Zometa news out of San Antonio....

What is Zometa exactly?  I am 38, finished chemo in March, and just got my period back in November.  (very surprised!)  

I've had 5 out of the 6 Zometa treatments. Is there discussion of extending tx beyond 3 years?

Athena... I can't wait to hear Gnant and Coleman speak again about their studies. How can Coleman take such a hard stance in light of Gnant's study? I think you are right about research. Someone needs to explain why these things are occurring on a molecular level. And we need to under stand the definition of menopause more clearly. Honestly, I was shocked to learn when they do studies they would arbitrarily refer to women under 50 as premenopausal and those over 50 as menopausal. When I read studies I never knew what applied to me because I was over 50, but was still menstruating. So how many women like me are included in statistics, when clearly we are in a gray area??

 Athena....Here's the controversy in a nutshell....I'm posting this so others can understand what we're talking about...hopefully.....

"At first glance, the AZURE trial results appear inconsistent with those of the ABCSG-12 trial, which showed significant DFS benefits (that have proven consistent over time) from adding zoledronic acid to adjuvant therapy in premenopausal women with breast cancer. However, ovarian ablation with goserelin therapy resulted in amenorrhea in all patients in ABCSG-12, and residual estrogen levels in these patients were probably similar to the levels in postmenopausal women [Gnant et al. 2009]. In contrast, premenopausal women in the AZURE study likely received only chemotherapy (according to local treatment practices), resulting in heterogeneity in hormonal status. Furthermore, a preplanned subgroup analysis of the ABCSG-12 data suggested that the DFS and survival benefits with adjuvant zoledronic acid found in the overall population may be greatest in the patients most likely to achieve a low-estrogen environment [Gnant et al. 2011a]. In analyses of subgroups defined by age, no significant DFS (HR = 0.91; log-rank p = 0.707) or overall survival (HR = 1.01; log-rank p = 0.982) benefits were observed with zoledronic acid therapy in women 40 years of age or younger (n = 413). However, adding zoledronic acid to adjuvant endocrine therapy significantly reduced the risk of DFS events by 34% (HR = 0.66; log-rank p = 0.013) and reduced the risk of death by 49% (HR = 0.51; log-rank p = 0.018) for women older than 40 years (n = 1390) [Gnant et al. 2011a].

These data are consistent with the AZURE subgroup analyses in which significant DFS and overall survival benefits were observed in the postmenopausal patient population, suggesting that adjuvant zoledronic acid may have anticancer activity in patients with low estrogen levels. Although these trials did not measure estrogen levels, hormonal status can be assumed on the basis of the type of adjuvant endocrine therapy received, age, and menopausal status. Indeed, the subset of patients in ABCSG-12 who were older than 40 years at baseline may have achieved more complete estrogen suppression than younger patients. Case reports of pregnancies or resumed menses during suppression of ovarian function with an LHRH analogue in very young premenopausal women with breast cancer suggest the potential for incomplete ablation of circulating estrogen levels in this population [Jimenez- Gordo et al. 2000; Uncu et al. 1996]. Furthermore, chemotherapy-induced amenorrhea has been reported to occur less frequently in women younger than 40 compared with those older than 40 years [Gnant, 2009; Del Mastro et al. 1997], indicating that age markedly influences ovarian function during cancer therapy. Consequently, women more than 40 years of age in the ABCSG-12 trial presumably had more complete suppression of ovarian function compared with women 40 years of age or younger.

The findings of the AZURE and ABCSG-12 subset analyses suggest that effects of estrogen on the bone microenvironment may play a substantial role in determining who may benefit most from adjuvant zoledronic acid therapy. Ongoing analyses of the ZO-FAST trial database may offer additional insights into the possible relationship between menopausal status (established compared with newly menopausal) and improved disease outcomes with zoledronic acid. Overall, current clinical data suggest that both estrogen deprivation and reduction of bone turnoverderived growth factors in the bone marrow microenvironment are needed for sufficient suppression of dormant micrometastases in patients with early stage, hormone-receptor-positive breast cancer."

Here's more about AZURE and Coleman:

N Engl J Med. 2011 Oct 13;365(15):1396-405. Epub  2011 Sep 25.

Breast-cancer adjuvant therapy with zoledronic acid.

