Meditations of an oncology geek

Archive for October, 2013

An Amazing Weekend with Pedal the Cause

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30 October 2013

Pedal the Cause is many things. It’s a cancer research fundraiser. It’s a bike ride. It’s a celebration of trial, tribulation, and growth. It’s a metaphorical and physical act honoring the stamina of cancer patients. It’s a community.

For one weekend a group of cancer patients, friends of cancer patients, researchers, caretakers, doctors, and kindred spirits made their way from the UCSD Moores Cancer Center to the mountain town of Julian and back. Via bicycles. The entire experience was simply amazing. There are too many things I could say about it, so instead I will guide my story with photographs.

Image: I’m up there, I promise!

My Saturday started pretty early. I refused to drive to the start and had a nice warmup hauling my 30lb backpack up Gilman Drive. I dropped it off, said hello to many familiar faces, and quickly found my way to the starting chute.

The course profile to Julian is pretty much up, up, and up. A long bike ride in San Diego County can take one through many microclimates. Saturday did not disappoint. Gray skies at the start transitioned to mist and fog as we ascended up to Poway, then as we hit Scripps Poway Parkway we ascended above that as well, finding clear skies.

Image: My buddy Andrew Ulvestad shot this (while moving, yes he’s talented!) as we ascended above the clouds and up to the desert air of Ramona.

Within a matter of miles mist and fog gave way to Ramona and desert air. I managed to find company with those that just love to ride hard and fast, so I tagged along. Before I knew it we were at the Santa Ysabel aid station snacking on orange slices, which at that moment in time was quite possibly the most pleasant thing in the world.

Our extraordinarily ambitious friends headed north from there to circle around Julian and ascend from the east side. My friend Andrew Ulvestad and I felt that lunch sounded like a better idea, and ascended the final 7 miles straight up to Julian.

Image: I had the honor of being the first cyclist into the riders’ village

Throughout the afternoon and evening I met so many amazing people at the riders’ village. It was inspiring to hear the stories of those that not only survived, but were made stronger by their experiences with cancer. Everyone there had no facade. Any metaphorical mask was magically discarded somewhere on the road to Julian.

Image: It’s hard to find better company. Here I am with Bill Koman, Diane Hyat, Robert Kaplan, and Mike McHale

Hundreds of people present were completely open and exchanging their incredible, extremely personal life experiences and stories. I was somewhat apprehensive that perhaps a depressed or sad mood might underly an event associated with something (cancer) that causes grief to so many people. What I found instead was an honesty, openness, and kinship with almost complete “strangers” that became the theme of my Pedal the Cause. It’s taken a few days, but it’s still registering how uplifting, enlightening, and rich that was. The spice of life was served up all night.

Image: The evening’s ceremonies flawlessly transitioned the vibe, with cancer survivor Bill Koman laying down some extremely ambitious goals for the coming years, including 1000 riders for next year’s event.

As expected, the night was pretty cold up on the mountain. And also as expected, this coast-loving weakling didn’t pack warmly enough. Lesson learned! The next morning saw clear skies, and a FAST descent down the mountain to Santa Ysabel. We also descended the stunning Highway 78 down to Escondido. Again, those microclimates… we went from clear and cold, to clear and warm-ish, to borderline hot in Ramona, all the way down to the fog bank that met us at the base of the 78.

Up Torrey Pines and on to UCSD, we were greeted by a finishing chute lined with cheering people and cowbells! I wanted to thank everyone there at the same time, but realizing the absurdity of that wish rolling by at 15mph I simply sat up and pointed and smiled at everyone that came to cheer.

Image: well, no image yet. I’m hoping the photographer at the end got this. He might still be editing and getting them online. I’ve got my fingers crossed!

I want to thank all of my friends and family that supported me in this cycling and fundraising journey, even if it was in the smallest way. Thanks for reading, and I am already looking forward to next year’s event!

Sincerely,
Ryon

KFMB Channel 8 coverage of Pedal the Cause

Written by Ryon

October 30th, 2013 at 3:06 pm

Posted in Science Blog

Could the liquid biopsy circumvent tumor heterogeneous hurdles?

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24 October 2013

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Nature magazine recently had a special Insight on tumor heterogeneity, complete with no less than six fantastic review articles on the topic.

Barbara Marte gave an introduction on the matter:

Cancer is not one but many diseases. It is different in each patient and continuously evolves into a progressively complex interplay of diverse tumour cells with their changing environment.
In an insightful and prescient 1976 paper, Peter Nowell proposed the now prevailing view of cancer as a process of clonal evolution, in which successive rounds of clonal selection give rise to tumours with diverse genetic and other molecular alterations that may necessitate ‘personalized’ therapies.

There is great variability between cancers, but it is the variability within tumors that I see as the biggest hurdle for diagnosis, treatment, and resistance even with the multi-faceted revolution in sequencing and targeted therapies.

If every cancer, and perhaps every cancer cell, is unique, and some cancer cell populations are more ‘unique’ than others, this needs to be taken into consideration for the improvement of cancer diagnoses and prognoses, for the treatment and monitoring of each patient and for the design of clinical trials to evaluate new therapies.

