Chemotalk Newsletter, Vol. 87: July 1, 2015
Half a year gone...or half a year left, whichever you prefer.
It's hard to get oncologists to open up about their career choice. This one did, and it's worth reading:
THE TIE THAT BINDS
by Craig R. Hildreth, MD
In a perfect world the best teachers are also the saddest, for as their students eventually find nothing new to learn, the classroom falls silent. Likewise, those parents who succeed in raising happy, independent adults feel a sense of emptiness at the closing of a long, momentous project. What about people living with CANCER? If a cure was found, would oncologists lament the breaking of this unique bond?
If they did I¹d say they had a screw loose somewhere. Nothing would make a sane doctor happier than to say adios to cancer. Perhaps in a few generations we will finally bury this disease forever and push a gaggle of oncologists over to the unemployment office. Until then, cancer is still a worldwide health problem. Its remedies, however, are multiplying quickly and becoming more complicated, thus challenging cancer doctors to raise their game. Selecting the best therapy from an expanding inventory of agents requires knowledge of genomics, proteomics, cell biology, and drug toxicity, to name a few. A modern-day treatment plan requires coordination with surgeons, radiation oncologists, pathologists, oncology nurses, and many other disciplines.
It also requires patients.
For clinicians, a day without patients is grounds for retirement. Despite the narrow scope of our relationship compared with the family doctor, we do get close to our patients. It is unavoidable. Sometimes we see them every week for months on end, and these visits are not grocery store aisle ³whassup?² chitchats. Our patients typically have multiple issues to manage at one time. From my experience, it is impossible to spend too much time with a cancer patient. In fact, I often feel bad when I realize I must move on, lest our waiting room resemble an electronics store on Black Friday.
Like a director and his actors or a sergeant and his platoon, our work is defined by what we do to teach, guide, and protect patients in our care. Without patients our expertise is meaningless and our professional calling is forfeited. Working together, sharing happy times as well as sad, binds our patients to us like acrobats swinging through high space, each hanging on to the other for dear life. Oncologists thrive on being on high alert for danger, whether in the form of missed diagnoses, complications, treatment failure, or even hindering emotions such as discouragement. Without patients we have no mission to accomplish; whenever we lose someone to cancer our responsibilities, our skills, our very identity of ourselves as cancer fighters is threatened with extinction.
Therefore dear patients, families, caregivers, never think that oncologists, at least the good ones, ply their trade in solitude. Never wonder if we ever worry about the people entrusted to us; never doubt our commitment because it is you who defines who we are. We are entwined with our patients, and the loom that wove us together uses only the strongest threads‹respect, love, mercy, and understanding. It can never be unraveled by human hands‹only the tolling bell can rip it asunder.
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TRYING TO FOOL CANCER
By Mikkael A. Sekeres
When it aired, Ken Burns-produced documentary "Cancer: The Emperor of All Maladies" emphasized how much we now know about the genetic basis for Cancer. This year, according to President Obama, cancer research and funding will focus on so-called precision, personalized or targeted medicine -- using cancer's molecular underpinnings to develop drugs that attack the genes or gene products that make up cancer's factory while sparing normal cells. What a beautiful concept.
The problem is, cancer is rarely that simple, or that easily fooled.
Three recent studies, all published or presented late last year, highlight the challenges of building a national cancer therapy policy around precision medicine.
The first, from me and my colleagues at the Cleveland Clinic in collaboration with Japanese researchers performed genetic analyses on more than 600 patients with one of two related bone marrow cancers: myelodysplastic syndromes or acute myeloid leukemia. These conditions occur typically in people in their seventh or eighth decades, and can be fatal often within months, if left untreated. As with any cancer, they arise through the acquisition of genetic mutations over a person's lifetime. These mutations may cause a cell, for example, to outgrow other cells around it, forming a mass, or to remain in an immature state, thus unable to conduct normal functions, like preventing bleeding. We found that patients had developed an average of 10 distinct genetic mutations before either of these two cancers was diagnosed.
