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Wednesday, September 6, 2017

Siddhartha Mukherjee's latest on cancer


In my New Yorker (a great long-read; may be firewalled):

Given our current family circumstance regarding my daughter's illness, I found this extremely interesting.

"It is a basic insight that an undergraduate ecologist might find familiar: the “invasiveness” of an organism is always a relative concept."

He's analogically alluding to "mets," -- metastasis. It's the mets that end up killing you. Brain mets killed my elder daughter in 1998.
One evening this past June, as I walked along the shore of Lake Michigan in Chicago, I thought about mussels, knotweed, and cancer. Tens of thousands of people had descended on the city to attend the annual meeting of the American Society of Clinical Oncology, the world’s preĆ«minent conference on cancer. Much of the meeting, I knew, would focus on the intrinsic properties of cancer cells, and on ways of targeting them. Yet those properties might be only part of the picture. We want to know which mollusk we’re dealing with; but we also need to know which lake...
"We’ve tended to focus on the cancer, but its host tissue—“soil,” rather than “seed”—could help us predict the danger it poses."
We aren’t particularly adept at predicting whether a specific patient’s cancer will become metastatic or not. Metastasis can seem “like a random act of violence,” Daniel Hayes, a breast oncologist at the University of Michigan, told me when we spoke at the asco meeting in Chicago. “Because we’re not very good at telling whether breast-cancer patients will have metastasis, we tend to treat them with chemotherapy as if they all have potential metastasis.” Only some fraction of patients who receive toxic chemotherapy will really benefit from it, but we don’t know which fraction. And so, unable to say whether any particular patient will benefit, we have no choice but to overtreat. For women like Guzello, then, the central puzzle is not the perennial “why me.” It’s “whether me..."
Why was the liver so hospitable to metastasis, while the spleen, which had similarities in blood supply, size, and proximity, seemed relatively resistant? As Paget probed deeper, he found that cancerous growth even favored particular sites within organ systems. Bones were a frequent site of metastasis in breast cancer—but not every bone was equally susceptible. “Who has ever seen the bones of the hands or the feet attacked by secondary cancer?” he asked. Paget coined the phrase “seed and soil” to describe the phenomenon. The seed was the cancer cell; the soil was the local ecosystem where it flourished, or failed to. Paget’s study concentrated on patterns of metastasis within a person’s body. The propensity of one organ to become colonized while another was spared seemed to depend on the nature or the location of the organ—on local ecologies. Yet the logic of the seed-and-soil model ultimately raises the question of global ecologies: why does one person’s body have susceptible niches and not another’s?
I found the following of particular interest, in light of my own 2015 wrangle with prostate cancer.
Widely used gene-expression assays, such as MammaPrint and Oncotype DX, have helped doctors identify certain patients who are at low risk for metastatic spread and can safely skip chemotherapy. “We’ve been able to reduce the overuse of chemotherapy in about one-third of all patients in some subtypes of breast cancers,” Daniel Hayes said.

Hayes is also grateful for the kind of genetic tests that indicate which patients might benefit from a targeted therapy like Herceptin (those whose breast cancers produce high levels of the growth-factor receptor protein HER2) or from anti-estrogen medications (those whose tumors have estrogen receptors). But, despite our advances in targeting tumor cells using genetic markers as guides, our efforts to predict whose cancers will become metastatic have advanced only slowly. The “whether me” question haunts the whole field. What the oncologist Harold Burstein calls “the uncertainty box” of chemotherapy has remained stubbornly closed...
 "OncoType DX"?

From my 2015 blog post:
...Without asking me, my urologist sent my biopsy to a company that performs "OncoType dx" genetic assays of biopsies for several cancers, including prostate. He simply wanted to know whether mine was a good candidate for this type of test.

They just went ahead and ran it, without the urologist's green light order, or my knowledge or consent. I got a call out of the blue one day from a lady wanting to verify my insurance information, and advising me that this test might be "out of your network," leaving me on the hook for some $400, worst case (I subsequently came to learn that it's a ~$4,000 test). I thought it odd, and thought I'd follow up with my doc.

My urologist called me. He was embarrassed and pissed. A young rep from the OncoType dx vendor also called me shortly thereafter. He was in fear of losing his job, having tee'd up the test absent explicit auth.

