Taxol does not for most bc, today's headline

[CLTann]

do any of you see this headline this morning, Oct 11, 2007?

[Lani]

I have not seen any headlines yet, but 24 hours ago I came across the following. I did not post it, as it is in a journal that I cannot access the entire article and it seemed it might alarm people without any back up material with which to evaluate whether the study was in fact valid.

here is the abstract I found--don't know if this is what you are referring to:

Breast. 2007 Oct 6; [Epub ahead of print]
Benefit from adjuvant taxanes and endocrine responsiveness in breast cancer.

Martin M, Mackey J, Vogel C.
Servicio de OncologÃ*a Médica, Hospital Universitario San Carlos, 28040 Madrid, Spain.
Several phase III trials have been coincident in showing a benefit with adjuvant taxanes in node-positive breast cancer (BC). These trials provide level I evidence of the efficacy of these drugs. The absolute 5-year DFS gain obtained with the taxane-containing regimens in the positive studies ranged from 4% to 7%. However, the regimens including taxanes are more toxic than the conventional anthracyline-containing combinations. Therefore, the pre-treatment identification of the small proportion of patients who actually benefit from taxanes is of major importance. Several attempts have been made to identify the biological peculiarities of the BC patients who benefit most with taxanes, largely based on retrospective subset analyses. Hormone receptor (HR) status, one of the critical determinants of BC biology, had been suggested to be a factor modulating response to adjuvant chemotherapy in general and taxanes in particular. Unfortunately, none of the first-generation adjuvant taxane trials was designed to address the question of the differential efficacy of taxanes in the specific subgroups of HR positive and HR negative BC patients. Indirect (retrospective, unplanned) analysis suggest that the magnitude of benefit from taxanes is somewhat more in the HR negative subset, but the benefit also exists, and is clinically relevant, in patients with HR positive cancers. Therefore, the predictive value of HR status in the selection of patients for adjuvant taxane therapy is low. The predictive value of HER2 status in addition to HR status to select patients for the same purpose remains controversial.

[Lani]

it shows taxanes ARE helpful in those who are her2+ Here it is:


Oct. 10, 2007, 11:33PM
Study gives hope of narrowing breast cancer chemo
Finding could help refine therapy

By TODD ACKERMAN
Copyright 2007 Houston Chronicle


SURPRISING RESEARCH ON TAXOL
The widely used chemotherapy drug Taxol does not work for the most common form of breast cancer and helps far fewer patients than has been believed, surprising new research suggests. If further study bears this out, more than 20,000 women each year in the United States alone might be spared the side effects of this drug or similar ones without significantly raising the risk their cancer will return. That would be roughly half of all breast cancer patients who get chemo now. In the study, Taxol did the most good for women who had overactive HER-2 genes — the target of the newer breast cancer drug Herceptin. These women were about 40 percent less likely to have a recurrence if they received Taxol. Conversely, Taxol did not significantly help women whose tumors were HER-2 negative and were being helped to grow by estrogen. This is the most common form of the disease.
Researchers have learned how to target chemotherapy for breast cancer to only those women most likely to benefit, an advance that should spare roughly 20,000 women annually from unnecessary side effects.

The study by the University of Texas M.D. Anderson Cancer Center and other institutions found that women with the most common form of breast cancer didn't gain any benefit from the widely prescribed drug Taxol.

But those with overactive HER-2 genes — about 15 percent to 20 percent of women with breast cancer — were helped.

"We hope this discovery one day marks an end to the one-size-fits-all approach of chemotherapy," said Dr. Daniel Hayes, clinical director of the University of Michigan Comprehensive Cancer Center's breast oncology program and the study's lead author.

"Historically, treatment has been based on whether a woman is at high risk of the breast cancer recurring, without any idea of whether she'd benefit from additional therapy. In the future, we hope to focus chemotherapy on just those patients it's most likely to help."

The researchers are not recommending any changes in practice yet. They said more studies need to be conducted to confirm the finding.

The study appears in today's issue of the New England Journal of Medicine.

Following surgery, doctors typically prescribe more chemotherapy drugs if the cancer is in the lymph nodes and likely to spread. Taxol, also known as paclitaxel, is one of a class of drugs called taxanes added after four cycles of chemotherapy drugs Adriamycin and Cytoxan.

