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Happy New Year:

Welcome to the year 5770

September 25, 2009

We celebrated the Jewish New Year last week and we have arrived into the year 5770. It is a little more than five and a half millennia since Genesis.

I didn’t have time to attend Denver’s annual Gem and Mineral show last weekend.  I like fossils and kid of wanted to buy something that was alive hundreds of millions of years ago.  Is the world 5770 years old or, as the geologists tell us, 4.54 billion years (109) years old? Or does it matter?

It gives me pleasure to let these two different worldviews coexist in my mind.  To paraphrase Whitman, “Do I contradict myself ?... I contain multitudes….”  

We live in a world of plurality, where we coexist with people and cultures that see the world differently and we learn to see the world from multiple viewpoints.  Our modern view is informed by scientific principles, of hypotheses tried, proven or rejected.  Yet retaining some part of those other unscientific worldviews has its place.  Doing so gives the world more dimension and makes it a more interesting place.  I have no problem with the world being both 5770 years old and at the same time four ad a half billion years old.  

Disregarding the newer scientific worldview in favor of other views has its downside. There are no shortage of examples of individuals clinging too fixedly to incorrect views.

The first that comes to mind is how South Africa’s former President Thabo Mbeki based healthcare policy on the view that HIV infection does not cause AIDs.  Current research suggests his denial and the policies it engendered are responsible for 365,000 premature deaths.

Or consider the slaughter of pigs in Cairo.  Late last Spring, Egyptian authorities slaughtered all the city’s pigs out of fear of the ‘Swine Flu.’  Never mind that the flu was spreading person to person already and Cairo’s pigs were not infected.   The people raising the pigs were Cairo’s garbage collectors and without pigs to feed they now see no profit in collecting garbage.  A little bit late, authorities in Cairo are wondering what to do with the garbage that has piled up on the streets since May.

There is clear advantage to seeing the world in black and white, of having set and narrow views as to how things are.  It isn’t just the lay public or the uneducated Third World.  All of us are affected, often without us noticing it. Unfortunately, falling into the rut of strongly held assumptions can be a problem for researchers as well and limit scientists from exploring new or even old ideas. These ramblings bring me to a study published in the August 19 issue of JAMA that turns some strongly held opinions upside down.  The research suggests that estrogen may be a useful treatment in advanced breast cancer.  Most breast cancer cells have estrogen receptors on their surface and when estrogen binds to these receptors it stimulates the cancer cells causing them to multiply.  Tamoxifen has been used for 30 years to block these estrogen receptors.   In more recent years, aromatase inhibiting drugs have been used to prevent estrogen production.  After so many  years of thinking that estrogen is bad for breast cancer,  it is rather hard to let go of the idea and believe that estrogen can in some instances be very useful. Yet it seems that at least in some breast tumors and in women who are running short of treatment options, estrogen can trigger apoptosis.  Apparently in the years before Tamoxifen dominated treatment, estrogen like compounds, for example DES, were commonly used to treat breast cancer.  Somehow along the line, we forgot about this. As many of us have sadly witnessed, estrogen blocking therapies used to treat women with advanced breast cancer stop working after awhile.  The tumors become insensitive to the hormone and grow without it.  In this study, Matthew Ellis and colleagues report on their treatment of 66 breast cancer patients experiencing cancer relapse while being treated with estrogen blocking therapy.  Half the women were given high dose estrogen, 30 mg/day and half low dose, 6 mg/day.  After 24 weeks of treatment the tumors had stopped growing or shrunk in about one-third of the women in both groups. The researchers say they found a way to predict which women were likely to respond. Using combined PET-CT scans with a tracer attached to glucose produced a specific reaction on the scan that predicted the responders with about 80% accuracy.

How many of us will be able to let go of the world view that estrogen is bad for breast cancer and how many will be able to see that, ‘estrogens effects on a tumor are not one-dimensional,’ but rather multi-dimensional?

 

  How quickly can we let go of our long held view and make use of this new information?  This is part of the reason why I like to remember two separate numbers for the age of the earth in my mind.  We need to stay mentally flexible if we hope to keep up in practice with the information research provides. Although it is more comfortable and easy to stick to one’s view of the world, it does not serve the cause of patient care to hold too fast to currently thinking that we miss new developments, or in this case, the emergence of old ideas.

