from latest article on CNS mets in her2+ metastatic breast cancer pts on herceptin

[Lani]

authors include Burstein, Harris, Winer

An obvious question is this: should screening
be considered in asymptomatic patients? For example,
women treated with trastuzumab have a 30 – 40% risk
of developing CNS disease. Should they be screened?
To our knowledge, there currently are no data to in-
dicate that the earlier detection of CNS metastases will
have any effect on overall survival. Nevertheless, neu-
rologic impairment from symptomatic brain metasta-
ses, even if it is transient, can be devastating. If the
high incidence of CNS disease reported herein is con-
firmed by other investigators, it may be worthwhile to
reevaluate screening procedures. Ultimately, it will be
critical to develop new agents that are able to pene-
trate the blood-brain barrier or we will continue to
encounter similar problems with the development of
new and more effective therapies.

http://www3.interscience.wiley.com/cgi-bin/fulltext/104535508/HTMLSTART

[pattyz]

Chemotherapy induces regression of brain metastases in breast carcinoma

Dutzu Rosner, MD *, Takuma Nemoto, MD, Warren W. Lane, PHD Departments
of Breast Surgery and Biomathematics, Roswell Park Memorial Institute,
Buffalo, New York

*Correspondence to Dutzu Rosner, Department of Breast Surgery, Roswell
Park Memorial Institute, 666 Elm Street, Buffalo, NY 14263

Funded by: National Cancer Institute, Department of Health and Human
Services.; Grant Number: CA-16056

Abstract: This study improves treatment options and ultimately survival
by using systemic chemotherapy in brain metastases from breast
carcinoma, since most of these patients have disseminated disease and a
dismal prognosis when treated by conventional brain irradiation alone.

One hundred consecutive patients with symptomatic brain metastases
documented by radionuclide and/or computerized tomography scan were
treated with systemic chemotherapy. Fifty of 100 patients demonstrated
an objective response of brain metastases which was similar for
extracranial metastases. There were 10 complete responders (CR), 40
partial responders (PR), 9 stable, and 41 nonresponders.

Median duration of remission was 10+ months for CR and 7 months for PR
(range, 2-72 months). Primary chemotherapy of brain metastases yielded
responses in 27 pf 52 patients (52%) treated with Cytoxan
(cyclophosphamide) (C), 5-fluorouracil (F) and prednisone (P); 19 of 35
(54%) receiving CFP-methotrexate (M) and vincristine (V); 3 of 7 (43%)
treated with MVP, and 1 of 6 (17%) receiving Cytoxan plus Adriamycin
(doxorubicin) (CA). Thirteen of 35 patients (37%) who subsequently had
relapse of brain metastases were retreated successfully with secondary
chemotherapy. The median survival for CR and PR was 39.5 months and 10.5
months, respectively, in contrast with nonresponder patients who had a
median survival of 1.5 months. Thirty-one percent of all treated
patients survived more than 12 months.

These findings suggest that the chemotherapeutic agents used penetrate
the blood-brain barrier inducing regression of brain metastases. This
approach offers a significant benefit by simultaneously controlling
extracranial disease, improving the response and prolonging survival.



----------------------------------------------------------------------
----------
Accepted: 29 November 1985

Oh, how I loved finding this info dated 23 years ago!

[Phoenix]

Lani,

The study you found was from 2003. The one below is from 2007. Just Google your Title for more info.


http://pda.asco.org/portal/site/ASCO/menuitem.34d60f5624ba07fd506fe310ee37a01d/?vgnextoid=76f8201eb61a7010VgnVCM100000ed730ad1RCR D&vmview=abst_detail_view&confID=52&abstractID=40383

[KellyA]

30-40% ?! Is the number really this high? That figure seems very high...

[Gerri]

Lani,

My understanding, and I could be WAY off, is that the 30% - 40% statistics are for those with metastatic disease. Can you confirm that? And if so, are there stats out there for CNS mets and early stage bc? Should early stagers be getting routine brain MRIs? Would love to know!

As always, thanks for your input.

[Becky]

The stats and the studies are for women with mets in the body. For women with metastatic disease, about one third will get brain mets as well. It is NOT statistics for all those who have been diagnosed with early Her2+ bc.

[Gerri]

Thanks Becky for the clarification. That makes me feel somewhat better. I have never had a brain MRI and wonder if I should push for having one done.

[Lani]

articles they list as just appearing in press/online for the first time.

Sorry I did not notice it was from 2003!

The reason I posted it was because of their discussion of getting periodic brain MRIs rather than waiting for symptoms to appear

[hutchibk]

However - I wonder what the statistics say about CNS after early stage dx, but with known node involvement at dx? Anyone know?

