Go, Max Wicha!!! Herceptin effective even in her2- patients because it nips the bone

[Lani]

micrometastases in the bud!!

Now how about testing for those bone micrometastases in her2+ and her2- patients to see who will be resistant to herceptin and need additional therapy
...and who can skip chemo altogether

Lots to learn, but have to start with LOOKING @ the bone marrow


Public release date: 26-Feb-2013

Contact: Nicole Fawcett
nfawcett@umich.edu
734-764-2220
University of Michigan Health System
U-M study challenges notion of using Herceptin only for HER2-positive breast cancer

Breast cancer stem cells express HER2, even in 'negative' tumors, study finds





IMAGE: This image shows Max S. Wicha, M.D., University of Michigan Comprehensive Cancer Center.



ANN ARBOR, Mich. — New research from the University of Michigan Comprehensive Cancer Center finds that the protein HER2 plays a role even in breast cancers that would traditionally be categorized as HER2-negative – and that the drug Herceptin, which targets HER2, may have an even greater role for treating breast cancer and preventing its spread.

About 20 percent of women with breast cancer have tumors labeled HER2-positive. And since the drug Herceptin has come on the scene, it has had a tremendous impact on survival for these women, particularly when it is given in the adjuvant setting, after surgery to remove the primary cancer. The new findings have potential implications for an additional 65 percent of women with breast cancer.

A recent study based on new analyses of old data found some tumors were incorrectly categorized as HER2-positive and as a result those women received adjuvant Herceptin. It turns out, they benefited as much from the treatment as woman with actual HER2-positive cancer.

"We now provide a molecular explanation for the surprising finding that adjuvant Herceptin benefited some women with HER2-negative breast cancer. If this is confirmed in clinical trials, it could alter our approach to breast cancer treatment," says study author Max S. Wicha, M.D., distinguished professor of oncology and director of the U-M Comprehensive Cancer Center.

At this point, patients with HER2-negative breast cancer are not advised to take Herceptin.

The explanation is that HER2 is selectively expressed in the cancer stem cells of many HER2-negative breast tumors. Because the stem cells represent such a small number of cells in a tumor, the amount of HER2 is not high enough to meet the threshold for a HER2-positive cancer.

The researchers had previously shown HER2 plays an important role in cancer stem cells – the small number of cells in a tumor that fuel its growth and spread. These cells represent 1 percent to 5 percent of all the cells in a tumor. They are resistant to current chemotherapy and radiation treatments – but since they express HER2, they are effectively targeted by Herceptin.

Further, the researchers in this new study found that for tumors classified as HER2-negative, HER2 levels were higher in bone metastases compared to the primary breast tumor. Bone is the most frequent site to which breast cancer spreads.

The researchers administered Herceptin to mice with these bone lesions and found that it was most effective when given early, when tumors were small or mere "micrometastases." In these cases, Herceptin almost completely blocked the tumors from growing. When the drug was given later, after tumors were established, it had little effect.

"We have shown that the bone microenvironment induces HER2 expression in these tumors. If Herceptin can target bone micrometastases, then administering it to patients before metastases develop could help reduce tumor recurrence," says study author Hasan Korkaya, Ph.D., research assistant professor of internal medicine at the U-M Medical School.

The implications of this finding are that we need cancer treatments that target the small number of cancer stem cells in addition to traditional chemotherapies that eliminate the bulk tumor cells. This means that merely looking at whether a tumor shrinks is not good enough to determine whether the treatment will have long term benefit.

"This work has very significant implications for how we have developed adjuvant therapies. The idea of using drugs that cause tumors to shrink, which has been the accepted paradigm for developing therapies, is flawed. Our work suggests that adjuvant therapies will need to target the cancer stem cell population. Eliminating cancer stem cells by effective adjuvant therapies should prevent tumor recurrence, ultimately resulting in more cures," Wicha says.

###
A large randomized clinical trial sponsored by the National Institutes of Health is currently open at U-M and other sites across the country to address this question. Patients whose tumors are not considered HER2-positive by classic testing should not receive Herceptin outside of this trial. For information about the trial, call the U-M Cancer AnswerLine at 800-865-1125.

Additional authors: Suthinee Ithimakin, Kathleen C. Day, Fayaz Malik, Qin Zen, Scott J. Dawsey, Tom F. Bersano-Begey, Ahmed A. Quraishi, Kathleen Woods Ignatoski, Stephanie Daignault, April Davis, Christopher L. Hall, Nallasivam Palanisamy, Amber N. Heath, Nader Tawakkol, Tahra K. Luther, Shawn G. Clouthier, Whitney A. Chadwick, Mark L. Day, Celina G. Kleer, Dafydd G. Thomas, Daniel F. Hayes

Funding: National Cancer Institute grants CA129765 and CA101860; Breast Cancer Research Foundation; Komen for the Cure; Taubman Institute at the University of Michigan; Fashion Footwear Charitable Foundation of New York/QVC Presents Shoes-On-Sale; Stand Up to Cancer grant SU2C-AACR DT0409

Disclosure: Max Wicha has financial holdings in OncoMed Pharmaceuticals, receives support from Dompe and MedImmune and serves on the scientific advisory board of Veristem; Hasan Korkaya receives research support from MedImmune; Daniel Hayes has received research support from Pfizer, Novartis and Veridex and holds stock options for his role on the scientific advisory board for OncImmune.

