Recycling chemo drugs
 

Hi,
I have probably exhausted all the chemo regimens possible. In the last 5 yrs I have had AC,taxol, navelbine,Xeloda, Gemzaar and Cisplatin in combo with herceptin. Each chemo worked for sometime and I had to move on. I stopped Gemzaar and cisplatin because of toxicity. I have never been in remisssion, Is there any other chemo drug for me? Has anybody recycled and of the chemos already used and what was the response? I am thinking on the lines of Navelbine as the side effects werem tolerable and this drug lasted the long. I have also taken arimidex and femara and this does not seem to be working either. Any response from you would be appreciated.
Hugs,
Ragini

HI there, yep there are still chemo drugs left, Abraxane is one and in the taxane family but not as harmful and apparently better than Taxol or Taxotere. Most chemos can be used again after a break of about 12 months. Lolly always seem to go back to Navelbine and it works for her. I was on Aromasin (femara did nothing for me) for a while and enlarged glands disappeared and I didn't need radiation, but like you I never seem to into remission and I have been doing this since 1998, lymph glands and skin, now other breast, what are you treating this time?

Love & Hugs Lyn

Hi Ragini; As Lyn says, Abraxane has shown some good results, and some docs are combining Avastin, one of the new anti-angiogenisis drugs, with chemo/Herceptin combos.
I have been lucky to be able to go back to Navelbine for each of my recurrences; I just started it last month for the third time since 2001. My onc says the key is if a drug has provided a good response and if it's been over a year since the last use of that drug it may be effective again. Apparently the cells can "forget" the previous expousure. It's definitely worth exploring with your onc.
<3 Lolly

My doc took me off taxol, and carboplatin last November after 6 months of tx. Although my ca15-3 counts were down to 21, he thought I was progressing because I had pleural effusion.

I was put on Navlebine in Dec. 04 and counts climbed to 37.

We switched to gemsar in Feb. 05 and my last counts were 117 Oct. 05. My current doc wants to keep me on gemsar because my pleural effusion has lessened and bone mets are stable.

I've been on monthly zometa since Feb. 04 and herceptin since May 04, with the exception of a 3 month break from herceptin May-Aug. 05.

The first 2 months of the tax., carb., herc., and zom. tx. were rough, mostly achey flu-like symptoms. Mr tx. were 3 weeks on/1off. I never had neuropathy. My hair thinned and started to grow back after the 4th round. I'm thinking that maybe I could go back on the taxol, carbo., her., zom., combo if I run out of options.

This whole game is like a crapp shoot. I never did like to gamble.

Love and Blessings, Lu Ann.

Suggestions
 

Perhaps you could try Fulvestrant. It works via a totally different mechanism of action than tamoxifen or raloxifene (which block the estrogen receptor) or the AIs which block an enzyme which converts precursors to estrogen in post-menopausal women in an effort to "starve" the estrogen receptor of its ligand.
Unfortunately breast cancer cells have their OWN estrogen factory which uses one of THREE different enzymes to make estrogen and AIs only block one of these.

Fulvestrant binds to the estrogen receptor and then degrades it PERMANENTLY.

Unfortunately it does this not only on breast cancer cells, but on all cells containing estrogen receptors. Not a big problem for someone like you who has withstood multiple chemotherapy regimens.

I have posted in other threads at least four articles on the use of fulvestrant and will again if you let me know that you can't find them.

In addition, unless you have lost a lot of weight, it might be interesting to try Xenical, a weight loss medication made by Roche (who market Herceptin in Europe).

I don't think it could hurt unless you forgot to take your fat soluble vitamins (Vitamins A,D,E, and K) several hours before or after you took your Xenical
or if you got very dehydrated by diarrhea, which I am quite sure you could look out for and avoid. Also you would have to remember to take your flaxseed oil, evening primrose oil, and/or olive oil simultaneously ( with similar timing as that described above)

The article, based on in vitro experiments (in the lab, not in live humans) has shown strong synergy with Herceptin.

I am posting the reference:
: Menendez JA, Vellon L, Lupu R. Related Articles, Links
Antitumoral actions of the anti-obesity drug orlistat (XenicalTM) in breast cancer cells: blockade of cell cycle progression, promotion of apoptotic cell death and PEA3-mediated transcriptional repression of Her2/neu (erbB-2) oncogene.
Ann Oncol. 2005 Aug;16(8):1253-67. Epub 2005 May 3.
PMID: 15870086 [PubMed - in process]

I will post the abstract in my next post--I am always losing my efforts when attempting to switch between programs and cut and paste--

What could be better than fighting your breast cancer and becoming "svelt"
in one fell swoop! ( I hope the chemo has not left you overly thin preventing you from trying this option). This may be an unorthodox option, but if it might work....!