I've yet to hear anything further. I think they're all just trying to make this one go away. Though, it would not surprise me one whit to see a charge pop up in my BCBS/RI portal one of these days.

The OncoType test result merely served to confirm (expensively -- for someone) what my urologist already suspected. The malignancy aggressiveness in my case is in a sort of "grey zone." The emerging composite picture is "don't dally with this."
That was not a fun year (but, I'm OK now). Neither is this one.

BACK TO MUKHERJEE
David Adams’s father never suffered a recurrence of melanoma; he died from prostate cancer that had spread widely through his body. “Years ago, I would have thought of the melanoma versus the prostate cancer in terms of differences in the inherent metastatic potential of those two cell types,” Adams said. “Good cancer versus bad cancer. Now I think more and more of a different question: Why was my father’s body more receptive to prostate metastasis versus melanoma metastasis?”

There are important consequences of taking soil as well as seed into account. Among the most successful recent innovations in cancer therapeutics is immunotherapy, in which a patient’s own immune system is activated to target cancer cells. Years ago, the pioneer immunologist Jim Allison and his colleagues discovered that cancer cells used special proteins to trigger the brakes in the host’s immune cells, leading to unchecked growth. (To use more appropriate evolutionary language: clones of cancer cells that are capable of blocking host immune attacks are naturally selected and grow.) When drugs stopped certain cancers from exploiting these braking proteins, Allison and his colleagues showed, immune cells would start to attack them.

Such therapies are best thought of as soil therapies: rather than killing tumor cells directly, or targeting mutant gene products within tumor cells, they work on the phalanxes of immunological predators that survey tissue environments, and alter the ecology of the host. But soil therapies will go beyond immune factors; a wide variety of environmental features have to be taken into account. The extracellular matrix with which the cancer interacts, the blood vessels that a successful tumor must coax out to feed itself, the nature of a host’s connective-tissue cells—all of these affect the ecology of tissues and thereby the growth of cancers...
...Considering the limitations of our knowledge, methods, and resources, our field may have had no choice but to submit to the lacerations of Occam’s razor, at least for a while. It was only natural that many cancer biologists, confronting the sheer complexity of the whole organism, trained their attention exclusively on our “pathogen”: the cancer cell. Investigating metastasis seems more straightforward than investigating non-metastasis; clinically speaking, it’s tough to study those who haven’t fallen ill. And we physicians have been drawn to the toggle-switch model of disease and health: the biopsy was positive; the blood test was negative; the scans find “no evidence of disease.” Good germs, bad germs. Ecologists, meanwhile, talk about webs of nutrition, predation, climate, topography, all subject to complex feedback loops, all context-dependent. To them, invasion is an equation, even a set of simultaneous equations...
"...In the field of oncology, “holistic” has become a patchouli-scented catchall for untested folk remedies: raspberry-leaf tea and juice cleanses. Still, as ambitious cancer researchers study soil as well as seed, one sees the beginnings of a new approach. It would return us to the true meaning of “holistic”: to take the body, the organism, its anatomy, its physiology—this infuriatingly intricate web—as a whole. Such an approach would help us understand the phenomenon in all its vexing diversity; it would help us understand when you have cancer and when cancer has you. It would encourage doctors to ask not just what you have but what you are."

Again, great article. Seriously worth your time. Also way worth your time is his last book:


I first cited it here.
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MORE ON THE DX FROM HELL

One of my daily surfing stops is Wired.com. Looking for relevant tech stuff. Ran across this, concerning a Seattle AI tech startup guy:
THE DAY I FOUND OUT MY LIFE WAS HANGING BY A THREAD
Matt Benke


IT STARTED WHILE I was on a Hawaiian vacation in May. I thought I’d just tweaked my back lifting a poolside lounge chair. Back home, my back pain became severe, and I started noticing nerve pain in my legs. For eight days I could barely crawl around the house. My wife and two daughters nicknamed me “the worm.” At 45, I’m in pretty good shape—avid cyclist, runner, weightlifter, yoga enthusiast with a resting pulse in the 50s.