[caya]

Thanks Becky for clearing up that 30 -40% figure - I thought it was for those already confirmed with mets in the body - PHEW!!!

all the best
caya

[Mary Anne in TX]

Brenda, I was wondering the same thing about early with nodes. I seem to be at the end of my battle with my insurance company and it looks like I'll have 3 more (H) treatments and then off to the circus for me! I've got scans (bone, chest, abdomen) planned and was just wondered if I should also ask for a brain MRI (last one about 9 - 10 months ago).
Anyway, Lani, thanks for stirring up more great discussion.
ma

[bashmaz]

It's great to read that herceptin pre. CNS mets makes for a better prognosis once you get mets, but the abstract didn't say the actual number of women who got CNS mets - if a much higher percent who got CNS mets were her2+ve (with prior Hecept.), then that can put a different interpretation on the article.

My daughter is actually doing her senior project for high school on Her2+ve BC and her thesis title is "Is being Her2+ve still a negative?" - so I'm helping her gather all the "good" info. but as a reference librarian I feel the need to get all the info!

Has anyone read the whole paper of this study?

Best wishes,
Marianne

[StephN]

The first question in the opening post asks about ASYMPTOMATIC patients.

I had mets, but was getting a routine brain MRI about once a year.

Had NO symptoms of a 3cm tumor in the lower left back lobe called cerebellum. If it had gone much longer, I am sure there would have been more complications and I would have had to stay on the "dreaded Decadron" for longer.

Just a reminder that previous stats quoted on this site were that it is about 10 percent of brain tumors where they are the FIRST site of distant mets in HER2 positive patients stages 1 to 3.

That stat is a few years old and I don't know if new information has come to Joe & Christine that would change this, but I feel sure that if they had any new information we would know about it.

HER2 driven brain mets seems to grow faster than other kinds, but maybe pattyz can comment on that.

[pattyz]

Steph: "HER2 driven brain mets seems to grow faster than other kinds, but maybe pattyz can comment on that."

No, I have no information on this. I have not seen where this has been mentioned as possible.

As for overall, I have this saved to desktop, fyi:

Brain metastases, unfortunately are very common and grave condition in the natural history of patients with cancer. It is estimated that approximately 250,000 patients with cancer will develop brain metastasis in the United States each year.

Autopsy data have shown that up to 50% of patients who die with cancer have evidence of spread to the central nervous system, with approximately 40% of these patients having a solitary or single metastasis . (Solitary means that this metastasis is the only evidence of cancer in the whole body, whereas single means that there are other deposits of cancer outside the brain).

· Tumors more prone to brain dissemination are: Lung, breast, melanoma, renal cell carcinoma, colorectal, sarcoma.
· The temporal pattern of presentation is of interest:
1. Preccocious (occult primary). Some authors state that up to one-third of patients who present with brain metastasis do not have previous cancer history, and in 16-35% of these patients a systemic cancer is never found
2. Synchronous
3. Metachronous (81%) Usually tertiary event: Short intervals (Lung, melanoma, renal CC). Long intervals (Breast, Colon, Sarcomas)

STAGING
Clinical Presentation: (the percentages vary largely with the published series)
Headaches 53%, usually caused by edema, CSF (Cerebral spinal fluid) flow compromise, traction of pain sensitive obstruction like sinuses, duramatter, blood vessels, or cranial nerves. These headaches are typically worse in the morning, and increase progressively in duration and intensity.
Focal weakness (40%), mental disturbance (31%), gait disorder (20%) visual problems (12%)

[StephN]

Thanks, pattyz, there was some info there that is new to me.

3. Metachronous (81%) Usually tertiary event: Short intervals (Lung, melanoma, renal CC). Long intervals (Breast, Colon, Sarcomas)

It is the "long interval" part that is interesting to our cancer. All the more reason to keep checking us on a regular basis. Especially as it is KNOWN that the cancer cells can be dormant for years.

I went back to some notes I took at rad onc consult. Talking about the seeding and becoming active of HER2 brain mets. (I think vs. other types of breast cancer brain mets.)

If the tumor is high grade and HER2 pos it has means to proliferate quickly. My larger tumor had grown from undetectable in 12 months to 3cm. My docs seemed to think that was a pretty fast growth rate as my CEA marker did not go up until about 7 -8 months after the previous MRI. That gave it about 5 - 6 months in their estimation to achieve that size.

My liver mets also grew VERY fast. Took over 60% of my liver in 3-4 months time. Not everyone will have that kind of growth rate, but that is the nature of my particular cell biology.

[pattyz]

Steph,
that rapid a growth to your liver mets tends toward an assumption that it could/would be true for Her2+ brain mets, too. Atleast under the conditions that you stated about your particular 'breed' of this disease.

My own 'breed' of little f*&ers seem to be of a slower growth kind. With the 2nd dx of 14, it was not until twelve months later that the last batch were radiated. Growth not being overly much, but gradual.