Hope these ideas help!

LANI

Here it is
 

1: Ann Oncol. 2005 Aug;16(8):1253-67. Epub 2005 May 3. Related Articles, Links

Antitumoral actions of the anti-obesity drug orlistat (XenicalTM) in breast cancer cells: blockade of cell cycle progression, promotion of apoptotic cell death and PEA3-mediated transcriptional repression of Her2/neu (erbB-2) oncogene.

Menendez JA, Vellon L, Lupu R.

Department of Medicine, Breast Cancer Translational Research Program, Evanston Northwestern Healthcare Research Institute, Evanston, IL, USA. jmenendez@enh.org

BACKGROUND: Orlistat (Xenicaltrade mark), a US Food and Drug Administration (FDA)-approved drug for bodyweight loss, has recently been demonstrated to exhibit antitumor properties towards prostate cancer cells by virtue of its ability to block the lipogenic activity of fatty acid synthase (FAS). FAS (oncogenic antigen-519) is up-regulated in about 50% of breast cancers, is an indicator of poor prognosis, and has recently been functionally associated with the Her2/neu (erbB-2) oncogene. MATERIALS AND METHODS: We assessed the antitumoral effects of orlistat against the human breast cancer cell line SK-Br3, an in vitro paradigm of FAS and Her2/neu overexpression in breast cancer. RESULTS: Cell cycle analyses revealed that micromolar concentrations of orlistat induced, in a time- and dose-dependent manner, significant changes in the distribution of cell populations including a complete loss of G2-M phase, S-phase accumulation and a concomitant increase in the emerging sub-G1 (apoptotic) cells. Poly (ADP-ribose) polymerase (PARP) cleavage, an early event required for cells committed to apoptosis, was more predominant in orlistat-treated G1 phase cells. When we characterized signaling molecules participating in the cellular events following orlistat-induced inhibition of FAS activity and preceded inhibition of breast cancer cell proliferation, a dramatic down-regulation of Her2/neu-coded p185(Her2/neu) oncoprotein was found in orlistat-treated SK-Br3 cells (>90% reduction). Interestingly, a significant accumulation of the DNA-binding protein PEA3, a member of the Ets transcription factor family that specifically targets a PEA3-binding motif present on the Her2/neu gene promoter and down-regulates its activity, was observed in orlistat-treated SK-Br3 cells. When a Luciferase reporter gene driven by the Her2/neu promoter was transiently transfected in SK-Br3 cells, orlistat exposure was found to dramatically repress the promoter activity of Her2/neu gene, whereas a Her2/neu promoter bearing a mutated binding DNA sequence was not subject to negative regulation by orlistat, thus demonstrating that the intact PEA3 binding site on the Her2/neu promoter is required for the orlistat-induced transcriptional repression of Her2/neu overexpression. RNA interference (RNAi)-mediated silencing of FAS gene expression similarly repressed Her2/neu gene expression in a PEA3-dependent manner, thus ruling out a role for non-FAS orlistat-mediated effects. When the combination of orlistat and the anti-Her2/neu antibody trastuzumab (Herceptintrade mark) in either concurrent (orlistat + trastuzumab) or sequential (orlistat --> trastuzumab; trastuzumab --> orlistat) schedules was tested for synergism, addition or antagonism using the combination index (CI) method of Chou-Talalay, co-exposure of orlistat and trastuzumab demonstrated strong synergistic effects (CI10-90 = 0.110-0.847), whereas sequential exposure to orlistat followed by trastuzumab (CI10-90 = 0.380-1.210) and trastuzumab followed by orlistat (CI10-90 = 0.605-1.278) mainly showed additive or antagonistic interactions. Indeed, orlistat-induced FAS inhibition synergistically promoted apoptotic cell death when concurrently combined with trastuzumab as determined by an ELISA for histone-associated DNA fragments. Importantly, the degree of FAS expression in a panel of human breast cancer cell lines was predictive of sensitivity to orlistat-induced anti-proliferative effects as determined by a MTT-based characterization of metabolically viable breast cancer cells. Moreover, hypersensitivity to orlistat-induced cytotoxicity was observed in MCF-7 breast cancer cells engineered to overexpress Her2/neu (MCF-7/Her2-18 cells), which exhibit a significant up-regulation of FAS expression and activity. CONCLUSIONS: These findings reveal that the development of more potent and/or bioavailable orlistat's variants targeting the lipogenic activity of FAS may open a novel therapeutic avenue for treating Her2/neu-overexpressing breast carcinomas.

