. Additionally, PGE2 increased in vitro invasion 2.5-fold, whereas exposure to PGE3 significantly decreased invasion. Our results demonstrate that incubation of 70W cells with either AA or PGE2 increased invasiveness, whereas incubation with EPA or DHA downregulated both COX-2 mRNA and protein expression, with a subsequent decrease in Matrigel invasion. Taken together, these results indicate that omega-3 PUFA regulate COX-2-mediated invasion in brain-metastatic melanoma.

PMID: 15772428 [PubMed - indexed for MEDLINE]