Previous research showed the cocktail produced a small but statistically significant benefit, and the result changed clinical practice. Taxol's use rose dramatically starting early this century.

But Taxol causes significant side effects, particularly numbness and tingling in the hands and feet. Eighteen percent of the women in the original study had the problem months and even years after taking Taxol.


Who doesn't need it?

"The most important question in invasive breast cancer is who does and doesn't need chemotherapy?" said M.D. Anderson biostatistics chief Don Berry.
"We're good at adding therapies to a patient's regimen, but not as confident subtracting them. This study suggests we'll be able to limit therapies to those who'll truly benefit from them, and other patients can be spared their side effects without loss of benefit."

The new study involved retrieving frozen tissue samples from 1,500 of the original study participants and conducting genetic tests to better identify their types of cancer. The researchers found a huge difference in who responded to Taxol.

Those with HER-2 genes, the target of the newer breast cancer drug Herceptin, had a 41 percent lower rate of having their cancer return. Those whose tumors were HER-2 negative and were being helped to grow by estrogen, the most common category of the disease, did not get added benefits.

In an accompanying editorial in the journal, Dr. Ann Moore, of Weill Medical College of Cornell University, joined Hayes in predicting the days of "one size fits all" therapy for breast cancer patients is coming to an end.

"Oncologists have a responsibility to their patients to be aware of this report," she wrote.

M.D. Anderson officials said they will wait for confirmation of the study results to change their patient regimens. Berry, for instance, is reanalyzing an earlier Taxol study.

In recent years, doctors increasingly have been able to target newer drugs, such as tamoxifen, aromatase inhibitors and Herceptin, for certain kinds of breast cancer patients. But such targeting had eluded chemotherapy.

todd.ackerman@chron.com

[Lani]

EDITORIAL

Can Biology Trump Anatomy? Do All Node-Positive Patients With Breast Cancer Need Chemotherapy?

N. Lynn Henry, Daniel F. Hayes
Department of Internal Medicine; Breast Oncology Program, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI

Mortality resulting from breast cancer is decreasing in the Western world,1 in part because of adjuvant chemotherapy,2 and most treatment guidelines for women with lymph node-positive disease dictate the use of adjuvant chemotherapy.3 Therefore in developed countries almost all such patients, regardless of the biology of their cancer, receive toxic and expensive chemotherapy. In this era of molecular medicine, one wonders whether we couldn't use biologic factors to be more selective for our therapies.

Perhaps the most clinically important biologic factor in all of oncology is the estrogen receptor (ER). ER expression is a powerful positive predictive factor for antiestrogen therapy.4 However, ER expression may also be a negative predictive factor for chemotherapy. This effect was first proposed more than 30 years ago,5 and a recent review of Cancer and Leukemia Group B trials suggested that the benefits of chemotherapy are substantially less in node-positive women with ER-positive cancers than in those with ER-negative cancers.6 These results raise a derivative to the question posed in the title of this editorial: Can ER expression be used to individualize chemotherapy as well as hormone therapy?

Historically, subset analyses have suggested that the benefits of adjuvant chemotherapy are greater in women under 50, and might be negligible in older patients.7 This age-specific observation is curious. Some have speculated that it can be completely explained by ER expression.8 Incidence of ER-positive breast cancer differs by age. Approximately 60% of women under the age of 50 have ER-positive disease, compared with 80% of those over the age of 50.9 If chemotherapy is more effective against ER-negative than ER positive tumors, then a greater proportion of younger women overall would benefit from its direct cytotoxic effects.6 In addition, those premenopausal women with ER-positive disease appear to gain secondary benefit from chemotherapy-induced ovarian failure, which does not occur in postmenopausal women.

These considerations suggest that ER might be useful not only to select hormone therapy but also to avoid chemotherapy, and multiple clinical trials have evaluated hormone therapy versus chemotherapy in ER-positive premenopausal women.10-14 In this issue of the Journal of Clinical Oncology, Schmid et al15 describe one such study, designated the Takeda Adjuvant Breast Cancer Study with Leuprorelin Acetate (TABLE) trial. Their results suggest that 2 years of adjuvant depot luteinizing hormone–releasing hormone agonist therapy is at least as or even more effective than 6 months of adjuvant chemotherapy (cyclophosphamide, methotrexate, and fluorouracil [CMF]). Disease-free survival was statistically similar in the two arms, whereas overall survival was, if anything, superior for the group that received endocrine treatment.

