her2 positivity changes everything--tumor cells can disseminate from earliest stages

[Lani]

Cancer Cell. 2008 Jan;13(1):58-68.
Systemic spread is an early step in breast cancer.

Hüsemann Y, Geigl JB, Schubert F, Musiani P, Meyer M, Burghart E, Forni G, Eils R, Fehm T, Riethmüller G, Klein CA.
Department of Pathology, Division of Oncogenomics, University of Regensburg, Regensburg 93053, Germany.
It is widely accepted that metastasis is a late event in cancer progression. Here, however, we show that tumor cells can disseminate systemically from earliest epithelial alterations in HER-2 and PyMT transgenic mice and from ductal carcinoma in situ in women. Wild-type mice transplanted with single premalignant HER-2 transgenic glands displayed disseminated tumor cells and micrometastasis in bone marrow and lungs. The number of disseminated cancer cells and their karyotypic abnormalities were similar for small and large tumors in patients and mouse models. When activated by bone marrow transplantation into wild-type recipients, 80 early-disseminated cancer cells sufficed to induce lethal carcinosis. Therefore, release from dormancy of early-disseminated cancer cells may frequently account for metachronous metastasis.
PMID: 18167340 [PubMed - in process]

[mts]

This topic is what onc's and patients dwell on quite a bit. To chemo or not to chemo in Stage 1...especially with tumors smaller than 1cm.

Maria

[Lani]

Before it was just a "judgement/guess" that perhaps breast cancer behaved differently than many other cancers because cutting it out and radiating it did not cure as many people as other cancers.

Now we have the technology to discover if that is true, machines to test for circulating tumor cells and better techniques to look for individual cells in bone marrow samples--yet those aren't hardly being used.

Here they showed in mice that they could see disssemination of tumor cells even from DCIS when her2 was present. To me, that means looking for signs of micrometasis when staging the breast cancer would make sense.

Also, many drugs languish for years being used for those with macrometastasis only, which could be tried at an earlier stage with the understanding if micrometastasis were looked for and found to see if that would impact the disease. That is just beginning with trials of herceptin with avastin in the adjuvant setting, but perhaps highrisk patients should no longer be defined by the number of lymph nodes positive, but by whether there are isolated tumor cells in their bone marrow.

I don't want to annoy people who will say, yes, but I could never get my oncologist to look for that, only to make people aware that evidence has been found for what oncologist only suspected and perhaps this knowledge should be used to look freshly upon how cancer is staged, clinical trials run and patients treated

[penelope]

almost all DCIS is her2+. I believe this is written in Susan Love's book as well as other papers.

If this is the case doesn't it make sense that more women would get mets with a diagnosis of DCIS only, but this does not seem the case.

[Lani]

Her2/neu overexpression in DCIS
is common and is associated with higher grade and
comedo necrosis; these pathologic features are associ-
ated with a higher risk of local recurrence.
Almost half of ER-negative DCIS lesions express
Her2/neu, and a majority of Her2/neu-positive DCIS
lesions are ER negative and there are few effect-
ive medical treatments for ER-negative DCIS...
About 12% of ER-positive DCIS cases overexpress Her2/neu,
and there is some concern that ER expression may pro-
vide some resistance to tamoxifen.

Also keep in mind:

--THERE ARE DCIS THAT NEVER DEVELOP INTO IDC--WITHOUT KNOWING HOW many of these THERE ARE, HOW DO WE KNOW WE ARE NOT MISSING A WHOLE LOT OF DATA FROM PEOPLE WHO NEVER HAVE MAMMOGRAMS WHICH COULD BE USED TO ALLAY THE CONCERNS OF THOSE WHO DO AND ARE FOUND TO HAVE DCIS ONLY (ie without invasive component)
AND WHO is TO ASSUME THAT MOST CASES OF DCIS that occur are even discovered--MANY women DIE PROBABLY DIE OF OTHER CAUSES WITHOUT EVER DISCOVERING the DCIS. THIS MAKES IT VERY HARD TO SAY HOW MANY DCIS ARE ER+,HER2+, EVENTUALLY INVADE ETC.

Just pointing this out as it is necessary that periodically those things that are "generally accepted" get questioned.

[Jean]

of a trial of bone biopsey being performed on patients during lumpectomy.
I do know of a trial being done at Cornel NY, I was a bit annoyed at the time (2005) that I was not informed about it prior to my lumpectomy
as I would have been glad to participate in the trial since I fit the profile
small tumor, SNB, ....have not a heard about it in almost three years.

Happy New Year !
jean

[Lani]

here, why more bone marrow biopsies are not done to stage breast cancer patients and determine their risk of recurrence (particularly as part of clinical trials)

Here is an article from MD Anderson recommending further studies.

{I remember several years ago UCSF was going to include bone marrow samples taken at the time of initial surgery in some trial of theirs, but have never seen any results published.

The results published are mostly out of Germany from the group headed by Braun. They have published a great deal on this topic.}


Expert Rev Anticancer Ther. 2007 Oct;7(10):1463-72. Links
Significance of micrometastasis in bone marrow and blood of operable breast cancer patients: research tool or clinical application?

