Pharma Strategy Blog

Commentary on Pharma & Biotech Oncology / Hematology New Product Development

Hormone replacement therapy (HRT) is one of those subjects where many have a strong opinion either way and I suspect even if we have another dozen trials evaluating at the pros and cons, those opinions won’t change very much.

That said, the latest large randomised, double blind, placebo controlled study from the Women’s Health Initiative (WHI) in postmenopausal women with a prior hysterectomy (n=10,739) taking conjugated equine estrogens (CEE) such as Premarin has just reported their health outcomes analysis.

The original goal of the trial was to examine health outcomes after a mean of 10.7 years of follow-up.  The study was stopped, however, after a mean of 7.1 years of follow-up because there was an increased risk of stroke. LaCroix et al., (2011) provided some context:

“The Women’s Health Initiative Estrogen-Alone Trial was stopped early after a mean of 7.1 years of follow-up because of an increased risk of stroke and little likelihood of altering the balance of risk to benefit by the planned trial termination date. Postintervention health outcomes have not been reported.”

The baseline characteristics looked well balanced between the two arms, so I took a quick look at the hazard ratio plots to see which factors favoured placebo and noted not only stroke, but also deep vein vein thrombosis (DVT) and pulmonary embolism.  It was easy to see why the trial was stopped early based on those results, especially as there were no significant differences in statin or aspirin use between the two groups.

Interestingly, looking at the topline hazard ratios on the cancer side, invasive breast cancer was lower on the treatment side, but colorectal cancer was more favourable in the placebo arm.  Previous trials have shown an increase in treatment related breast cancers. Part of this reason may lie in the type of hormone treatments given (estrogens only versus combination therapy) and variations in the patient groups.  Of course, the news media instantly picked up on the cancer issue rather than the cardiovascular effects.

Things started to get interesting, however, as I noticed that in the abstract, LaCroix et al., (2011) clearly stated:

“Among postmenopausal women with prior hysterectomy followed up for 10.7 years, CEE use for a median of 5.9 years was not associated with an increased or decreased risk of CHD, deep vein thrombosis, stroke, hip fracture, colorectal cancer, or total mortality.  A decreased risk of breast cancer persisted.”

Eh?  That’s not what you see in the hazard ratio plots, so I went back to re-read the paper and discussion in more detail.

The differences can be explained in the long term follow-up after treatment:

“Among postmenopausal women with prior hysterectomy who stopped taking CEE after a median of 5.9 years of use, several patterns of health risks and benefits seen during the intervention period were not maintained during the postintervention period, while other trends persisted.”

In other words, you often lose an effect post treatment, which can be a good or bad thing depending upon the parameter itself.

With the stroke and cardiovascular events seen in the intervention period on treatment, for example, in the post intervention period those effects “rapidly dissipated” during the postintervention period.

No doubt we will see future subgroup analyses emerge from this trial, it would be interesting to see, for example, whether mammogram screening was higher in either group and whether that impacted the findings or not.  Certainly that has been suggested in the past as one reason for the higher incidence of breast cancer in HRT users in other studies – in other words if you got looking for it more often you may well find it.

That said, the HRT story is likely to run and run as will emotions and opinions.

For some different perspectives, I can highly recommend checking out blog posts on the subject from Medical Lessons for a physician’s take and Flash Free for a science writer’s thoughts.  There was also an insightful commentary (open access) in Cancer Prevention Research from Craig Jordan and Leslie Ford (see references), who noted:

“Administration of estrogen replacement therapy (ERT) to hysterectomized postmenopausal women decreases the incidences of breast cancer.  Though paradoxical because estrogen is recognized to stimulate breast cancer growth, laboratory data support a mechanism of estrogen-induced apoptosis under the correct environmental circumstances.”