Ten genetic mutations. So, if you're developing a drug to treat these cancers, which mutation would you choose to target? If your drug attacked the ninth or 10th mutation, the cancer would quickly regrow, because one through eight would still thrive.
Our next task, then, was to determine the order of the mutations - which came first and which followed - in hopes that we could identify the root of the evil. We did this two ways: first, by focusing on 73 patients whose disease evolved over time, to see which genetic mutations occurred first; and second, by using statistical methods to compare the frequency of genetic variants in these patients with a healthy population. Genetic mutations found in both groups could be singled out as the original "founder" events.
Targeting these mutations would be the best way to fight these cancers, right?
But what if it turns out that the founder mutations are part of a given person's normal human genome -- what are called "germline" mutations, which are present in both cancerous and noncancerous cells? Killing them could wreak havoc. Or the founder mutations could give birth to secondary mutations that are actually much more virulent, and targeting the founder mutations might not affect the cancer at all.
A second study from our group, this time in collaboration with Japanese and German researchers, started with identical twin men in their late 60s who came to my clinic. They both had a bone marrow cancer that causes anemia and low platelet counts, and generously donated blood samples for our research. I treated them with a drug that had a low chance of working -- approximately 25% -- and hoped for the best.
Within a month, their blood counts righted themselves, much more quickly and more dramatically than I would have expected. We also got the results of the genomic tests, which revealed that they shared the same mutation -- a DDX41 abnormality that is found on Chromosome 5. T appeared in both their cancerous and normal cells, so we knew that they must have been born with it; this was the original, germ line mutation.
When we looked back to our database of more than 1,000 patients with similar disorders, we were able to identify eight others with this mutation who had already been treated with the drug I gave to my identical twin patients, and all had improved blood counts. This would seem to argue in favor of a national cancer policy focusing on targeted drugs.
Or does it? True, the twins had a founder genetic mutation for which we identified (by accident) a drug that worked really well, and neither had major side effects. But despite the improvements in their blood counts, when we examined their bone marrow after they had been treated, the twins' cancer never went away, and one died from an infection related to his disease only months later.
Additionally, when we looked at more than 1,000 other people with the same disease, we could find the mutation in only 25, representing 2.4% of people with a disease that affects about 4.5 per 100,000 Americans each year. It's wonderful news for those patients, but not exactly the disease prevalence around which we should be based a national policy.
One final study should give us all pause. Researchers from Harvard and M.I.T. analyzed genomic tests from more than 17,000 patients enrolled in diabetes or heart disease studies. They found that many had mutations more commonly associated with blood and bone marrow cancers, despite the fact that the patients did not have any known blood disorders. Thos with these mutations -- 5.6% of those in their 60s and 9.5% of those in their 70s -- were 11 times more likely to develop these cancers later in life, compared with those without these mutations. But it wasn't guaranteed that they would develop cancer.
The implications of this are profound. These are many genetic mutations associated with cancer that won't actually cause it in a majority of people, probably because they don't lead to those secondary mutations that are requisite in developing disease. Telling people with those mutations that they have the potential for cancer would surely introduce unnecessary, lifelong anxiety. Some might even receive targeted CHEMOTHERAPY for a cancer that doesn't exist.
Even for patients who have a genetic mutation and a clearly defined cancer, that mutation might have nothing to do with causing the cancer. Targeting it with a drug could just damage cells that might be innocent bystanders.
Without doubt, therapies that target genetic abnormalities have made huge inroads in the survival of cancer patients, most notably in some chronic leukemias, MELANOMAS and LUNG and BREAST CANCERS.
But they haven't been curative. And we shouldn't delude ourselves, or our patients, in thinking that standard chemotherapy is a thing of the past. Or that a few more months of life which is what many targeted drugs have been able to deliver on average, is a panacea in cancer care.