So it was weird when my primary care doctor put me on a cocktail of pain killers, nerve blockers, and cortisone shots. I even tried acupuncture. But as my back began to improve in late June, I started to feel off. Sick to my stomach. Weak. Couldn’t sleep. I lost more than 10 pounds. But I chalked this up to a month of too much Vicodin after a lifetime of thinking two Advil was excessive. My doctor said I was fit and healthy and that there was no need to run any blood tests. He wondered aloud if this was all in my head…

...After nearly a month of feeling horrible despite my back getting better and being off all medications, I hit a wall. On July 26, a Wednesday, I finished my day’s meetings and drove myself to the least busy ER I know of—the one at Swedish Medical Center in the Issaquah Highlands, 20 miles east of downtown.

A couple hours later I called Amy and asked her to join me. They’d already done a bunch of tests and ruled out the obvious—urinary tract infection, epidural abscess—and were sort of grasping at straws. Over the phone, I asked Amy, who is a clinical psychologist, if she could think of anything else I should tell the doctors. “Have you told them about the night sweats?” she asked, her stomach sinking. The look on the ER doc’s face when I passed that on should have been my first clue. (Night sweats are a symptom of some early cancers.) They drew more blood and did a CT scan.

About an hour later, a doctor who specializes in hospital admissions joined the ER doc to report on their findings. The ensuing scene is seared into my brain. He introduced himself to Amy and me so awkwardly that we could not understand him. I gently interrupted his prepared remarks to ask his name, hoping this might put him at ease.

It didn’t. He went on to explain that I had many tumors in my liver, pancreas, and chest. In addition, he explained that I had quite a few blood clots, including in my heart and lungs. “What is ‘many’ tumors?” I asked. He looked defeated, saying they stopped counting after 10. I thought he might cry, and then he started in with some nonsense about how maybe it was all just bad tests, or maybe I had a rare water-borne pest infection. Amy began crying, hard. I went into silent shock and just tried to get this guy to shut up and leave…
...They took a biopsy of one of the tumors on my liver. They surgically implanted a stent in my gall bladder, which immediately relieved my backed-up liver. The medical staff also looked for secondary impacts of the cancer. First among them was blood clots. A couple doctors examined my legs and said, “Slim to zero chance you have clots in your legs—they look too healthy. But let’s check.” A few hours later, bad news: My left leg had clots from my hip to my ankle, though thankfully not fully occlusive. My right leg had clots from knee to ankle...
On Friday the docs woke me with an urgent problem: They had found a blood clot the size of a Ping-Pong ball in my heart’s right ventricle. If it broke loose, I would die instantly, whether I was in an ER or my basement. To make matters worse, they showed me an image of the clot, and it was precariously wiggling on an already-loose attachment. Each time my heart beat, the ticking time bomb swayed precariously. The clot was too big to suck out with a vacuum, too risky to slice and remove bit-by-bit, and too large to remove from the side by breaking open a few ribs. Nope, removing it was urgent and would require cracking my sternum. Today...
Shit. His family has mounted a "members-only" Facebook support and updates group. I asked to join. My request was granted. I don't know any of them. Just have, beyond acute empathy, a decades-long affinity for the Seattle area, where I still have many dear friends (both of my girls were born in Seattle).

I feel enjoined to not share what I've learned there from their frank updates. I just wish them all the strength they will all need.

Pancreatic cancer. Truly "the dx from Hell."

My daughter had a brain scan this morning. No rad report yet.

DX TECH UPDATE

IBM pitched its Watson supercomputer as a revolution in cancer care. It’s nowhere close

It was an audacious undertaking, even for one of the most storied American companies: With a single machine, IBM would tackle humanity’s most vexing diseases and revolutionize medicine.

Breathlessly promoting its signature brand — Watson — IBM sought to capture the world’s imagination, and it quickly zeroed in on a high-profile target: cancer.

But three years after IBM began selling Watson to recommend the best cancer treatments to doctors around the world, a STAT investigation has found that the supercomputer isn’t living up to the lofty expectations IBM created for it. It is still struggling with the basic step of learning about different forms of cancer. Only a few dozen hospitals have adopted the system, which is a long way from IBM’s goal of establishing dominance in a multibillion-dollar market. And at foreign hospitals, physicians complained its advice is biased toward American patients and methods of care...
Another long-read. Rather scathing.

"Free Beer Tomorrow?"

Good audio discussion at NPR's WBUR:

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More to come...

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