 

Main Study:

Ellis MJ, Gao F, Dehdashti F, Jeffe DB, Marcom PK, Carey LA,  et al.  Lower-dose vs high-dose oral estradiol therapy of hormone receptor-positive, aromatase inhibitor-resistant advanced breast cancer: a phase 2 randomized study. JAMA. 2009 Aug 19;302(7):774-80. 

Walt Whitman, “Song of Myself”

http://www.nytimes.com/2008/11/26/world/africa/26aids.html

http://www.nytimes.com/2009/05/01/health/01egypt.html

http://www.nytimes.com/2009/09/20/world/africa/20cairo.html?pagewanted=2

JAMA. 2009 Aug 19;302(7):774-80.Click here to read Links

Comment in:

JAMA. 2009 Aug 19;302(7):797-8.

Lower-dose vs high-dose oral estradiol therapy of hormone receptor-positive, aromatase inhibitor-resistant advanced breast cancer: a phase 2 randomized study.

Ellis MJ, Gao F, Dehdashti F, Jeffe DB, Marcom PK, Carey LA, Dickler MN, Silverman P, Fleming GF, Kommareddy A, Jamalabadi-Majidi S, Crowder R, Siegel BA.

Department of Medicine, Division of Oncology, Washington University School of Medicine, St Louis, MO 63110, USA. mellis@dom.wustl.edu

CONTEXT: Estrogen deprivation therapy with aromatase inhibitors has been hypothesized to paradoxically sensitize hormone-receptor-positive breast cancer tumor cells to low-dose estradiol therapy. OBJECTIVE: To determine whether 6 mg of estradiol (daily) is a viable therapy for postmenopausal women with advanced aromatase inhibitor-resistant hormone receptor-positive breast cancer. DESIGN, SETTING, AND PATIENTS: A phase 2 randomized trial of 6 mg vs 30 mg of oral estradiol used daily (April 2004-February 2008 [enrollment closed]). Eligible patients (66 randomized) had metastatic breast cancer treated with an aromatase inhibitor with progression-free survival (> or = 24 wk) or relapse (after > or = 2 y) of adjuvant aromatase inhibitor use. Patients at high risk of estradiol-related adverse events were excluded. Patients were examined after 1 and 2 weeks for clinical and laboratory toxicities and flare reactions and thereafter every 4 weeks. Tumor radiological assessment occurred every 12 weeks. At least 1 measurable lesion or 4 measurable lesions (bone-only disease) were evaluated for tumor response. INTERVENTION: Randomization to receive 1 oral 2-mg generic estradiol tablet 3 times daily or five 2-mg tablets 3 times daily. MAIN OUTCOME MEASURES: Primary end point: clinical benefit rate (response plus stable disease at 24 weeks). Secondary outcomes: toxicity, progression-free survival, time to treatment failure, quality of life, and the predictive properties of the metabolic flare reaction detected by positron emission tomography/computed tomography with fluorodeoxyglucose F 18. RESULTS: The adverse event rate (> or = grade 3) in the 30-mg group (11/32 [34%]; 95% confidence interval [CI], 23%-47%) was higher than in the 6-mg group (4/34 [18%]; 95% CI, 5%-22%; P = .03). Clinical benefit rates were 9 of 32 (28%; 95% CI, 18%-41%) in the 30-mg group and 10 of 34 (29%; 95% CI, 19%-42%) in the 6-mg group. An estradiol-stimulated increase in fluorodeoxyglucose F 18 uptake (> or = 12% prospectively defined) was predictive of response (positive predictive value, 80%; 95% CI, 61%-92%). Seven patients with estradiol-sensitive disease were re-treated with aromatase inhibitors at estradiol progression, among which 2 had partial response and 1 had stable disease, suggesting resensitization to estrogen deprivation. CONCLUSIONS: In women with advanced breast cancer and acquired resistance to aromatase inhibitors, a daily dose of 6 mg of estradiol provided a similar clinical benefit rate as 30 mg, with fewer serious adverse events. The efficacy of treatment with the lower dose should be further examined in phase 3 clinical trials. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00324259.

Seppa, N. From troublemaker to treatment: study finds estrogen may fight persistent breast cancer. Science News September 12, 2009 pg 13