Zometa in adjuvant for younger women
 

Zometa saga continues. Here it is a "new standard of care"

http://www.washingtonpost.com/busine...GgO_story.html

Re: Zometa in adjuvant for younger women
 

Hi Rich,

Thank you for this article. I have a question for you. In the second to last paragraph it says: Other studies reported at the conference this week strengthen the view that Zometa works best with women with little estrogen. A consistent picture is emerging, Ravdin said.

Do you know what other study he is refering to? It sounds like they are determining that Zometa works well in ER- women. That would be superb. I would like to take a look at what he is refering to and address my oncologist on the matter. Have you any information on this?

Thanks as always..

Re: Zometa in adjuvant for younger women
 

This article is not exactly clear. Seems to be suggesting benefit is greater when circulating estrogen is minimal.

Here is an abstract from Gnant:

Breast Dis. 2011 Dec 5. [Epub ahead of print]
Intravenous bisphosphonates for breast cancer: Impact on patient outcomes and scientific concepts.

Gnant M.
Source

Medical University of Vienna, Vienna, Austria.

Abstract

Among women worldwide, breast cancer is the most common malignancy and a leading cause of death, accounting for approximately 6% of all cancer deaths globally. The predilection of breast cancer to metastasize to bone provides a strong rationale that antiresorptive agents such as bisphosphonates may have the potential to prevent disease recurrence. Bisphosphonates are established therapies for bone loss and for preventing skeletal-related events (SREs) from bone metastases. Moreover, intravenous nitrogen-containing bisphosphonates, such as zoledronic acid, have been shown to block multiple steps in tumor metastasis (e.g., angiogenesis, invasion, and adhesion). Recent clinical data from ABCSG-12, ZO-FAST, and AZURE demonstrate that zoledronic acid can significantly improve disease-free survival (DFS) in the adjuvant breast cancer setting in women who are naturally postmenopausal or have endocrine therapy-induced menopause. Furthermore, the ABCSG-12 trial showed durable disease-free survival benefits 2 years after completion of adjuvant therapy. These data suggest a potential role for zoledronic acid beyond bone health in breast cancer. Although it is too early to determine which patients are most likely to benefit from the anticancer potential of bisphosphonates, future research will help further guide therapy in this setting.

PMID:22142663 [PubMed - as supplied by publisher]


Ther Adv Med Oncol. 2011 Nov;3(6):293-301.
Zoledronic acid in breast cancer: latest findings and interpretations.

Gnant M.
Source

Department of Surgery, Comprehensive Cancer Center, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria.

Abstract

The intravenous nitrogen-containing bisphosphonate zoledronic acid has been shown to block multiple steps in tumor metastasis (e.g. angiogenesis, invasion, adhesion, proliferation) in preclinical and translational studies. Moreover, clinical data from the ABCSG-12 and ZO-FAST trials demonstrate significantly improved disease-free survival with zoledronic acid in the adjuvant breast cancer setting. In contrast to these two trials, recent interim results from the AZURE trial do not show a benefit from adding zoledronic acid to adjuvant therapy in the overall patient population. However, subset analyses of AZURE data show that zoledronic acid significantly improved overall survival in women who were more than 5 years postmenopausal or older than 60 years at baseline. Similarly, subset analyses of the ABCSG-12 trial data demonstrate greater benefits from zoledronic acid treatment in patients who theoretically would have achieved more complete ovarian suppression. These observations, together with the AZURE postmenopausal data, suggest that the endocrine environment may affect the potential anticancer activity of zoledronic acid. Indeed, current data support the possibility that zoledronic acid might be most effective for improving disease-free survival in the adjuvant breast cancer setting in women who are postmenopausal or have endocrine therapy-induced menopause.

PMID:22084643 [PubMed]
PMCID: PMC3210470
Free PMC Article

Re: Zometa in adjuvant for younger women
 

Hi Rich

thanks. this might be a stupid question, but what does this mean: endocrine therapy-induced menopause?

I am er/pr - and her2+

So is this not appropriate for me?

Thanks

Re: Zometa in adjuvant for younger women
 

After reading the free paper, I don't get the sense the current research addresses ER-/Her2+. situation one way or the other. Keep in mind they are talking about benefits of Zometa beyond the usual bone issues it is typically prescribed for. If you have bone mets or osteoporosis, Zometa or Denosumab would seem a given. Whether you would benefit in terms of recurrence or slowing progression seems harder to decipher.

Re: Zometa in adjuvant for younger women
 

Thanks Rich. I was hoping to add it to my arsenal and ask my onc to give it to me, though I appear to have some pretty terrific strong bones. And thus I am estrogen negative and it sound to me like there could have been another part to the azure trial. But after doing me reading with what you posted, i guess not.

Re: Zometa in adjuvant for younger women
 

On the other hand...might have an argument to take Zol preventatively based on.....

Mol Cancer Ther. 2011 May;10(5):732-41. Epub 2011 Mar 10.
CCN1, a candidate target for zoledronic acid treatment in breast cancer.

Espinoza I, Liu H, Busby R, Lupu R.

LINK

Source

Department of Medicine and Pathology, Division of Experimental Pathology, Mayo Clinic Cancer Center, Mayo Clinic, Rochester, MN 55905, USA.