It may be down to cell biology for all, to be able to predict any kind of progression rate...

pattyz

[Hopeful]

This interview appeared in Breast Cancer Update in the February, 2008, edition. It has some interesting stats:

http://www.breastcancerupdate.com/medonc/2008/2/lin.asp

Hopeful

[StephN]

http://www.breastcancerupdate.com/medonc/2008/2/images/arrow-yellowTransp.gif DR LIN: Yes, and I believe trastuzumab is a particularly large molecule and probably doesn’t penetrate well. Dr Burstein evaluated CNS relapse and CNS progression versus non-CNS progression among patients receiving first-line trastuzumab-containing chemotherapy. This analysis revealed that approximately 10 percent of patients in the first-line setting experienced isolated CNS progression at a time when their non-CNS disease was completely quiescent (Burstein 2005; [6.2]).

There is the 10% I mentioned. She also says there appeared to be NO DECREASE in the number of brain as first distant site for those who had Herceptin as adjuvent treatment. But, that stat was from 2005, so I would like to see what it is today.

I still find this percentage lage enough that HER2 pos. patients should have brain screenings. Or at least the med oncs should be more open to it for requested.

[Gerri]

http://theoncologist.alphamedpress.org/cgi/content/full/13/6/620

Taken from the above referenced article:

Another concern regarding the use of trastuzumab has been the association of its use with the development of metastatic CNS disease. A higher incidence of progression in the CNS has been observed in several retrospective studies of patients with HER-2–positive metastatic breast cancer treated with trastuzumab [43 (http://theoncologist.alphamedpress.org/cgi/content/full/13/6/620#B43)–45 (http://theoncologist.alphamedpress.org/cgi/content/full/13/6/620#B45)]. Our analysis demonstrated a higher incidence of CNS metastasis as the first recurrence event among patients treated with trastuzumab, which nonetheless was outweighed by the overall lower risk for distant recurrence (non-CNS visceral disease) and the impressive benefits in survival. The exact reasons for this phenomenon are unclear, but the etiology is probably multifactorial, involving a lower bioavailability of trastuzumab in the CNS because of poor blood–brain barrier penetration and its high effectiveness in preventing the development of non-CNS visceral disease. Although some investigators have suggested that HER-2–positive disease may preferentially involve the CNS, evidence from large retrospective datasets of nontrastuzumab-treated patients is inconclusive [46 (http://theoncologist.alphamedpress.org/cgi/content/full/13/6/620#B46), 47 (http://theoncologist.alphamedpress.org/cgi/content/full/13/6/620#B47)].

So, do I show this to my onc to get her to order an MRI?

[pattyz]

For those who were wondering, but not specifically for her2+ I found this info stated in part of a trial:

The incidence of CNS metastases in breast cancer has been estimated as 1-16% in clinical series, with higher rates (18-30%) in autopsy series. Recently a trend towards increasing CNS relapse has been noted, up to 25-34%. This may be partly explained by the increasing use of contrast-enhanced magnetic resonance imaging (MRI), heightened awareness by patient or clinicians, or an alteration in the natural history of breast cancer with improvements in systemic therapies, resulting in a prolongation of survival.


Therefore, with improvements in treatments, metastases are better controlled, resulting in the CNS becoming a sanctuary for residual disease. The treatment of CNS metastases in breast cancer remains challenging. Surgical resection of tumor will prolong survival only in patients with a single lesion and with well controlled systemic disease. For patients with multiple lesions, whole brain radiotherapy (WBRT) remains the backbone in the management of CNS metastases.


Recently the use of stereotactic radiosurgery alone or in combination with WBRT has been explored. Although better local control was achieved with the combination therapy, minimal overall survival benefit was seen.


This may be secondary to the competing risk of death from systemic (extra-CNS) progression. The use of systemic agents including chemotherapy and hormonal therapy has been generally disappointing. This is often attributed to the impermeability of the blood-brain and blood-tumor barriers. Furthermore, P-glycoprotein (Pgp), a drug efflux pump encoded by the multidrug resistance gene, mdR1, is expressed in brain endothelial cells.


Therefore, agents such as doxorubicin, cyclophosphamide, 5-fluorouracil, paclitaxel, docetaxel and vinorelbine, which are active against breast cancer, may either penetrate CNS poorly, or be transported out of the CNS environment.


However, the blood brain barrier may be more leaky and permeable than previously thought in patients with CNS metastases, and these agents may achieve therapeutic concentrations in the CNS.


As evidence for this, patients without prior exposure to agents such as cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, and doxorubicin, can have significant objective responses in the CNS metastases. Today, most patients would have received these agents in the adjuvant setting, thus emphasizing the importance of both chemo-sensitivity together with CNS penetration, in the treatment of CNS metastases.