I could not agree more. A caveat to every molecular analysis on tumor tissue is that it offers only a spatial and temporal snapshot of the disease. This caveat is seldom acknowledged in oncology literature, almost never directly addressed in discussions, and sometimes completely ignored in experimental methodology that would be greatly affected by the heterogeneous snapshot caveat. What was present at that moment in time might be no more in weeks’ or months’ time. While there is a potential for a malignant tumor to continue to evolve, tremendous spatial heterogeneity already exists in many tumors. (1-4)

Any targeted therapy might not hit every tumor cell even with perfect pharmacodynamics, because a particular target might not be present in every tumor, and it’s difficult to know what other targets exist in other regions of a tumor without a comprehensive survey of tumor heterogeneity. Genetic testing requires biopsies for genomic surveys, and even the most advanced sequencing technologies cannot get past a particular caveat: it is impossible to survey an entire tumor’s genetic heterogeneity. Repeat biopsies are highly invasive to cancer patients and pose logistical and ethical problems. Besides, and if a particular tumor was easily accessible, it would likely be removed surgically anyway.

So, what part of a tumor could or should be biopsied? How much weight should be put on the driver mutations detected in a particular biopsy? What essential molecular targets might evade our notice?

While there is a growing appreciation (apprehension?) at the immense heterogeneity within tumors and the associated hurdles to more effective therapy, there is also a growing interest in cell free DNA (cfDNA). It was recently reported that advanced cancer patients have an order of magnitude higher amount of DNA floating around in their blood plasma than healthy volunteers (5). Furthermore, the amount of cfDNA was shown to correlate with disease progression (6), and to carry tumor-specific mutations that can be used to track genomic evolution of metastatic cancer in response to targeted therapy (7).

The origin of this cfDNA is likely the same cells that will cause the most harm to cancer patients: the ones that escape tumor(s) and seed the bloodstream. Studies from circulating tumor cells (CTC) indicate that the vast majority of CTC’s do not form tumors (8, 9), and the detection of shards of tumor cells along with long strands of genomic DNA is consistent with many of these cells being torn apart by sheer forces in the vasculature. The genomic interrogation of this cfDNA might not be too far away with the current trends in sequencing technology, giving rise to the non-invasive “liquid biopsy” of solid tumor heterogeneity surveyed with a blood draw (7, 10).

Such analyses are amendable to serial biopsies and might give light to the kinetics of tumor heterogeneity over time, portraying patterns of tumor evolution that could be exploited therapeutically, and perhaps even prophylactically.

Ryon


References:
1. Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. The New England journal of medicine. 2012 Mar 8;366(10):883-92. PubMed PMID: 22397650. Epub 2012/03/09. eng.
2. Yachida S, Jones S, Bozic I, Antal T, Leary R, Fu B, et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature. 2010 Oct 28;467(7319):1114-7. PubMed PMID: 20981102. Pubmed Central PMCID: PMC3148940. Epub 2010/10/29. eng.
3. De Mattos-Arruda L, Cortes J, Santarpia L, Vivancos A, Tabernero J, Reis-Filho JS, et al. Circulating tumour cells and cell-free DNA as tools for managing breast cancer. Nature reviews Clinical oncology. 2013 Jul;10(7):377-89. PubMed PMID: 23712187. Epub 2013/05/29. eng.
4. Park SY, Gonen M, Kim HJ, Michor F, Polyak K. Cellular and genetic diversity in the progression of in situ human breast carcinomas to an invasive phenotype. The Journal of clinical investigation. 2010 Feb;120(2):636-44. PubMed PMID: 20101094. Pubmed Central PMCID: PMC2810089. Epub 2010/01/27. eng.
5. Perkins G, Yap TA, Pope L, Cassidy AM, Dukes JP, Riisnaes R, et al. Multi-purpose utility of circulating plasma DNA testing in patients with advanced cancers. PloS one. 2012;7(11):e47020. PubMed PMID: 23144797. Pubmed Central PMCID: PMC3492590. Epub 2012/11/13. eng.
6. Dawson SJ, Tsui DW, Murtaza M, Biggs H, Rueda OM, Chin SF, et al. Analysis of circulating tumor DNA to monitor metastatic breast cancer. The New England journal of medicine. 2013 Mar 28;368(13):1199-209. PubMed PMID: 23484797. Epub 2013/03/15. eng.
7. Murtaza M, Dawson SJ, Tsui DW, Gale D, Forshew T, Piskorz AM, et al. Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature. 2013 May 2;497(7447):108-12. PubMed PMID: 23563269. Epub 2013/04/09. eng.
8. Allard WJ, Matera J, Miller MC, Repollet M, Connelly MC, Rao C, et al. Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clinical cancer research : an official journal of the American Association for Cancer Research. 2004 Oct 15;10(20):6897-904. PubMed PMID: 15501967. Epub 2004/10/27. eng.
9. Meng S, Tripathy D, Frenkel EP, Shete S, Naftalis EZ, Huth JF, et al. Circulating tumor cells in patients with breast cancer dormancy. Clinical cancer research : an official journal of the American Association for Cancer Research. 2004 Dec 15;10(24):8152-62. PubMed PMID: 15623589. Epub 2004/12/30. eng.
10. Lianidou ES, Mavroudis D, Georgoulias V. Clinical challenges in the molecular characterization of circulating tumour cells in breast cancer. British journal of cancer. 2013 Jun 25;108(12):2426-32. PubMed PMID: 23756869. Pubmed Central PMCID: PMC3694246. Epub 2013/06/13. eng.