Personally?  I wouldn’t take it and I’m too young anyway, but I would like to see more granular research on which subpopulations are most likely to benefit, something that is not really that clear even now.  I’ll leave you with a striking insight from Jordan and Ford:

“The important issue for the decision of breast cancer cells to survive or die in response to estradiol depends entirely on the cell populations present in an estrogenized environment or following estrogen deprivation.”

Maybe we need more cowbell.

References:

This post was chosen as an Editor's Selection for ResearchBlogging.orgLaCroix AZ, Chlebowski RT, Manson JE, Aragaki AK, Johnson KC, Martin L, Margolis KL, Stefanick ML, Brzyski R, Curb JD, Howard BV, Lewis CE, Wactawski-Wende J, & WHI Investigators (2011). Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a randomized controlled trial. JAMA : the journal of the American Medical Association, 305 (13), 1305-14 PMID: 21467283

Jungheim ES, & Colditz GA (2011). Short-term use of unopposed estrogen: a balance of inferred risks and benefits. JAMA : the journal of the American Medical Association, 305 (13), 1354-5 PMID: 21467291

Jordan, V., & Ford, L. (2011). Paradoxical Clinical Effect of Estrogen on Breast Cancer Risk: A “New” Biology of Estrogen-Induced Apoptosis Cancer Prevention Research DOI: 10.1158/1940-6207.CAPR-11-0185

2 Responses to “Hormonal therapy and cancer – the controversy rages on”

  1. Jessica Forester

    After 6 months of offering stem cell therapy in combination with the venous angioplasty liberation procedure, patients of CCSVI Clinic have reported excellent health outcomes. Ms. Kasma Gianopoulos of Athens Greece, who was diagnosed with the Relapsing/Remitting form of MS in 1997 called the combination of treatments a “cure”. “I feel I am completely cured” says Ms. Gianopoulos, “my symptoms have disappeared and I have a recovery of many functions, notably my balance and my muscle strength is all coming (back). Even after six months, I feel like there are good changes happening almost every day. Before, my biggest fear was that the changes wouldn’t (hold). I don’t even worry about having a relapse anymore. I’m looking forward to a normal life with my family. I think I would call that a miracle.”

    Other recent MS patients who have had Autologous Stem Cell Transplantation (ASCT), or stem cell therapy have posted videos and comments on YouTube. http://www.youtube.com/watch?v=jFQr2eqm3Cg.

    Dr. Avneesh Gupte, the Neurosurgeon at Noble Hospital performing the procedure has been encouraged by results in Cerebral Palsy patients as well. “We are fortunate to be able to offer the treatment because not every hospital is able to perform these types of transplants. You must have the specialized medical equipment and specially trained doctors and nurses”.  With regard to MS patients, “We are cautious, but nevertheless excited by what patients are telling us. Suffice to say that the few patients who have had the therapy through us are noticing recovery of neuro deficits beyond what the venous angioplasty only should account for”.

    Dr. Unmesh of Noble continues: “These are early days and certainly all evidence that the combination of liberation and stem cell therapies working together at this point is anecdotal. However I am not aware of other medical facilities in the world that offer the synthesis of both to MS patients on an approved basis and it is indeed a rare opportunity for MS patients to take advantage of a treatment that is quite possibly unique in the world”.

    Autologous stem cell transplantation is a procedure by which blood-forming stem cells are removed, and later injected back into the patient. All stem cells are taken from the patient themselves and cultured for later injection. In the case of a bone marrow transplant, the HSC are typically removed from the Pelvis through a large needle that can reach into the bone. The technique is referred to as a bone marrow harvest and is performed under a general anesthesia. The incidence of patients experiencing rejection is rare due to the donor and recipient being the same individual.This remains the only approved method of the SCT therapy. For more information visit http://ccsviclinic.ca/?p=838

