I have been a bit concerned for some time regarding the hype surrounding “personalized medicine” as it relates to cancer. The concern arises from the excitement generated when a novel mutation can be targeted in a specific subgroup of cancer patients with astonishing results. The media goes wild. A good example of this is the BRAF mutation in melanoma. The V600E mutation found in 40-60% of patients with melanoma can be targeted with a drug (vemurafenib) that inhibits this activated cancer causing enzyme. The results can be astonishing, including apparently complete remissions in a disease that only 5 years ago was always fatal when metastatic. However, less well “advertised” is the fact that in most cases, the duration of such responses is quite short (median time to progression with BRAF inhibitors seems to be in the 6 month range). You can read a nice article on this story here. The personalized medicine aspect is that there is no reason to treat with the expensive drug if you don’t find the mutation. That’s the good news of personalized medicine. The bad news is that for cancer, heterogeneity is the achilles heel of this approach. If even one cell doesn’t have the target, it will survive…and/or cells that do have the target have enough genetic instability to get around the block in short order.
Now comes a fascinating study from the outstanding Hopkins investigators who looked at prostate cancer in a single patient who was diagnosed with prostate cancer at age 47. In the beginning he had a lymph node that was involved and he received surgery, androgen ablation, localized radiation and eventually chemotherapy and vaccine therapy. He succumbed to widespread metastases 17 years later at age 64. By doing deep genetic analysis of the primary tumor, the researchers were able to identify the source of the metastases. Surprisingly, the lethal metastatic disease originated in a small part of the primary tumor that was low grade, Gleason pattern 3, not the more aggressive, larger volume tumor elsewhere. While this is the first such study I am aware of in prostate cancer, similar studies in a few patients with renal cancer were reported last year.
So, for personalized medicine, the situation is either a cup half-full or half-empty. If you are an optimist, you hope that the majority of cancer cells in a patient can be targeted with a “driver mutation” like the BRAF mutation, and that when all of the susceptible cells have died off, the immune system might be stimulated to take over with a vaccine, or one of the exciting drugs that potentiate an immune response by knocking down the control arm of the immune system (PD-1 inhibitors, ipilumimab, etc.) and that the last cell will be eliminated before genetic instability gives the cancer the upper hand. If you are on the “half-empty” side, you contemplate that the human genome has evolved over millions of years to be remarkably adaptable to everything from volcano sulfuric gases to solar radiation, and that without such adaptability we might not be here at all. In this scenario, it seems unlikely that we will easily conquer the myriad of survival pathways that got us here by just attacking one of them. And…which one to attack may depend on which biopsy site you look at.
I haven’t decided which philosophic point of view I favor. The incredible progress made in treating HIV by attacking multiple pathways and converting HIV-AIDS to a chronic illness, much like diabetes, provides hope. So does the fact that the Hopkins patient lived 17 years thanks to the progress made in treating prostate cancer. As I often remind my patients, “if you die of a heart attack, we will count that as a cure of your prostate cancer”. May we all live in a healthy condition until our time comes!
prost8blog 
Your comments remind me of the NY Times stories on Ralph Steinman who was awarded the Nobel Prize just days after he died. Typically Nobel Prizes are only given to living people. Steinman as the times reported two years ago died just before the announcement was made:
http://www.nytimes.com/2011/10/04/science/04steinman.html?_r=0
Steinman might be considered to have been one of the leaders in this movement to customize therapies to target cancer cells. Last year in an in depth article in the Sunday Magazine section titled, “Is the Cure for Cancer Inside You?” Daniel Engber looked at Steinman’s life, death and the promise of his research more carefully.
http://www.nytimes.com/2012/12/23/magazine/is-the-cure-for-cancer-inside-you.html
When Steinman was diagnosed with cancer he mobilized the best of the best in the scientific community to create a customized treatment. The details are in the article. Steinman’s research and efforts focused on ganglionic cells and his efforts to create vaccines that would trigger his immune system to target his own cancer cells specifically. What has stood out in my memory is this paragraph:
“If the old chemotherapies and radioactive treatments worked like napalm to blast away the canopy, the new breed of personalized therapies target only specific plants. For some cancers, the more homogeneous ones, they do the job just fine. For others, though, the approach comes up against the relentless rules of Darwinian selection. Wipe out one subtype of a cancer — the clone that seems most aggressive, say, or the one that’s most prevalent in a biopsy — and you may have slowed the disease or thinned it out. But the cells left behind might represent a fitter strain and fill the niche.”
Your comments remind me of the NY Times stories on Ralph Steinman who was awarded the Nobel Prize just days after he died.
http://www.nytimes.com/2011/10/04/science/04steinman.html?_r=0
Steinman might be considered to have been one of the leaders in this movement to customize therapies to target cancer cells. In an in depth article in the Sunday Magazine section titled, “Is the Cure for Cancer Inside You?” the Times looked at Steinman’s life, death and the promise of his research more carefully.
http://www.nytimes.com/2012/12/23/magazine/is-the-cure-for-cancer-inside-you.html
When Steinman was diagnosed with cancer he mobilized the best of the best in the scientific community to create a customized treatment. The details are in the article. Steinman’s research and efforts focused on ganglionic cells and his efforts to create vaccines that would trigger his immune system to target his own cancer cells specifically. What has stood out in my memory is this paragraph:
“If the old chemotherapies and radioactive treatments worked like napalm to blast away the canopy, the new breed of personalized therapies target only specific plants. For some cancers, the more homogeneous ones, they do the job just fine. For others, though, the approach comes up against the relentless rules of Darwinian selection. Wipe out one subtype of a cancer — the clone that seems most aggressive, say, or the one that’s most prevalent in a biopsy — and you may have slowed the disease or thinned it out. But the cells left behind might represent a fitter strain and fill the niche.”
I am sorry to report that my husband, Chuck Trevathan, passed away on 9/28/13 after a 10-year battle against prostate cancer. He lived longer than the doctors had predicted, and perhaps the your information was one of the reasons.
Dr Glode,
Thank You for your post, and for the hope they inspire.
Interesting that it was the gs 3 that was the source of the metastatic disease, and that he went on to live 17 years, I know of a Man who presented in 1997 with a psa of 7100 at age 71 with multiple bone mets, who had a fantastic response to adt for many years and is still alive today.
Also interesting is the multiple pathway idea, I am thinking this would be like the xtandi with zytiga that I am currently on, and really the first therapy since initial adt that really dropped my psa.
sincerely, Dan J
dx 2006,bpsa148, gs(5,5)10, widespread metatatic disease to bone and soft tissue , age 49. currently pain free , working ,enjoying life, sleeping 2 extra hours a day
Mike, You dispense real wisdom in your blogs. May they never cease!
I love that you are writing about this stuff. I agree with you that heterogeneity is the Achilles heel of personalized medicine. But until we sequence more advance cancer patients and analyze that data to make new discoveries, the era of cancer cocktails that block multiple driver pathways keeping cancer in check won’t occur. Even today, I think if we can target the driver mutations it buys more time than simply trial and error standard of care, no? I bet if we sequenced everybody with advanced cancer and started them on targeted treatments first (vs. failing standard of care resulting in a beast of a disease that is harder to tame), we’d advance science faster and have better outcomes immediately.
I completely agree with your comment. We need to do the hard work, but control the costs at the same time. Not easy.
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