PMID: 15870086

why recycle nonspecific treatment (chemo) when a smart bomb may be available?
 

Another new monoclonal antibody, bevacizumab has recently completed Phase III clinical trials for the treatment of locally advanced or metastatic breast cancer. Bevacizumab is a monoclonal antibody to vascular endothelial growth factor (VEGF) and acts to inhibit tumour angiogenesis (process of diverting nutrients to the tumour).

The randomised Phase III trial was coordinated by the Eastern Cooperative Oncology Group to compare the efficacy and safety of paclitaxel with or without bevacizumab as first line therapy in patients with locally advanced or metastatic breast cancer. 722 patients were recruited between December 2001 and May 2004 and were divided into two groups receiving either paclitaxel alone or the combination of paclitaxel and bevacizumab. The primary endpoint was progression-free survival (PFS).

The results were positive and indicated that the combination of paclitaxel and bevacizumab improved overall survival of patients than receiving paclitaxel alone (no final data available yet). Importantly the progression-free survival was improved with combination therapy, 10.97 months vs 6.11 months for paclitaxel alone. In addition, the investigators noted that combination therapy did not cause significant toxicity effects.

Speaking at ECCO 13, Dr Kathy Miller from the Indiana University Cancer Centre, USA, commented, "This is the first study to confirm the benefit of anti-angiogenic therapy in patients with breast cancer. Importantly, the improvements in response rate and progression-free survival were obtained with minimal increase in side effects. Given the benefit of bevacizumab in patients with metastatic disease, we look forward to initiating trials in the adjuvant setting."

http://www.toniclc.com
The above trial was for first-line therapy of MBC--you certainly do not fit that prescription.
I think Mark Pegram of UCLA is running a trial of Herceptin and Avastin. I am not
certain of the requirements to enter his trial, but there is a link on this website to UCLA clinical trials.

There may also be a trial of Ipimipazab ( will get the real name and add it to the post later) at the NIH and other sites, I believe. Again, I do not know the entry requirements.

Where are you located? How hormone positive was your tumor (not just the percentage positive, but a quantitative measurement of how MANY hormone receptors you have on your breast cancer cells)?

Lots of food for thought!

Good luck,
Lani

more on fulvestrant
 

The following are articles discussing the use of Faslodex (which is usually given as part of a “compassionate use” program and which is, by the way, given as an injection) and Herceptin:


1: Eur J Cancer. 2005 Oct 14; [Epub ahead of print]
Related Articles, Links
*
Fulvestrant ('Faslodex') in pre-treated patients with advanced breast cancer: A single-centre experience.

Steger GG, Bartsch R, Wenzel C, Pluschnig U, Hussian D, Sevelda U, Locker GJ, Gnant MF, Jakesz R, Zielinski CC.

Division of Oncology, Department of Internal Medicine I, Medical University of Vienna, 18-20 wahringer Gurtel, A-1090 Vienna, Austria.

Fulvestrant ('Faslodex') is a new oestrogen receptor (ER) antagonist with no agonist effects. This report describes the experience of a single centre including 126 postmenopausal women with advanced breast cancer (ABC) in a fulvestrant Compassionate Use Programme. All patients had previously received endocrine treatment for early or ABC. Patients received fulvestrant as first- (n=7), second- (n=51), third- (n=50) or fourth-line endocrine therapy (n=18) for ABC (median duration of treatment: 4 months [range 3-27(+) months], follow-up: 13 months [range 1-38(+) months]). Twelve patients had partial responses (PR) and 43 patients experienced stable disease (SD) 6 months (objective response rate: 9.5%; clinical benefit [CB] rate: 43.6%). Ten of 12 patients with a PR had HER2-negative tumours, and 9/12 had ER-positive and progesterone receptor (PgR)-positive disease (two patients had unknown HER2 status and one had unknown ER and PgR status). Nine of the 18 patients with HER2-positive tumours experienced CB with fulvestrant. Although CB rates were similar when fulvestrant was given as first- to fourth-line endocrine treatment, the proportion of those experiencing CB who had a PR appeared to decrease when fulvestrant was used later in the sequence. Fulvestrant was well tolerated; six patients experienced adverse events (all grade I/II). These data demonstrate that fulvestrant is an effective and well-tolerated therapy for patients with ABC progressing on prior therapies.