Strengths of this study include a homogenous patient population and exclusion of patients with known ER-negative breast tumors, and it is consistent with other, similarly designed trials of endocrine therapy versus chemotherapy in ER-positive women.10-13 However, the sample size is small and the follow-up is limited. Furthermore, the trialists used intravenous CMF chemotherapy, which may be inferior to classical oral CMF.16,17 Additionally, this trial did not account for effects from another important biologic factor, HER2. For example, in several studies, CMF chemotherapy has been shown, in HER2-positive patients, to be inferior to anthracycline-containing regimens.18,19 Thus, one might expect the HER2-positive subset, which may represent up to 20% of the ER-positive population, to do substantially better with more modern chemotherapy than CMF, regardless of how it is delivered. More recently, taxanes have been shown to add to anthracycline-based therapy, and these regimens may also be even more efficacious in patients with HER2-overexpressing tumors.20,21 These observations suggest that the results of the TABLE trial might not have been equivalent if the investigators had used more effective chemotherapy.

Taken together, these results are consistent with the hypothesis that ER expression might be used to avoid chemotherapy, but are they sufficient to change our guidelines and clinical practice for premenopausal women with node-positive breast cancer? We believe that the trial designs of the TABLE and other studies asked the wrong question. We propose that the issue is not chemotherapy alone versus hormone therapy alone. Rather, it seems that in ER-positive breast cancer, the more appropriate question is chemotherapy plus hormone therapy versus hormone therapy alone. We have no doubt that hormone therapy is effective in ER-positive patients and that all ER-positive patients should receive some form of endocrine therapy. The issue is whether all ER-positive patients with a poor prognosis based on an anatomic factor, such as positive lymph nodes, should be treated with chemotherapy in addition to endocrine therapy.

Few data are available to address this question. In the Southwest Oncology Group (SWOG) protocol 8814 (Intergroup 0100 trial), node-positive postmenopausal patients were randomly assigned to tamoxifen alone, tamoxifen plus concomitant CAF (cyclophosphamide, doxorubicin, fluorouracil), or CAF followed by tamoxifen.22 Patients treated with chemotherapy plus tamoxifen had a small but statistically significantly superior disease-free and overall survival compared with those treated with tamoxifen alone. In the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-20 trial, 2,306 node-negative patients were randomly assigned to tamoxifen alone or to CMF or MF plus concomitant and subsequent tamoxifen.23 Those patients randomly assigned to chemotherapy, especially those younger than 50 years of age, had superior disease-free and overall survival compared with those treated with tamoxifen alone. Conversely, results from a highly underpowered trial conducted by the International Breast Cancer Study Group (IBCSG; trial 11-93) failed to demonstrate a survival benefit for 174 premenopausal node-positive women randomly assigned to chemotherapy (doxorubicin and cyclophosphamide) plus goserelin and tamoxifen versus goserelin and tamoxifen alone.24

Overall, these results suggest that chemotherapy adds some additional benefit beyond endocrine therapy alone for the ER-positive, node-positive population, regardless of age. However, for the entire population, these benefits are small, and we agree with the TABLE investigators that most ER-positive patients might be treated with hormone therapy alone to avoid the toxicity of chemotherapy. Nonetheless, there appears to be a small subset of patients that do benefit from chemotherapy. Unfortunately, we are unable to identify these patients at present. Recent studies have suggested that additional biologic factors such as HER2 and/or measures of proliferation might identify patients with ER-positive cancers that actually behave more like ER-negative cancer in regard to hormone therapy resistance and/or chemotherapy sensitivity. Several recent studies have suggested that multiplex gene expression assays can distinguish patients with low- and high-risk cancers.25 For example, in node-negative, ER-positive patients, the OncotypeDX assay (Genomic Health Inc, Redwood City, CA) has been shown in retrospective studies to identify such patients who not only have a very low risk of recurrence on tamoxifen, but whose cancers also appear to be relatively resistant to chemotherapy.26,27 In at least one study, patients with a high recurrence score not only appear to have a high risk of recurrence, but also seem to have cancers that are very sensitive to the beneficial effects of chemotherapy.27 The North American Breast Cancer Intergroup is currently conducting a prospective randomized controlled trial, designated the TailorRx trial, to validate these exciting observations in node-negative women.

