What?

[Rich]

1: Lancet Oncol. 2004 Sep;5(9):523. Related Articles, Links


High incidence of brain metastases with trastuzumab treatment.

Burton A.

Publication Types:
News

PMID: 15384215 [PubMed - indexed for MEDLINE]

[triciak]

Dear Rich, can you put this article on so we can read it? This does not sound like good news! Thanks! Tricia

[Guest]

I guess it's old news or old observation....
Meeting: 2002 ASCO Annual Meeting Printer Friendly
Bookmark

Category: Breast Cancer
SubCategory: Metastatic Breast Cancer



High incidence of brain metastases in patients treated with trastuzumab for metastatic breast cancer at a large cancer center
Abstract No: 241
Author(s): Andrew M Wardley, Sarah Danson, Alison J Clayton, Mark Clemons, Paul Burt, Alan Stewart, Sharon Waine, Peter Wilkinson, Richard Welch, Brian Magee, Anthony Howell, Christie Hospital NHS Trust, Manchester, UK.
Abstract: Introduction. Trastuzumab (T) is an effective treatment for patients with metastatic breast cancer (MBC) that over-expresses HER-2. We noticed a high incidence of brain metastases (BM) in patients receiving T. Methods Retrospective chart review of all 33 patients treated with T for MBC. Results. 11/33 (33%) patients have developed brain metastases (BM). Of the 11 patients that have developed BM 2 had hormone receptor positive breast cancer (HR+BC). HER-2 positivity (CB-11) was 2+ in 3 and 3+ in 8 patients. All except 3 (2 progressive disease (PD), 1 not assessable (NA)) had a response of at least durable stable disease (SD). All except 3 patients developed BM whilst receiving T (in 1 BM preceded T). In 5 patients BM was the first/only site of PD on T. Median time to BM (10 patients) was 285 days (42-799) and median duration T treatment (11 patients) was 253 days (36-905). Of the 22 without BM 10 had HR+ BC, 20 were HER-2 3+ and 2 were 2+. 8/22 patients without BM received T as part 1st line treatment for MBC (7 with Taxane, 1 monotherapy and 2 with vinorelbine on study). 13 continue T treatment (median time 228 days, 36-563) and 10/22 have a response of SD or better. 7/22 discontinued T because of PD and 2 due to cardiac reasons. Conclusions. HER-2 positive breast cancer may have a predilection for the brain or T may have changed the disease pattern. New strategies (such as prophylactic cranial irradiation) require investigation to prolong the time to progression.

[Lisa]

My understanding is that about 1/3 of all Stage IV women get brain mets. This would correspond, rather than differ from these study figures. At least the older one. I, too, can't get to the recent one.

Love and light,

Lisa

[al from canada]

Hi Rich,
I don't know if I would get bent out of shape over a study involving 33 patients. The point is: is it the herceptin or is it HER2? As the authors note maybe it is HER-2 positive breast cancer that may have a predilection to brain mets. Even if there are some truths in correlating HR status vs HER2 status vs brain mets, we would need a study far greater than 33 subjects to draw any conclusions of any merit.
So the question remains: why have there been no studies about this since 2002?? Because somehow it was buried (by the drug company?) OR was the study flawed to begin with? From reading it, it is obvious that this was a British study, (whilst?), so does that make a difference? The truths remain, as Lisa commented, that 30% of HER2 BC patients will get brain mets.
I would love to see an analysis of HER2 vs HR status vs brain mets over the last 5 years. I don't think that this information would be that difficult to tabulate but it may be difficult to access.
Regards,
Al

[scott]

Rich,

Herceptin doesn't cross the blood brain barrier and would not be effective there, so these women were probably destined for brain metastses anyway. It was probably the Herceptin stopping mets in other areas of the body that made it appear that the first site of metastases was the brain. I think I read this or a similar study and that was their conclusion.

[Christine Adams]

Dear Al and all,

There are quite a few small studies out there regarding herceptin, her2, and brain mets. As with anything you can find positive conclusions, as well as negative and, oftentimes, neutral. I work in a clinical medical library and these things cross my desk everyday...

Here's a paper from 2003 re: herceptin and brain mets. This one has an unquestionably positive conclusion for those on herceptin:

Clin Breast Cancer. 2003 Jun;4(2):114-9. Related Articles, Links

Increased rate of brain metastasis with trastuzumab therapy not associated with impaired survival.

Lower EE, Drosick DR, Blau R, Brennan L, Danneman W, Hawley DK.

University of Cincinnati Medical Center, Department of Internal Medicine, OH, USA. lowere@uc.edu