Abstract

CCN1, also known as CYR61, is a survival and proangiogenic factor overexpressed in about 30% of invasive breast carcinomas, and particularly in triple-negative breast carcinomas (TNBC). CCN1 expression in breast cancer promotes tumorigenicity, metastasis, antihormone, and chemoresistance. TNBCs often develop bone metastasis, thus the vast majority of patients receive bisphosphonate treatment as a companion to chemotherapy. Zoledronic acid (ZOL), a bisphosphonate currently in use, inhibits bone resorption, prevents development of new osteolytic lesions induced by tumor metastasis, and has a direct antitumor activity in breast cancer cells and tumors. We have shown that ZOL inhibits anchorage independent growth as well as branching and morphogenesis in CCN1 overexpressing cells. However, the mechanism is not yet well understood. In this study, we investigate the effect of ZOL in breast cancer cells with high and undetectable CCN1 expression levels. We show that CCN1-expressing cells are more sensitive to ZOL, that ZOL induces downregulation of the CCN1 promoter activity and CCN1 protein expression in a dose-dependent manner, and that ZOL is associated with a decrease in phosphorylated Akt and translocation of FOXO3a, a negative regulator of CCN1 expression, to the nucleus. Deletion of the FOXO3a binding site in the CCN1 promoter prevents ZOL inhibition of the CCN1 promoter activity showing that FOXO3a transcriptional activation is necessary for ZOL to induce CCN1 inhibition. This study provides evidence that ZOL targets the proangiogenic factor (CCN1) through FOXO3a and reveals a new mechanism of ZOL action in breast cancer cells.

PMID:21393426 [PubMed - indexed for MEDLINE]

Re: Zometa in adjuvant for younger women
 

hi rich

thank you for the article. Problem is that i er/pr- and her2+. so not sure how that affects things. any ideas?

Re: Zometa in adjuvant for younger women
 

Well..helpful in ER+, helpful in ER-..and in her2 + mice:

J Cell Mol Med. 2010 Dec;14(12):2803-15. doi: 10.1111/j.1582-4934.2009.00926.x.
Zoledronic acid repolarizes tumour-associated macrophages and inhibits mammary carcinogenesis by targeting the mevalonate pathway.

Coscia M, Quaglino E, Iezzi M, Curcio C, Pantaleoni F, Riganti C, Holen I, Mönkkönen H, Boccadoro M, Forni G, Musiani P, Bosia A, Cavallo F, Massaia M.

http://www.ncbi.nlm.nih.gov/corehtml...x_FullText.gif


Source

Divisione di Ematologia dell'UniversitÃ* di Torino, Azienda Ospedaliero Universitaria S. Giovanni Battista di Torino, Torino, Italy. marta.coscia@unito.it

Abstract

It is unknown whether zoledronic acid (ZA) at clinically relevant doses is active against tumours not located in bone. Mice transgenic for the activated ErbB-2 oncogene were treated with a cumulative number of doses equivalent to that recommended in human beings. A significant increase in tumour-free and overall survival was observed in mice treated with ZA. At clinically compatible concentrations, ZA modulated the mevalonate pathway and affected protein prenylation in both tumour cells and macrophages. A marked reduction in the number of tumour-associated macrophages was paralleled by a significant decrease in tumour vascularization. The local production of vascular endothelial growth factor and interleukin-10 was drastically down-regulated in favour of interferon-γ production. Peritoneal macrophages and tumour-associated macrophages of ZA-treated mice recovered a full M1 antitumoral phenotype, as shown by nuclear translocation of nuclear factor kB, inducible nitric oxide synthase expression and nitric oxide production. These data indicate that clinically achievable doses of ZA inhibit spontaneous mammary cancerogenesis by targeting the local microenvironment, as shown by a decreased tumour vascularization, a reduced number of tumour-associated macrophages and their reverted polarization from M2 to M1 phenotype.
© 2009 The Authors Journal compilation © 2010 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

Re: Zometa in adjuvant for younger women
 

Rich

Thank you. Very informative. I see my onc in Feb. I am going to give it another whirl to ask for Zometa. Last time he rejected the idea without a bone issue and really didn't think insurance would go for it as my bone density scan was superb. But, hey, I am one year older now and just maybe that bone density is diminishing.

In any event, Happy Holidays to you and your Mom.

Re: Zometa in adjuvant for younger women
 

Interesting quote

Re: Zometa in adjuvant for younger women
 

It sounds like it is good for er+ women but also appears to work on the bone in a positive manner too. I would wonder what the downfall would be in using it on er- women, or would there even be one.

Re: Zometa in adjuvant for younger women
 

Looking at the various info above, seems to me the balance tips towards benefit. Downside probably eth usual additional kidney stress and the controversial osteonecrosis of jaw and fracture risk. All relative of course.
Regarding insurance, I think it's good practice to see how much a non-covered treatment actually costs before taking it off the table.

Re: Zometa in adjuvant for younger women
 

Rich

Yes, I think you are right in terms of checking the price out. My first hurdle though, to get my onc to prescribe it. He does not necessarily go by the book as he has me still on Herceptin now for an additional 8 months and I am not stage 4, but high risk stage 3, so.....I should certainly address it with him once again . I should get an idea of what an infusion for zometa costs so that if it was not covered, I could brace myself.

thank you for your guidance and being a sounding board for me. Merry Christmas!!