PMID: 16230005 [PubMed - as supplied by publisher]


1: Cancer Treat Rev. 2005;31 Suppl 2:S17-25. Epub 2005 Sep 29.
Related Articles, Links
*
Case studies of fulvestrant ('Faslodex') in postmenopausal women with advanced breast cancer.

Abram P, Maass N, Rea D, Simon SD, Steger GG.

Belvoir Park Hospital, Hospital Road, Belfast, Northern Ireland, UK.

Fulvestrant is a new oestrogen receptor (ER) antagonist that is licensed for the treatment of postmenopausal women with advanced breast cancer progressing following antioestrogen treatment and may also be effective in those progressing after non-steroidal aromatase inhibitors. The use of fulvestrant in a Compassionate Use Programme (CUP) in a 'real-life' setting has permitted its activity and tolerability profile in patients with different disease characteristics to be observed. Here, we present five case reports of fulvestrant use in postmenopausal women with advanced breast cancer progressing after prior endocrine therapy. Clinical experience from the CUP supports the published clinical trial data and suggests that fulvestrant is a valuable new treatment for postmenopausal women with advanced breast cancer, including those with visceral metastases and human epidermal growth factor receptor 2-positive disease.

PMID: 16199128 [PubMed - in process]


1: Cancer Treat Rev. 2005;31 Suppl 2:S10-6. Epub 2005 Sep 28.
Related Articles, Links
*
Fulvestrant ('Faslodex'): Clinical experience from the Compassionate Use Programme.

Steger GG, Gips M, Simon SD, Lluch A, Vinholes J, Kaufman B, Wardley A, Mauriac L.

Department of Internal Medicine I, Division of Oncology, Medical University of Vienna, 18-20 Wahringer Gurtel, A-1090 Vienna, Austria.

Fulvestrant ('Faslodex') is a new oestrogen receptor (ER) antagonist with no agonist effects that is licensed in the USA, Brazil, Europe and elsewhere for the treatment of advanced breast cancer (ABC) in postmenopausal women following progression on other endocrine agents. This report consolidates clinical experience from the 'Faslodex' Compassionate Use Programme, including a total of 339 patients treated at eight cancer centres. Patients received fulvestrant as first- (n=22), second- (n=125), third- (n=105), fourth- (n=58), fifth- (n=22) or sixth-line (n=5) hormonal treatment for ABC, with two patients receiving fulvestrant after more than six other endocrine therapies. Objective response was achieved by 40 patients and stable disease lasting 6 months by 92 patients, giving overall clinical benefit (CB) in 132/339 patients (39%). The CB rate decreased as fulvestrant was used later in the sequence of endocrine treatments, from 46% (10/22) with first-line fulvestrant to 27% (6/22) with fifth-line fulvestrant. Increased benefit was found in patients with tumours expressing both ER and progesterone receptor (PgR) compared with other combinations, although good activity was reported in patients expressing either ER or PgR as well as in tumours expressing human epidermal growth factor receptor 2. Fulvestrant was well tolerated; adverse events were noted in 18/339 patients (5%). These findings concur with data from the clinical-trial setting and further support the assertion that greater benefit is derived when fulvestrant is used early in the treatment sequence.

PMID: 16198057 [PubMed - in process]
*

1: Cancer Treat Rev. 2005;31 Suppl 2:S26-33. Epub 2005 Sep 28.
Related Articles, Links
*
The future of fulvestrant ('Faslodex').

Howell A.

CRUK Department of Medical Oncology, University of Manchester, Christie Hospital NHS Trust, Wilmslow Road, Manchester M20 4BX, UK.