Collaborators  (260)

Schwarz M, White S, Kannourakis G, Underhill C, Chirgwin J, Della-Fiorentina S, Beale P, Koczwara B, Thomson J, Jennens R, Bell R, Della-Fiorentina S, Chirgwin J, Boyle F, Chipman M, White M, Francis P, Lewis C, Patterson K, Chern B, De Boer R, Baron-Hay S, Boyle F, Bayliss E, Beith J, White K, Snyder R, Abdi E, De Boer R, McDermott R, O'Reilly S, Keane M, Keane M, McCaffrey J, McCaffrey J, Bulger K, Gupta R, O'Reilly S, Kennedy J, Crown J, Coelho JL, Aramendia JM, Lluch A, Andrés R, Mayordomo JI, Catalán JG, Ciruelos EM, Gómez P, Vázquez F, Arnedos M, Gil JM, Brunet J, Colomer R, Chen ST, Cheng TW, Sunpaweravong P, Pataranutraporn P, Hutcheon AW, Todd R, Ahmed A, Moody AM, Wilson C, Crawford M, Irwin C, Stein R, Bridgewater C, Lee C, Ella W, Trask C, Fraser G, Ritchie D, McAleer JJ, Hardman PD, Wadd N, Bradley C, Price C, Chaturvedi A, Spensley S, Lowdell C, Owen R, Din O, Purohit, Armstrong A, Wardley A, Spooner D, O'Reilly S, Slater A, Sadler G, Dodwell D, Corder A, Lumsden G, Ritchie D, Hardman PD, Woodings P, Kelly S, Kumar S, Butt M, Mack P, Ramakrishnan S, Evans T, Kunkler, Ring A, Robinson A, Murray P, Canney P, Fraser G, Fraser J, Cawthorn S, Shere M, Fresco L, Reinecke L, Worlding J, Bishop J, Ellis P, Harries M, Dunn MG, Yosef H, Clark P, O'Reilly S, Dodwell D, Joseph J, Slater S, Joffe J, Hardman PD, Churn M, Sims E, Ahmed S, Chan S, Hornbuckle J, Khan S, Ellis P, Rigg A, Dodwell D, Murray E, Ah-See ML, Makris A, Barraclough L, Hunter R, Jain P, Jyothirmayi R, Fernando I, Stein R, Makris A, Churn M, Sumpter K, Verrill M, Dewar J, Thompson A, Harnett A, Napier M, Walls J, Newby J, Branson A, Macmillan C, Chan S, Hornbuckle J, McAdam K, Murray E, Kumar S, Roberts F, Mukherjee S, Rea D, Poole C, Ahmad A, Bowman A, Chakraborti P, Sims E, Whillis D, Hatton M, Wilson G, Barrett J, Bishop H, Winstanley J, Wheatley DA, Hong A, Jones A, Gaffney, Mohammed H, Jones R, Morgan C, Waters S, Hall V, Murray N, Raj S, O'Reilly S, Smith IE, Yarnold J, Agrawal R, Houston S, Bloomfield D, Allerton R, Copson E, Gregory K, Harvey M, Spooner D, Sreenivasan T, Upadhyay S, Venkitaraman R, Bertelli G, Leonard R, Stockdale A, Tsalic M, Bozzino JM, Mazdai G, Weber B, Simmonds P, Robinson A, Hyatt, Gallagher C, Assersohn L, Mansi J, Palmeri C, Perren T, Yuille F, Morgan, Patel A, Gendy R, Alcock C, Chatterjee S, Mallick U, Reinecke L, Rich A, Wright K, Patel A, Manifold I, Purohit K, Bailey N, Donnelly P, Goodman A, Whipp L, O'Hagan J, Schofield P, Rathmell AJ, Taylor W, Brunt AM, Hennessy C, Barrett-Lee P, Grieve RJ, Walji N, Jones DA, Grieve RJ, Moody AM, Cameron D, Green M, Bowman A, George D, Tomlinson MJ, Coleman R, Ashford R, Hall M, Cottrill C, Jones A, Hicks J, Mackay H, Lannigan A, Waterstone A, Bundred N, Mitra S, Dodwell D, Bishop J.

Source

Academic Unit of Clinical Oncology, Weston Park Hospital, University of Sheffield, United Kingdom. r.e.coleman@sheffield.ac.uk

Abstract

BACKGROUND:

Data suggest that the adjuvant use of bisphosphonates reduces rates of recurrence and death in patients with early-stage breast cancer. We conducted a study to determine whether treatment with zoledronic acid, in addition to standard adjuvant therapy, would improve disease outcomes in such patients.

METHODS:

In this open-label phase 3 study, we randomly assigned 3360 patients to receive standard adjuvant systemic therapy either with or without zoledronic acid. The zoledronic acid was administered every 3 to 4 weeks for 6 doses and then every 3 to 6 months to complete 5 years of treatment. The primary end point of the study was disease-free survival. A second interim analysis revealed that a prespecified boundary for lack of benefit had been crossed.