Lang JE, Hall CS, Singh B, Lucci A.
The University of Texas MD Anderson Cancer Center, Department of Surgical Oncology, Unit 444, 1515 Holcombe Blvd, Houston, TX 77030, USA. jlang@surgery.arizona.edu
Approximately 25% of breast cancer patients without lymph node metastases develop systemic relapse. A growing body of data supports the notion that hematogenous dissemination of breast cancer cells occurs independently of lymphatic spread of disease; however, current clinical practice does not involve routine analysis of circulating or disseminated cells. Recent studies have documented that both circulating tumor cells (CTCs) within the blood and disseminated tumor cells (DTCs) in bone marrow can be identified using a variety of techniques. It is now clear that the presence of DTCs correlates with subsequent development of clinically evident bone metastases, and a worse outcome from breast cancer. While there are data identifying prognostic significance of CTCs in patients with metastatic breast cancer, there are few data regarding CTCs in operable patients. Factors such as presence of a cancer stem cell phenotype and/or certain microenvironmental conditions are involved in the establishment of distant metastases from a primary breast cancer, emphasizing the need for further studies within this area. The purpose of this report is to review the data regarding CTCs and DTCs in patients with operable breast cancer.
PMID: 17944570 [PubMed - indexed for MEDLINE]

Related Links
Detection and clinical implications of early systemic tumor cell dissemination in breast cancer.
[Clin Cancer Res. 2003]
Micrometastatic breast cancer cells in bone marrow at primary surgery: prognostic value in comparison with nodal status.
[J Natl Cancer Inst. 1996]
Current status in human breast cancer micrometastasis.
[Curr Opin Oncol. 2007]
Clinical significance of immunocytochemical detection of tumor cells using digital microscopy in peripheral blood and bone marrow of breast cancer patients.
[Clin Cancer Res. 2004]
[Micrometastatic cells in the bone marrow of patients with breast carcinoma]
[Radiologe. 2000]

[Lani]

Clin Cancer Res. 2003 Dec 15;9(17):6326-34. Links
Detection and clinical implications of early systemic tumor cell dissemination in breast cancer.

Pantel K, Müller V, Auer M, Nusser N, Harbeck N, Braun S.
Institut für Tumorbiologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany. pantel@uke.uni-hamburg.de
Blood-borne distant metastasis is the leading cause of cancer-related death in breast cancer. The onset of this fundamental process can now be assessed in cancer patients using ultrasensitive immunocytochemical and molecular assays able to detect even single metastatic cells. Analyses of bone marrow (BM) samples show that disseminated cells are present in 20-40% of primary breast cancer patients without any clinical or histopathological signs of metastasis. The common homing of circulating breast cancer cells in BM is indicative for systemic tumor cell spread and predictive for growth of overt metastases in relevant organ sites such as bone, lung, or liver. Recent clinical studies involving more than 3000 breast cancer patients demonstrated that the presence of tumor cells in BM at primary diagnosis is an independent prognostic factor for unfavorable clinical outcome. To date, sampling of BM, however, is not a routine procedure in clinical management of breast cancer patients. Therefore, several research groups have developed sensitive assays for detection of circulating tumor cells in peripheral blood. Studies evaluating the clinical relevance of these blood assays are ongoing. Here, we will review the existing tumor cell assays and discuss their current clinical relevance and perspectives for the clinical management of breast cancer patients.
PMID: 14695131 [PubMed - indexed for MEDLINE]

[Lani]

and spread the cancer
http://www.breastcancersource.com/br...10_0_0_0.aspx?

[mindersue]

I now have a whole new take on my upcoming bone marrow biopsy (1/16). My blood counts have never fully rebounded since chemo and my onc has finally decided to check my bone marrow. He thinks it will be negative and will then refer me to a rheumatologist for suspected auto-immune issues.

I'm the type who refuses to worry, but this sure gives me something to THINK about!

Thanks, Mindy

[Lani]

I think the bone marrow biopsy you are having will be looking for the number and type of blood cell precursors and how they are maturing to try to explain your low blood counts. That technology may be different than the technology they use to look for isolated tumor cells.

If you want to ask your oncologist to try to kill two birds with one stone and get two bits of info from one procedure--see if the technique he plans to use and the process by which they process the cells after removing them differs substantially from that described in the articles by Braun and Pantel on isolated tumor cells in bone marrow. I am in no way qualified to decide if they are, but know that it may be important to inquire --according to my readings, the processing technique may vary depending what they are looking for (blood cell precursors vs Isolated tumor cells)

As I understand it, those clinical trials at UCSF that were to look at the bone marrows of newly diagnosed patients were sent to Clarient/Chromavision in Southern California for processing (Google them if needed), their technique which involves a special type of microscope as well as staining was chosen for clinical trials
because of its high resolution and specificity as I understand it. Not only do Clarient have a special technique for looking for isolated tumor cells but they can also stain them , if ITCs are found, for her2. Clarient had a booth at the 2006 SABCS and a poster exhibited this year. Dr. Bloom, their head, just sat on a committee looking into improving accuracy of ER and her2 testing.


Your oncologist will probably only want to send your marrow specimen on for these additional tests if he thinks it may change your treatment--but maybe not. This is where things get sticky as our technology is outpacing our validation of the meaning its results.

Hope some of this helps rather than frustrates you!

[mindersue]

def. helps! Thanks, Lani!

Mindy