Thread by @ReformedTrader

1/ The Cancer Code (Jason Fung)

"The most important aspect of cancer progression is the growth pathways of the body, which are also the nutrient-sensing pathways. While there is more to discover, this new paradigm represents a huge leap forward." (p.311)

amazon.com/Cancer-Code-Re…

2/ "In medical research, opinions that dissent from the specified narrative are not welcome.

"John Maynard Keynes is quoted as having said, “The difficulty lies not so much in developing new ideas as in escaping from old ones.” " (p. 3)

3/ "From 1990 to 2002, 68% of the FDA approvals were for cancer drugs that did not necessarily improve life expectancy.

"The most common reason for approval is called the “partial tumor response rate:” the drugs were shown to shrink the primary tumor in volume by over 50%.

4/ "That measure is irrelevant to survival. Cancer is deadly because it moves (metastasizes), not because it is big.

"From 1990-2002, 71 new drug approvals were granted for 45 new drugs. Of those, only 12 were proven to save lives, most by only a few weeks or months." (p. 11)

5/ "Cancer was likely rare in ancient times because it is a disease of aging, and life expectancy was low. If people are dying young from famine, pestilence, and war, then cancer is not a big concern." (p. 16)

6/ "Because the Warburg effect (aerobic glycolysis) is less energy efficient, cancer requires far more glucose to sustain metabolism.

"A PET scan reveals those areas that take up glucose more briskly. These “hot spots” are evidence of cancer activity." (p. 37)

7/ "While chronic radiation is a carcinogen, acute radiation may not be as carcinogenic as initially feared." (p. 50)

"Even in cancers with known high genetic risk, environment plays the dominant role. In most common cancers, genetics contributes only 20-40% of the risk." (p.84)

8/ "The U.S. breast cancer rate is 2-4x higher than in China or Japan. A Chinese woman who moves to San Francisco doubles her risk vs. the same woman in Shanghai. Within a few generations, the risk for that immigrant’s family approximates that of a white woman in San Francisco.

9/ "The same phenomenon can be observed in other cancers.

"But for stomach cancer, we see the reverse. In this case, we know this reduced risk is likely the result of reduced exposure to bacterial infestation with H. pylori." (p. 88)

10/ "By 2006, there were signs that cancer mutations were much more complex than first imagined.

"Rather than 2 or 3 or 4 gene mutations, there are hundreds. Worse, these genetic mutations are distinct from one cancer to the next. Each tumor carries an average of 11 mutations.

11/ "Breast cancer number one would have eleven genetic mutations, but breast cancer number two would have eleven completely different mutations. Two breast cancers that looked identical clinically could be completely different genetically, barely resembling each other.

12/ "For most common cancers, one hundred random cases had one hundred different genetic profiles of mutations, each completely distinct from the others. This meant that a drug that was effective for colorectal cancer in person A would not likely be effective for person B.

13/ "By 2015, researchers had identified ten million different mutations. Mutations differed not only from patient to patient but even within the same tumor in the same patient.

"Different cancers had different rates of mutation. Some had hundreds. 73 cancers had none at all.

14/ "If mutations caused cancer, how could 35% of cancers not have a single mutation?

"And normal cells don’t mutate anywhere close to the rate needed to produce cancer.

"Cancer was a baffling mishmash of genetic peculiarities with almost no connection to one another." (p. 94)

15/ "Cancer patients had lots of mutations, but so did cancer-free people, some with identical mutations as those with cancer. A 2012 analysis concluded, “the vast majority of, if not all, aberrations in the cancer-affected cohort were also in the cancer-free subjects.” " (p.100)

16/ "The rate of mutation in the general population is very low: much, much lower that rate necessary to drive so many cancers. The process of randomly assembling 50-200 mutations together in a coherent form is so extraordinarily complex that cancer should be vanishingly rare.

17/ "In cancer, asbestos causes DNA damage, genetic mutations, and also a cancer called mesothelioma, but not breast or colorectal cancer. Almost nothing else in the world causes mesothelioma. So, the genetic damage caused by asbestos is clearly not random.

18/ "These hallmarks of cancer are carefully selected. Something is pushing these oncogenes and tumor suppressor gene mutations toward growth, movement, immortality, and the Warburg effect." (p. 104)

19/ "The focus on cataloguing mutations drained the lifeblood from other areas of research.

"Insisting that cancer is a disease of collected mutations is like insisting the Declaration of Independence is a collection of letters. So what? How does it help us understand cancer?

20/ "The somatic mutation theory tried to adjust for these unexpected findings by adding ad hoc modifications. Some mutations, termed “drivers,” mattered, and others, termed “passengers,” did not. There was not a single genetic clone, but changes in clonal evolution over time.

21/ "With each iteration, the complexity of the SMT increased until it was no longer a simple, elegant theory. It sported multiple unwieldy, cobbled-together additions.

"Finally, the entire SMT collapsed. It also failed to deliver more than a few effective treatments." (p. 108)

22/ "In cancer trials, progression-free survival (PFS: time from treatment to disease progression, defined as a less than 20% increase in tumor size) and response rate (RR: the % of patients whose tumor shrinks more than 30%) are two commonly used surrogates for overall survival.

23/ "82% of studies find the correlation between surrogate markers & overall survival to be low. Surviving cancer depends almost entirely on stopping metastasis, a different beast than reducing tumor size. Just because an outcome is easily measurable does not make it meaningful.

24/ "Cancer becomes more lethal when it mutates to become more aggressive or more likely to metastasize. Size-based surrogate outcomes like PFS & RR make little difference. Shrinking a tumor by 30% has virtually no effect on survival because of cancer’s uncanny ability to regrow.

25/ "Surgery is never done to remove 30% of tumor mass: that would be futile. Missing even a microscopic part means the cancer will recur. While only 6% of drugs reached provided complete remission, from 2006-18, 59 oncology drugs were approved by the FDA based on RR." (p. 112)

26/ "Despite the seventy-two “new” cancer medications approved between 2002 and 2014, the average drug extended life by only an average of 2.1 months. That’s only an average, and most drugs offered no survival benefits at all." (p. 114)

27/ "Combining high prices with low efficacy means that the cost-effectiveness ratio is off-the-charts bad. A generally acceptable cost of one quality-adjusted life year (QALY) is $50,000. Cervical cancer screening has an estimated cost/QALY of <$35,000. Imatinib's is $71,000.

28/ "Regorafenib, used for metastatic colorectal cancer, costs $900,000/QALY.

"A high-priced drug does not necessarily work better. Expensive drugs may not even work. This is a problem when drug costs are the single largest cause of personal bankruptcy in the U.S." (p. 117)

29/ "Millions of cancer research dollars over several decades produced an abundance of new drugs. Some are truly great, but most are marginally effective, yet fantastically expensive. Benefits are borderline, toxicity is high, and cost is higher still." (p. 117)

30/ "DNA methylation is one of the main mechanisms of epigenetic changes. Changes to the DNA methylation of tumor suppressor genes can silence those genes, which favors growth and cancer. This change to gene expression, and therefore risk of cancer, occurs without any mutation.

31/ "Environmental factors such as diet & exercise influence gene expression. Epigenetics upends the old dogma that the genetic code is the key determinant of gene expression/function. The packaging of the gene may be as important as, or even more important than, the gene itself.

32/ "By the time work on the Cancer Genome Atlas started, it was already well-known that changes in DNA methylation are vital to the development of some cancers. A number of known carcinogens are considered to act through epigenetic pathways." (p. 122)