RESULTS:

At a median follow-up of 59 months, there was no significant between-group difference in the primary end point, with a rate of disease-free survival of 77% in each group (adjusted hazard ratio in the zoledronic acid group, 0.98; 95% confidence interval [CI], 0.85 to 1.13; P=0.79). Disease recurrence or death occurred in 377 patients in the zoledronic acid group and 375 of those in the control group. The numbers of deaths--243 in the zoledronic acid group and 276 in the control group--were also similar, resulting in rates of overall survival of 85.4% in the zoledronic acid group and 83.1% in the control group (adjusted hazard ratio, 0.85; 95% CI, 0.72 to 1.01; P=0.07). In the zoledronic acid group, there were 17 confirmed cases of osteonecrosis of the jaw (cumulative incidence, 1.1%; 95% CI, 0.6 to 1.7; P<0.001) and 9 suspected cases; there were no cases in the control group. Rates of other adverse effects were similar in the two study groups.

CONCLUSIONS:

These findings do not support the routine use of zoledronic acid in the adjuvant management of breast cancer. (Funded by Novartis Pharmaceuticals and the National Cancer Research Network; AZURE Current Controlled Trials number, ISRCTN79831382.).

Could this be any more confusing? I just turned 39, have had chemo, have had exactly one menstrual period since ending chemo, about to start tamox, am Stage IIIa. Push Onc for Zometa or not? I seem to be right on the cusp of everything...

Maybe a dumb question, but does anyone give any indication WHY maintaining bone density/integrity/(what the zometa does) helps prevent recurrence?  I can make the connection of suppressing ovaries to decrease estrogen, which also can decrease bone density...but does previous research give any hints why these results?

I'm also 39, pre-menopausal, had chemo, and got my period back.  I thought I was so advanced because I'm starting zoladex injections...guess there's a lot more to it.

Maxine, I believe the theory is that most cancer spread occurs when stray cancer cells are able to land in the bone marrow where they find a conducive environment to grow. The cancer cells develop characteristics there which allow them to further invade the body spreading not only to bone but to other organs as well. Bone mets is very common as a first site of spread especially in breast cancer and because Zometa changes the normal bone environment it alters the ability of cancer cells to easily take hold and further spread from the bone.  At least that is what I have heard speculated by various medical oncologists.  So the hope was that not only could Zometa possibly reduce the chances of bone mets occuring, by doing so it might also reduce the chances of additional spread to other parts of the body. 

There is a normal cycle of bone cell growth and death in healthy bones.  This cycle is disrupted by Zometa so this is why bones become denser but also persons on Zometa have decreased ability to heal from a bone injury.  This disruption of that normal bone cycle is why they believe Zometa may prevent cancer from being able to "take hold" and fully complete the metastatic process from the bone marrow.

This is my simplistic understanding of the possible reason Zometa reduces recurrences.   I do not know if there is any research data to confirm the actual mechanism for this to occur.  I'm sure others more knowledgeable of the research data may offer further explanation.

according to the study, they examined Zometa WITH O/S.  That gave you the most bang for your buck...

It's an infusion, twice a year for three years and you can have it during your Zoladex injection appointment.

Voracious Reader -

Thank you for cluing me in on the heart risks. Since I already developed atrial fibrillation from Adriamycin, don't think this would be a good drug for me. Exciting news for lots of women though! 

re: Zometa and A-Fib 

Beeb - this study was a little bit different, Zometa is not oral - though it may be the same idea.

so here is my theory on all of this - if we knew what DID work for everyone - we would have a cure.  We know that chemo is effective for some, not all and the same is true for antihormonals, herceptin and zometa, etc - I say - I'll take it all!  

statistics are based a group of women but I am one women with two kids - on the off chance I am one of the people that dose dense chemo didnt work for I'll have zometa, on the off chance the anti-hormonals didnt work for me, I will take a hysterectomy.  

give me everything you got - and then some - in 20 years hopefully I will be around when they say the cure was chocolate all along!

BlueCowGirl - yes, you are correct.  It is an individual choice for us all - ironically, I turned down avastin when I was diagnosed.  Just didnt feel it was right for me.  But I begged for Zometa - probably a good thing since after having it for 2 years they did my first dexa scan and found I have osteopenia.  So even with tamoxifen, running daily, strenght training and zometa it either developed or it was worse before. So I am going to be on Zometa for life - or something similar so that I dont break right down the middle.

Hysterectomy - made the choice because I truly believe that my cancer was caused by something very wrong in my hormonal world. My breasts hurt constantly, I was getting my period 2 times a month and had horrible pms.  There is a heart risk but I have very low blood pressure and am a runner and dont eat meat or much fat so I hope that I balance that out

For every action there is an equal and opposite reaction - In my case, hopefully no cancer.

Beeb.. Gnant's Zometa study regarding premenopausal women... All of the women received O/S and EVERYONE benefited. It's just that the over 40 women benefited more. That press release was crafted poorly.

None of the women in Gnant's study had chemo. They also were stages 1 or 2.