TailorRx is a bold and important clinical trial designed to use this new technology to individualize treatment in anatomically low-risk patients. We propose that it is now time to use our understanding of biology to similarly readdress the need for chemotherapy in women who are felt to have "high-risk" cancer on the basis of anatomic features (TNM staging). The era of individualized therapy for breast cancer, which really started with the understanding of ER biology in the 1970s and took a step forward with the entry of HER2 in the 1990s, is now ready to take another great leap with a new set of molecularly driven prospective randomized controlled trials.

[Mary Jo]

Yes, I did read this article. And yes, it did say that taxol was beneficial for her2 positive, hormone negatives. It went on to say that for her2 positive cancer's recurrence was 40 percent less likely for those who received taxol.
Thanks for sharing.

Mary Jo

[dhealey]

What about those of us who are her2 pos and ER/PR pos? The regimine they talk about is what I was on. Confusing to me beause it will help if her2 pos, but does the ER/PR pos trump that? They are making headway, but I think we still have a long way to go.

[Sheila]

Gee, This is good news for me since I am darn near living on the stuff...would hate for them to be pouring gallons of this fine stuff in my veins and it not be the right stuff!
I am Her2+++ Er- PR-

[Jean]

Lani, once again thank you for your research and detailed information.
Just this morning on NBC (East coast time 7:15) there was a NYU onc.
on air, speaking about the different types of bc and the chemo trt that
would be best to choose for a patients type of cancer. We are now
beginning to hear more of this ...the shoe does not fit all feet.
I am happy to hear this information being supplied to the public.
Just a short time ago (4/05 when I was dx) discussions on different
subtypes were not what the onc. were discussing with their patients.
I had to reach out to this wonderful site to truly learn the details
of HER2...

We as HER2 bc patients must keep ourselves updated and informed
and not believe the "the sky is falling upon our heads".

Enjoy the Day!
God Bless
Jean

[Becky]

I saw the original study given by the researcher at ASCO 2006. Both the original presentation and the published results (read all the articles published on the board right now including the one on Articles of Interest posted by Mgarr (Mary)). Taxol gives benefit for all Her2+ patients REGARDLESS of hormone status. In the actual presentation of results, the difference in benefit between Her2+ patients that are hormone negative versus hormone positive was not significant, therefore the results of benefit are the same.

Because of seeing this paper firsthand, when Stage 1 women ask whether they should include taxol (as in the past many stage 1 women only receive 4 AC treatments followed by Herceptin), I have posted this original study stating, if given a choice, take the taxol too - it is the KEY ingredient.

Secondly - I believe this is why the TCH treatment works just as well as the AC followed by TH. It is the Taxol that is the more important chemo! More true research needs to be done to confirm this or more time needs to pass on current studies and long term results but I believe they will find that taxanes are key for Her2+ disease (regardless of hormone status) and for triple negative disease.

[tsonmez]

Dear members: I have read the article itself in New England Journal of Medicine and as Becky already indicated, Taxol very significantly benefitted HER2+ patients regardless of hormone status. (Recurrance reduced by 41% for Her2+ patients.) Patients were recruited between 1991 and 1995, and hence herceptin was not available to any of these patients.
So exactly how much taxol benefits in the presence of herceptin is unknown but intuitively one would expect it to be very significant. (This is at least what I hope since my wife received 16 weeks of neoadjuvant taxol herceptin with complete clinical but not pathological response).

The same study also showed that higher dose of doxorubicin (adrymycin) than standard did not have any additional benefit.


I want to indicate that I have been following this group for the last eight months and we benefitted enormously. I am emazed how much useful info is available here. We adjusted our lifestyle, diet habits etc. based on what I learned from this website. And I feel we were able to ask much better questions to my wife's oncologists because of what we learned from you. Just wanted to let you know that a lot more people benefit from the discussions here than you might realize.

Best regards....

Tayfun

[lilyecuadorian]

thanks Becky for the explanation ...I understand much better ....I glad that is Ok for both positive and negative ...

[Karen W]

Thanks for the info Lani and Becky.