Written by Ryon

October 24th, 2013 at 9:50 am

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Does the end of gene patents mean rising demand for diagnostic sequencing?

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1 October 2013

Image source: globalgenes.org

Last week I attended a fantastic panel debate on gene patents hosted by the San Diego chapter of Oxbridge Biotech Roundtable at The Scripps Research Institute. Rachel Tsui moderated a panel of four:

Pro gene Patents:
Lisa Haile
Anthony Kuhlman

Against Gene Patents:
Lisa Madlensky (Genetic Counselor at UCSD Moores Cancer Center)
Lana Feng (Founder, Personalized Diagnostics)

The debate itself was more of a discussion, with minimal rhetorical tactics used by either side. However, the debate could have been improved with a better overview of patent law in general; the nature of audience questions indicated inadequate fundamental knowledge about what was being debated.

That said, the questions and discussions were very good. A few ideas / questions that stuck out to me:

1) Along the lines of patenting a technique for detecting something “natural”: Is the Reference Genome actually “natural” or a best-fit amalgamation of the genetic heterogeneity of mankind? If so, perhaps this is not actually natural and could be patented in itself?

2) Companies holding gene patents usually do not sue academic institutions, though they can. It is in their best interests most of the time to let academic labs do research and publish, purportedly adding value to their patents. (Lisa Haile)

3) Currently, diagnostic sequencing of patented genes (in her experience as a genetic counselor) are not dramatically more expensive than non-patented genes. (Lisa Madlensky)

After the panel discussions and audience questions concluded, I had a chance to catch up with Dr. Madlensky on the topic of diagnostic testing. As a genetic counselor with decades of experience, she has literally witnessed the birth of the genomic age through the eyes of medicine. I always see a sense of irony about the incredible multitude of what we “know” about genetics and how little is used in the clinic. The reasons for this are multifaceted, but are quickly rising from esoteric to painfully relevant with the growing tide of the genomic age.

In particular, I was interested in the impact of platforms like Understand Your Genome from Illumina that aim to put personal genomic data directly into the hands of the consumer. The Understand Your Genome conference will take place next month here in San Diego, and for a $5000 ticket and a DNA sample, Illumina will provide participants with an iPad with their genome browser application containing participant’s entire genome! I could wax poetic about the dawn of personalized genomics and science fiction becoming science fact, but for I am most immediately concerned with the way this will affect the physician-patient relationship. I wrote recently about the harms of overdiagnosis in otherwise healthy patients and many of these concerns could be carried over for considerations relating to personal genomics and genetic curation.

I relayed some of these concerns to Dr. Madlensky, and she had a few perspectives to add to the mix. Although the FDA guidelines are evolving, there is regulation in place for diagnostic-grade sequencing information, and before making any recommendations in genetic counseling it is necessary to have gene(s) in question re-sequenced, usually via the Sanger method. Critically, diagnosis today is mostly phenotype driven, not genotype driven: physicians and genetic counselors do not usually go looking for things that could be “wrong” when no obvious malady is present. Even then, they do not usually do genetic interrogation without having other reasons for doing so, like presence of disease symptoms in the patient or a family history of such.

That said, there is a changing trend, and the rising genomic tide might entice more patients and physicians to use the emerging genetic tools for screening purposes. However, there is still one major gatekeeper for any medical intervention: the physician (as it should be, in my opinion. More on that some other time). The physicians’ recommendations and prescriptions, in turn, are regulated by follow-up medical grade sequencing diagnostics of individual genes. Given this scenario, it would not be too much of a stretch to imagine a hugely increased demand for diagnostic-grade sequencing tests and centers (private or public) and for qualified genetic counselors, as most primary care physicians are are not adequately trained in the nuances of molecular diagnostics to make use of the rising tide of personal genomics.

In summary:

The recent Supreme Court rulings will not directly, dramatically change the current medical genomic landscape for patients. However, it makes a smoother landscape for sequencing enterprises.

In the near future (less than a few years) we may all have our genomes on iPads.

Given this scenario, the rate limiting steps for medical action will still remain with physicians (I hope), and their actions are in turn limited by the availability of diagnostic-grade medical sequencing tests.

There might be vastly increased demand for FDA-approved medical diagnostic sequencing tests and centers.

-Ryon

Written by Ryon

October 1st, 2013 at 4:06 pm

Posted in Science Blog