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SCIENTISTS IDENTIFY KEY TO PREVENTING SECONDARY CANCERS
Leading scientists from the University of Sheffield and University of Copenhagen have identified a possible key to preventing secondary cancers in BREAST CANCER patients, after discovering an enzyme which enhances the spread of the disease.
Secondary (metastatic) breast cancer is the main cause of the 12,000 deaths which occur from breast cancer in the UK every year.
The most common site for the disease to spread is the bone - occurring in around 85 per cent of secondary breast cancer patients. The new research, which was conducted at The Institute of Cancer Research, London, found that the enzyme LysYl Oxidase (LOX) released from the primary tumour causes holes in bone and prepares the bone for the future arrival of cancer cells.
The findings suggest that identifying LOX in oestrogen receptor negative (ER negative) breast cancer patients early, could allow doctors to block the enzyme's activity, preventing bone damage and the spread of tumour cells to the bone (metastasis), halting the progression of the disease. The researchers also showed that treatment with bisphosphonate, an existing class of drug which prevents the loss of bone mass and is already used to treat diseases such as osteoporosis, was able to prevent the changes in the bone and the spread of the disease in mice.
The pioneering research, co-led by Dr Alison Gartland at the University of Sheffield's Department of Human Metabolism, could lead to a better prognosis for cancer patients in the longer term.
Dr Gartland said: "This is important progress in the fight against breast cancer metastasis and these findings could lead to new treatments to stop secondary breast tumours growing in the bone, increasing the chances of survival for thousands of patients. We are really excited about our results that show breast cancer tumours send out signals to destroy the bone before cancer cells get there in order to prepare the bone for the cancer cells' arrival.
"The next step is to find out exactly how the tumour secreted LOX interacts with bone cells to be able to develop new drugs to stop the formation of the bone lesions and cancer metastasis. This could also have implications for how we treat other bone diseases too."
Study co-leader Dr Janine Erler, formerly Team Leader in Cancer Biology at The Institute of Cancer Research, London, who now is Associate Professor at the Biotech Research & Innovation Centre (BRIC) at the University of Copenhagen, said: "Once cancer spreads to the bone it is very difficult to treat. Our research has shed light on the way breast cancer cells prime the bone so it is ready for their arrival. If we were able to block this process and translate our work to the clinic, we could stop breast cancer in its tracks thereby extending patients' lives."
The research, funded by Breast Cancer Campaign, Cancer Research UK, Novo nordisk foundation, Danish cancer society, lundbeck foundation, and both universities, is published today (27 May 2015) in the journal Nature. Katherine Woods, Senior Research Communications Manager at Breast Cancer Campaign and Breakthrough Breast Cancer, said: "By unveiling the role that the protein LOX is playing, these results open up a whole new avenue for research and treatments that could stop breast cancer spreading to the bone. The research also adds weight to the growing body of evidence supporting the role of bisphosphonates in stopping secondary breast cancer in its tracks.
"The reality of living with secondary breast cancer in the bone is a stark one, which leaves many women with bone pain and fractures that need extensive surgery just when they need to be making the most of the time they have left with friends and family." She added: "Secondary breast cancer kills 1,000 women each and every month in the UK alone and yet we still don't know enough about how and why breast cancer spreads to stop it. Our newly-formed charity is determined that by 2050, no one will lose their life to breast cancer and we'll do this by ramping up our research efforts, in this area in particular, doing everything possible to achieve that goal."
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See you next month.
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A final personal note: This July marks my 10th year with no evidence of the disease that was diagnosed stage 4. I know I'm not cured. Cancer is a sneak and a snake. It can come seemingly out of nowhere, even in a different form, even after decades of good health. For anyone in my position, I suggest that the best defense is vigilance. Don't obsess, but don't forget.
And if you have any thoughts of how this newsletter could be improved, please email me directly, at Elaine@elainejesmer.com.