In this follow-up to the previous Doc Gumshoe missive about cancer, entitled “Cancer 2023 – What’s Happening in the Combat Zone,” which posted on July 18, we’ll be discussing several general types of cancer – brain, lung, ovarian, breast, liver, and cancer caused by obesity. In each case, however, there are special conditions associated with these cancers that have required further research in an effort to find treatment options that improve outcomes beyond those resulting from previous treatment options. And not all of these efforts have been outstandingly successful, to say the least. But in every case, the knowledge base increases as a result of the research. It can be said that no cancer research is a waste of effort, regardless of the result.

I guess what I’m doing here is preparing you for a fairly complex read that contains no miracles, but does describe some slow and steady advances. On the whole, slow and steady advances are what characterize the cancer treatment field… I don’t think that even the most sanguine cancer researcher expects to see a day like August 14, 1945 in the cancer treatment battlefield, where the enemy surrenders unconditionally.

Let’s look at what’s going on in the treatment of some individual cancers.

Brain cancers

One form of brain cancer that has been resistant to treatment is papillary craniopharyngioma (PCP), which is a brain tumor on the axis between the pituitary and hypothalamus glands. Treatment with surgery, radiation, or a combination of the two has not proved successful, frequently leading to loss of vision, memory loss, and neuroendocrine dysfunction.

It has been shown that more than 90% of these tumors have a mutation in a gene called BRAF. The non-mutated BRAF gene, working through a common protein, regulates normal cell growth. But the mutation in the BRAF gene, called BRAF V600E, triggers uncontrolled cell growth, including the growth of cancer cells.

A small clinical study in 16 patients who had this form of brain cancer investigated the effect of a combination of agents designed to inhibit the BRAF V600E gene. The agents, vemurafenib (Zelbograf) and cobimetinib (Cotellic), both from Genentech, are also MEK inhibitors, MEK being another gene that fosters the growth of cancer cells. (MEK, by the way, is also a factor in other cancers including pancreatic cancers.) The drug combination was given every 28 days during a median follow-up period of 22 months.

Of the 16 patients in the study, 15 were judged to have a durable objective partial response or better to the therapy. The median reduction in the volume of the tumor body was 91%, and at 12 months after conclusion of the study, 87% of the patients showed no progression of the tumor. At 24 months after conclusion of the study, that percentage had dwindled to 58%. The single patient who did not have any response to therapy had stopped treatment after 8 days due to toxic effects from therapy.

Adverse events that were at least possibly related to treatment occurred in 12 patients, including rash in six patients. In two patients, somewhat more serious adverse events were reported – hyperglycemia in one patient and elevated creatine kinase levels in one patient. Three patients in total discontinued treatment because of adverse events.

The combination of vemurafenib and cobimetinib is generally used to treat melanoma, which, by the way, frequently carries that same mutation to the BRAF gene. Targeting specific pathways that foster the growth of cancer cells is an increasingly favored tactic in cancer treatment.

The study was published in the New England Journal of Medicine on July 13, just a couple of weeks ago as I am writing this. (N Engl J Med 2023. 389;118-126)

A potential treatment for low-grade glioma

Gliomas are cancers of the glial cells, a group of cells that are very numerous in the brain and provide a supportive environment for neurons, which as you know are the active cells that essentially do all the work of the brain. Glioma as a category includes glioblastomas, of which there are several types. Glioblastomas mostly affect one type of brain cell, the astrocytes. As you may remember, that’s what killed Senator John McCain.

However, the specific clinical trial we’re discussing here was not in a glioblastoma, but in the more common, low-grade glioma, which is a form of brain cancer for which there has been no treatment advance in several decades. The options have been surgery when possible, or radiation and chemotherapy, with very limited success and significant adverse effects.

A study in 331 subjects with low-grade glioma found that vorasidenib (from Servier Pharmaceuticals)  was effective in lengthening the period of time before the patients’ cancers progressed, with no observed adverse effects. Compared with the placebo cohort, the trial subjects who took vorasidenib had a median of nearly 28 months of progression-free survival. The result was considered as an unprecedented improvement over previous treatment options.