Karen

[Lani]

This study was only done in node positive
patients (interestingly because chemotherapy was recommended in the US to all invasive bc patients whether node negative or node positive)

I think that is why they are quoting 20,000 as the number of women who might avoid chemo--had they done the study includiing node negative patients and IF they got the same result, there would probably be four to five times as many women angry this morning.

Was that purposeful? Or did they just assume that the node negatives would be covered by the TAILOR RX study out in a few years (which really does not answer the same question as it uses a methodology/algorith derived on tamoxifen treated patients who received chemotherapy regimens which I don't believe are required to be identical).

So when repeating the study, be sure you know it counts only for node positive patients...but as node negative patients are considered less likely to recur than node positive patients (at least when looking at breast cancer as a whole vs subsets of it) it would seem that the absolute (vs relative) benefits/of lack of benefits of taxanes would be even smaller

How about now adding serum her2neu testing, bone marrow biopsies and/or Circulating tumor cell testing to the ER and her2 testing(and hopefully eventually gene expression profiling) to even better delineate who is most likely to recur/metastasize, thus treating those most likely to benefit and avoiding over treatment of those not likely to benefit (and more likely to have lifelong problems from the treatment)

Getting off my soapbox...

Hope this helped

[AlaskaAngel]

Lani and Becky,

Thanks very much for understanding so well how everyone feels about this and that it is a topic high on the anxiety scale for everyone.

As one of the Lost Regiment of HER2's (those with tumors that were either under 2 cm or node-negative and ineligible for the Herceptin study), to learn that HR-responsive HER2's were also prohibited from benefitting from the TAILOR-X study has been frustrating to say the least. They cannot get good answers to questions about node-negative HER2's if they keep excluding us.

All of this is all the more important in considering Maryann's poignant post of yesterday regarding chemotherapy-induced leukemia, and her efforts to be as honest as possible with everyone about her experience, no matter how hard it is for her to express the negative.

The most difficult therapy (i.e., "throwing the book at it") does not equate to the most protection for everyone.

AlaskaAngel

[Lani]

Meant Positive--have Corrected It!

[Hopeful]

This may sound like hair-splitting, but identifying patients who are most at risk is not exactly the same thing as identifying patients who will benefit the most from a specific treatment. Here is a link to an article posted a few weeks ago by Jean, under the heading "New test for early stagers" :http://www.medicalnewstoday.com/articles/81755.php It discusses research being done at MD Anderson using three different genomic tests to determine risk and sensitivity to chemo and endocrine therapies in the same patient, all independently of each other. The results yielded a number of patients classified as high risk that were insensitive to both therapies. It will no more help a high risk patient than a low risk patient to treat them with a therapy that will not work for the specific person. We need better tools to pair the patient with the treatment.

Hopeful

[Barbara H.]

I had AC and T in 1998. I didn't have a recurrence until May of 2004. At that point a few treatments of Herceptin wiped it out of my lungs, skin, lymph nodes and liver. Unfortunately, it did return to the bones in February a year ago and I am currently dealing with that. Nevertheless, everything else remains clear. I really believe that if I had been able to receive Herceptin back in 98, I might not have had a recurrence. I do believe the taxol helped to give me six years without treatment.
Best regards,
Barbara H.

[StephN]

Some of the snippets I have seen on this subject are so trimmed down and vague that I don't know why some editor even bothered to take up a bit of space with it. The subject is too complex to pare down, as they left out some vital parts of the story.
One article made it seem like Taxol was a bad drug!!

I had 27 weekly treatments of it along with Navelbine and Herceptin for raging liver mets. Mets shut down within 4 weeks.

Like Barbara H. I am hoping I can thank Taxol for the over 5 progression free years I have had (excepting the 2 brain mets of 2003).

Note that I am hormone negative and MUST depend on the chemo and Herceptin to control my cancer. (What cancer??)

[tousled1]

I'm so thankful for Taxol as that's what I'm on now and I just got my results of my scan today that showed shrinkage of the nodules. This is great for me. I'm also ER/PR-.

[Wendywins]

WOW. That study on Taxol IS an amazing update. I had Taxol AND still,5 years later.. have the side-effects ..including foot problems(beyond "tingling") back when such lingering problems were predicted to be extremely rare. Its wonderful to know that the treatment was actually THAT effective (about 10 times more than we thought)in preventing reoccurence and therefore was worth it!