Trastuzumab is important for treatment of metastatic breast cancer patients with tumors that overexpress HER2/neu, but its penetration to the brain is poor. The aims of this study are to determine the prevalence of bone and brain metastasis during therapy, to compare the survival of breast cancer patients with brain metastasis who received trastuzumab to those patients not receiving trastuzumab, and to assess the impact of brain metastasis on the overall survival of trastuzumab patients. Of 103 patients treated with trastuzumab, 16 had brain metastasis and 43 had bone metastasis at the beginning of trastuzumab. The control group consisted of 196 patients with metastatic breast cancer who had never received trastuzumab. Six had brain metastasis and 75 had bone metastasis at the beginning of therapy. During therapy, only 9 of 60 trastuzumab patients (15%) developed bone metastasis, while 170 of 186 control patients (91%; c2 = 129.8, P < 0.0001) developed bone metastasis. In addition, 22 of 87 trastuzumab patients (25%) and 58 of 190 control patients (31%) subsequently developed brain metastasis. Control patients without brain metastasis experienced significantly better survival (median survival = 928 days) than those with brain metastasis (median survival = 639 days, c2 = 8.34, P < 0.005). There was no difference in survival for trastuzumab-treated patients if they acquired brain metastasis (median survival = 1400 days) or no brain metastasis (median survival > 2000 days, c2 = 0.12, P > 0.05). Patients receiving trastuzumab were unlikely to develop new bone metastasis but were as likely as control patients to develop brain metastasis. However, patients who developed brain metastasis experienced better survival compared with those patients with brain metastasis who never received trastuzumab.

PMID: 12864939 [PubMed - indexed for MEDLINE]


and this one from the Feb 1/05 issue of the journal "Cancer":

Increased Risk of Brain Metastases in Patients with HER-2/neu-Positive Breast Carcinoma

Ramin Altaha, M.D.
Edward Crowell, M.D.
Gerry Hobbs, Ph.D.
Gerry Higa, Pharm.D.
Jame Abraham, M.D.

Section of Hematology/Oncology, Mary Babb Randolph Cancer Center, West Virginia University,
Morgantown, West Virginia

Preliminary data have indicated that overexpression of HER-2/neu is correlated with more aggressive disease, an increasedmetastatic potential, and a poorer prognosis in patients with breast carcinoma.
(1–3) Trastuzumab, a humanized anti-HER-2 antibody, reportedly
is unable to penetrate the blood–brain-barrier and to our knowledge
its efficacy in patients with brain metastases remains unclear.(4–6) We
conducted a retrospective study to evaluate whether patients with
HER-2/neu-positive breast carcinoma have an increased risk of developing
brain metastases.
After approval from the institutional review board of West Virginia
University, the pathology reports of 703 breast carcinoma patients
who were diagnosed between April 1998 and January 2003 were
reviewed. Based on immunohistochemistry or fluorescence in situ
hybridization positivity, all patients who were positive for HER-2/neu
were identified and their medical charts reviewed with regard to their
course of disease and sites of metastases.
Of the 703 patients studied, 164 (23%) were found to be positive
for HER-2/neu; a sufficient oncologic history was available for
102 patients. Thirty-one patients (30%) developed distant metastases
(95% confidence interval [95% CI], 0.223– 0.399) during follow-
up lasting a median of 57 months. Brain metastases were
reported to have developed in 15 of these 31 patients (48%)(95% CI,
0.320 – 0.652). A proportional hazards model was fit to the data to
explore the association between patient age and time to the development
of metastases. A significantly positive association (P

0.01) was found to exist between the two variables. Other models
for censored data (Weibul, log-normal, and exponential models)
were fitted and were found to produce nearly identical P values
(Fig. 1).
The results of this small retrospective study demonstrate that
younger women with HER-2/neu-positive breast carcinoma may have
a higher risk of developing brain metastases than previously reported
for the general metastatic breast carcinoma patient population. This
442
© 2004 American Cancer Society

And, the conclusion of a 2004 article from the same journal...

CONCLUSIONS: Despite the impression of many oncologists, the results of this study did not support an association between trastuzumab therapy and an increased risk of CNS metastases. Copyright 2004 American Cancer Society.

I visit the board infrequently, but will try and be better in the future about posting anything that passes my way...

Kind regards,

/Christine

[Christine Adams]

Hi again,

Here's the first paragraph from the "Lancet Oncology' item that Rich mentioned (unfortunately, we don't subscribe to this journal and this is all that is available 'free' on their website). The conclusion is just what many have stated previously:

UK researchers have reported more evidence that associates trastuzumab treatment for HER2 positive breast cancer with a greater incidence of brain metastases (Br J Cancer 2004; 91: 639–43). The reasons, however, could simply be the drug's efficiency: the improved survival achieved with trastuzumab might be giving brain metastases long enough to develop and become clinically evident.

/Christine

[al from canada]

Dear Christine,
Thank you for your response to this very interesting question, and thanks to Rich for bringing it up. Any possible correlation could have significant imapact to many on this board. I think most would be relieved that there are some recent studies addressing this issue.

Some thoughts: The 25% BM is in line with those Lisa quoted however the scarey one is in study #2 where the rate is up to 48%, although the study did suggest it could be age related.
The silver lining: median survival of 1400 days. That is far longer than I have read before and even 2000 days for non-BM. As well, even if herceptin doesn't cross the blood-brain barrier, it still had a positive outcome on survival. This also could have interesting conclusions for our members with brain mets. If you have brain mets, why should you stop taking herceptin? Regardless, we can all agree that herceptin is (still) a God's send.

Hope to hear more from Christine A.,
Al

[Guest]

Exactly the message that our brain mets members have been stressing, IF one develops brain mets it does not follow that you've "failed" Herceptin and need to be taken off. Rather, if spread to the rest of the body is being controlled with Herceptin and addition of chemo if necessary, then brain mets can be treated independently. Thanks Christine, we appreciate your input.

Love, Lolly