Reference: Cancer Research, published online Feb. 26, 2013

Resources:

U-M Cancer AnswerLine, 800-865-1125
U-M Comprehensive Cancer Center, www.mcancer.org
Clinical trials at U-M, www.UMClinicalStudies.org/cancer

[StephN]

Thanks for posting this, Lani.

These finding will turn breast cancer treatment on its head if the new trials using Herceptin on HER2 negative patients pans out.

This will mean working out an effective length of Herceptin treatment for these other patients.

We need breakthroughs, and hopefully this will be a major one.

I am curious about the development of bone mets in those of us HER2 positive patients. Has this decreased with Herceptin use adjuvently? Which sites are now the most likely for mets to show?

This new info is starting to make my head spin!!!

[mamacze]

I tell you what Lani, when I see you post an update with a "THUMBS UP" AND 2 exclamation marks - then I know research is on to something.

Science must be turning a corner....LOVE your enthusiasm for knowledge and your joy in sharing it.

Kim (from CT)

[Debbie L.]

Thanks, as always, for keeping us up to date, Lani.

I don't know if it's me, or the write-up, or what -- but I was confused by the article. Cancer stem cells (which may like to hang out in bone) are not the same thing as bone mets, right?

Ever since they've been talking about Herceptin having efficacy for cancers that are not HER2 positive, I've been wondering several things. Do we know the answers to these questions, or who to ask?

1. Back when they were first starting with Herceptin, how did they decide what level of HER2 positivity was enough to be called positive? Was it in a petri dish, a mouse, a human? I know they determined initially that the level of HER2 positivity didn't predict response, so how did they arrive at a cut-off?

2. Were there never any clinical trials that compared HER2- and HER2+ responses to Herceptin? Not just the tumor response itself, but the survival and/or progression-free survival? If so, were those metastatic trials or adjuvant ones?

3. Could this (Herceptin gets the stem cells) explain the apparent cures (or at the least, the very longterm remissions) now being seen in some women with HER2+ stage IV cancers? Does it imply that this possibility of curing some stage IV disease may not be limited just to HER2+ cancers?

Debbie Laxague

[mamacze]

Hi Deb,I am not a whiz kid like our dear Lani, but I am thinking that a lot of your questions are answered in the book:


The Making of Herceptin. - (link below)
http://www.amazon.com/gp/aw/d/0812991842/ref=redir_mdp_mobile


Have you read it? It is a great read and informative. I am sure others will also have
More insight.


Kim (from CT)

[Joan M]

Lani, thanks for this post, and I know you always have a thing about bone marrow!

At SABCS I sat in on a session that I thought was intriguing and could potentially indicate that there are more of us out there than FISH can actually count. The researcher discussed how gene sequencing has shown that women who test negative for HER2 may actually be positive. This idea seems potentially related to this discussion. And bc is very heterogeneous, so perhaps this discovery is actually not surprising.

http://www.abstracts2view.com/sabcs1...u=SABCS12L_795

Joan

[Jackie07]

It makes sense ...

Breast cancer tumors are classified as Her2 positive when the overexpression is Her2+++. The Her2++ and Her2+ are classified as Her2 negative. However, those tumors still contain Her2 genes ... (just fewer copies of the genes in the samples being counted.)

http://her2support.org/her2-breast-c...tments?start=1

*********************
Here's the abstract of the article:

Cancer Res. 2013 Feb 26. [Epub ahead of print]
HER2 Drives Luminal Breast Cancer Stem Cells in the Absence of HER2 Amplification: Implications for Efficacy of Adjuvant Trastuzumab.

Ithimakin S, Day KC, Malik F, Zen Q, Dawsey SJ, Bersano-Begey TF, Quraishi AA, Ignatoski KW, Daignault S, Davis A, Hall CL, Palanisamy N, Heath AN, Tawakkol N, Luther TK, Clouthier SG, Chadwick WA, Day ML, Kleer CG, Thomas DG, Hayes DF, Korkaya H, Wicha MS.
Source

Authors' Affiliation: University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan.

Abstract

Although current breast cancer treatment guidelines limit the use of HER2-blocking agents to tumors with HER2 gene amplification, recent retrospective analyses suggest that a wider group of patients may benefit from this therapy. Using breast cancer cell lines, mouse xenograft models and matched human primary and metastatic tissues, we show that HER2 is selectively expressed in and regulates self-renewal of the cancer stem cell (CSC) population in estrogen receptor-positive (ER(+)), HER2(-) luminal breast cancers. Although trastuzumab had no effects on the growth of established luminal breast cancer mouse xenografts, administration after tumor inoculation blocked subsequent tumor growth. HER2 expression is increased in luminal tumors grown in mouse bone xenografts, as well as in bone metastases from patients with breast cancer as compared with matched primary tumors. Furthermore, this increase in HER2 protein expression was not due to gene amplification but rather was mediated by receptor activator of NF-κB (RANK)-ligand in the bone microenvironment. These studies suggest that the clinical efficacy of adjuvant trastuzumab may relate to the ability of this agent to target the CSC population in a process that does not require HER2 gene amplification. Furthermore, these studies support a CSC model in which maximal clinical benefit is achieved when CSC targeting agents are administered in the adjuvant setting. Cancer Res; 73(5); 1-11. ©2013 AACR.

['lizbeth]

Herceptin for lower expression of Her2 is already in a clinical trial:

http://www.clinicaltrials.gov/ct2/sh...2E75%22&rank=1

With an added bonus of a cancer vaccine. Way to go Dr. George Peoples & Genentech!!!

The awesome thing about this is you can have it at an early stage, in primary treatment.

Go Big H!