Changes in clinical practice regarding favoured first-line and adjuvant treatments for postmenopausal women with advanced breast cancer (ABC) mean that it is becoming increasingly important to identify agents that are effective following aromatase inhibitor (AI) failure as well as tamoxifen failure. Fulvestrant ('Faslodex') is a new oestrogen receptor (ER) antagonist with no agonist effects that binds, blocks and degrades the ER. Fulvestrant is at least as effective as anastrozole following tamoxifen failure and also shows activity after progression on AIs. Its very good tolerability profile and novel mode of action, might offer potential for the use of fulvestrant in combination regimens, and there is also scope for investigating the use of loading and higher dose regimens in an attempt to further enhance efficacy. Here, the rationale and evidence for the efficacy of fulvestrant following AI failure and its combination with AIs and novel agents such as gefitinib and trastuzumab will be reviewed. The ongoing clinical development programme for fulvestrant will more fully the role of this valuable new agent in the treatment of postmenopausal ABC.

PMID: 16198056 [PubMed - in process]



1: Cancer Treat Rev. 2005;31 Suppl 2:S3-9. Epub 2005 Sep 28.
Related Articles, Links
*
Clinical development of fulvestrant ('Faslodex').

Howell A, Abram P.

CRUK Department of Medical Oncology, University of Manchester, Christie Hospital NHS Trust, Wilmslow Road, Manchester M20 4BX, UK.

This paper outlines the development of fulvestrant, the first in a new class of antioestrogen agents with no agonist effects, to be used for the treatment of hormone receptor-positive advanced breast cancer in postmenopausal women. The role of the oestrogen receptor in breast cancer growth and development and the evolution of pharmacological strategies to manipulate it are also discussed. Preclinical and clinical evidence for the efficacy of fulvestrant are also reviewed, along with the tolerability profile of this agent in relation to other endocrine therapies. Further research will define the role of this exciting new agent in the endocrine treatment of breast cancer.

PMID: 16198055 [PubMed - in process]

As you can see, these are hot off the press. AND IN FACT TWO MORE ARTICLES ON FULVESTRANT CAME in the last 2 WEEKs

Promised reference to Ixabepilone
 

Meeting: 2005 ASCO Annual Meeting
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Category: Breast Cancer
SubCategory: Other



Ixabepilone (BMS-247550) plus trastuzumab combination chemotherapy induces synergistic antitumor efficacy in HER2 dependent breast cancers and is accompanied by modulation of molecular response markers
Abstract No: 561
Author(s): F. Y. Lee, S. Castaneda, I. Inigo, D. Kan, B. Paul, M. Wen, C. Fairchild, E. Clark, H. Lee
Abstract: Background: Ixabepilone (Ixa) belongs to a class of structurally novel, microtubule-stabilizing agents that exert their antimitotic action by binding to tubulin with a binding mode that is distinct from the taxanes. Ixa is non-cross-resistant with the taxanes in preclinical human primary tumor models. In Phase II trials Ixa exhibited robust activities in breast cancers, with or without prior taxanes. Here we determined the activity of combined treatment with Ixa plus trastuzumab in preclinical breast cancer models, and identified potential pharmacogenomic correlates that predict responsiveness to the trastuzumab/Ixa combination Methods: BT474 and KPL-4 human breast cancer cell lines were used; both express the receptor tyrosine kinase HER2 and are dependent on HER2 signalling for growth. Effects of drug treatments in vitro were determined by a vital dye uptake assay (MTS) or a colony formation assay. In vivo, BT474 and KPL4 were grown as SC tumors in mice. Gene expression profiling was performed using the Affymetrix HG-U133 arrays Results: In cell culture, trastuzumab was cytostatic and inhibited the proliferation of BT474 and KPL-4 in a dose-dependent manner from 0.1-5 ?g/mL. Ixa in contrast was cytotoxic to both BT474 and KPL-4 cells with IC50s of 13.7 and 9.2 nM, respectively. Co-treatment of BT474 and KPL-4 cells with trastuzumab plus Ixa augmented the cytotoxic potency by more than 2-fold over Ixa alone (P<0.05). Treatment of KPL-4 tumored mice (n=8/group) with trastuzumab plus Ixa produced synergistic therapeutic effects. Trastuzumab treatment alone (10 mg/kg) produced no complete (CR) or partial (PR) response. Ixabepilone alone at its MTD (4 mg/kg) yielded 1 PR, 1 CR. The combined regimen produced 8 CR (4 of which were cured). Gene expression profiling revealed that trastuzumab treatment modulated the expression of several predictive marker genes, including the down-regulation of microtubule-associated proteins, tau Conclusions: Trastuzumab and Ixabepilone combination produced therapeutic synergism, which may be explained by changes in expression of predictive gene markers of drug response