  2. leo Voisey

    Stem cells are “non-specialized” cells that have the potential to form into other types of specific cells, such as blood, muscles or nerves. They are unlike “differentiated” cells which have already become whatever organ or structure they are in the body. Stem cells are present throughout our body, but more abundant in a fetus.
    Medical researchers and scientists believe that stem cell therapy will, in the near future, advance medicine dramatically and change the course of disease treatment. This is because stem cells have the ability to grow into any kind of cell and, if transplanted into the body, will relocate to the damaged tissue, replacing it. For example, neural cells in the spinal cord, brain, optic nerves, or other parts of the central nervous system that have been injured can be replaced by injected stem cells. Various stem cell therapies are already practiced, a popular one being bone marrow transplants that are used to treat leukemia. In theory and in fact, lifeless cells anywhere in the body, no matter what the cause of the disease or injury, can be replaced with vigorous new cells because of the remarkable plasticity of stem cells. Biomed companies predict that with all of the research activity in stem cell therapy currently being directed toward the technology, a wider range of disease types including cancer, diabetes, spinal cord injury, and even multiple sclerosis will be effectively treated in the future. Recently announced trials are now underway to study both safety and efficacy of autologous stem cell transplantation in MS patients because of promising early results from previous trials.
    History
    Research into stem cells grew out of the findings of two Canadian researchers, Dr’s James Till and Ernest McCulloch at the University of Toronto in 1961. They were the first to publish their experimental results into the existence of stem cells in a scientific journal. Till and McCulloch documented the way in which embryonic stem cells differentiate themselves to become mature cell tissue. Their discovery opened the door for others to develop the first medical use of stem cells in bone marrow transplantation for leukemia. Over the next 50 years their early work has led to our current state of medical practice where modern science believes that new treatments for chronic diseases including MS, diabetes, spinal cord injuries and many more disease conditions are just around the corner.
    There are a number of sources of stem cells, namely, adult cells generally extracted from bone marrow, cord cells, extracted during pregnancy and cryogenically stored, and embryonic cells, extracted from an embryo before the cells start to differentiate. As to source and method of acquiring stem cells, harvesting autologous adult cells entails the least risk and controversy. 
    Autologous stem cells are obtained from the patient’s own body; and since they are the patient’s own, autologous cells are better than both cord and embryonic sources as they perfectly match the patient’s own DNA, meaning that they will never be rejected by the patient’s immune system. Autologous transplantation is now happening therapeutically at several major sites world-wide and more studies on both safety and efficacy are finally being announced. With so many unrealized expectations of stem cell therapy, results to date have been both significant and hopeful, if taking longer than anticipated.
    What’s been the Holdup?
    Up until recently, there have been intense ethical debates about stem cells and even the studies that researchers have been allowed to do. This is because research methodology was primarily concerned with embryonic stem cells, which until recently required an aborted fetus as a source of stem cells. The topic became very much a moral dilemma and research was held up for many years in the US and Canada while political debates turned into restrictive legislation. Other countries were not as inflexible and many important research studies have been taking place elsewhere. Thankfully embryonic stem cells no longer have to be used as much more advanced and preferred methods have superseded the older technologies. While the length of time that promising research has been on hold has led many to wonder if stem cell therapy will ever be a reality for many disease types, the disputes have led to a number of important improvements in the medical technology that in the end, have satisfied both sides of the ethical issue.
    CCSVI Clinic
    CCSVI Clinic has been on the leading edge of MS treatment for the past several years. We are the only group facilitating the treatment of MS patients requiring a 10-day patient aftercare protocol following neck venous angioplasty that includes daily ultrasonography and other significant therapeutic features for the period including follow-up surgeries if indicated. There is a strict safety protocol, the results of which are the subject of an approved IRB study. The goal is to derive best practice standards from the data. With the addition of ASC transplantation, our research group has now preparing application for member status in International Cellular Medicine Society (ICMS), the globally-active non-profit organization dedicated to the improvement of cell-based medical therapies through education of physicians and researchers, patient safety, and creating universal standards. For more information please visit http://www.neurosurgeonindia.org/

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