Vorasidenib is an inhibitor of the adverse effects of mutations in two enzymes, IDH1 and IDH2. These mutations can cause a number of cancers, including blood, bone, liver and other cancers. As with many new cancer drugs, demonstrating efficacy in a single cancer can lead to use – and perhaps FDA approval – in other cancers.

Non small-cell lung cancer (NSCLC)

We’ll be looking at a couple of trial results in NSCLC patients. One was in patients with a certain form of lung cancer who were diagnosed early enough to have their tumors surgically removed. The other is not about a drug, but about an electrical device that cancer patients wear, which generates tumor treating fields which are supposed to help fight cancer.

AstraZeneca’s Tagrisso scores a big hit

In a 682-patient trial called ADAURA, Tagrisso (osimertinib) was evaluated against a placebo in earlier-stage EGFR-mutated NSCLC patients who had undergone surgery to remove their primary tumor. In most patients who have such surgery, the tumor returns.

EGFR is epidermal growth factor receptor, which is a protein found on the surface of most cells. This protein controls the growth of cells; mutated EGFR instructs cancer cells to grow and multiply more quickly, speeding the growth and spread of the cancer.

In the trial, about 88% of patients treated with Tagrisso were alive five years after the start of the trial. This compares with 78% of those on placebo. In a different calculation, Tagrisso was estimated to cut the risk of death by 51% compared to placebo. Tagrisso is the only drug that has been proved to cut the risk of death in mutated NSCLC.

Thus far, Tagrisso’s FDA approvals have all been in the treatment of NSCLC and its several variants.
Tagrisso is described as the “crown jewel” in AstraZeneca’s portfolio, taking in about $5.4 billion per year.

An electrical device for treating metastatic NSCLC

The device in question is called Optune, from Novocure, an outfit specializing in medical devices.

Novocure is headquartered on the island of Jersey, off the coast of the UK. Optune is a device that cancer patients can wear. It generates electric fields, called tumor-treating fields (TTF) that are supposed to combat cancerous tumors.

At the recent meeting of ASCO, Novocure presented results from the Phase 3 LUNAR clinical trial, which evaluated the use of TTF in conjunction with standard therapies for the treatment of NSCLC. The LUNAR trial met its primary endpoint with a statistically significant and clinically meaningful 3-month improvement in median overall survival when TTF therapy was added to standard therapies. The survival of trial subjects receiving the Optune TTF in addition to standard therapy was approximately 36% greater than the survival of the cohort on standard therapy alone.

A profound overall survival benefit from TTF therapy was demonstrated in the immune checkpoint inhibitor (ICI) subgroup. Patients randomized to receive TTF therapy and physician’s choice ICI demonstrated a median overall survival of 18.5 months versus a median overall survival of 10.8 months in patients treated with ICIs alone. The Optune TTF therapy was well-tolerated with no systemic toxicities, very few device-related grade 3 adverse events and no grade 4 or 5 adverse events.

Those improvements in survival may not seem like much to those of us who are (fortunately!) in good health and looking forward to many years of life on Planet Earth. But bear in mind that those are median figures. Some individuals may indeed have many years to look forward to. And we should also regard these comparatively small improvements in survival as meaningful gains in our overall campaign against the widely-diverse capital C adversary.

Breast cancer

A study by Harvard Medical School researchers asserts that as many as one-third of breast cancer cases arise through a newly-identified mechanism, which shows that the sex-hormone estrogen is the culprit causing a molecular dysfunction which alters the DNA of cells. The study’s senior investigator, Peter Park, a Harvard Medical School professor, said, “We have identified what we believe is the original molecular trigger that initiates a cascade culminating in breast tumor development in a subset of breast cancers that are driven by estrogen.”

In a general sense, estrogen has a role in all breast cancer cases because it stimulates the division and proliferation of all breast tissue cells, which increases the risk that cancer-causing mutations will emerge. The new study, however, demonstrates that estrogen causes harm in a more direct manner.

Most breast cancers are caused by accidental and purely random breaks in the DNA of cells which are improperly repaired, such that chromosomes get rearranged. In most instances, scrambled chromosomes prevent the cell from multiplying as usual; instead the messed-up cells perish without replicating. But some cells with chromosomes that have patched together incorrectly are able to multiply as usual, and, in some cases, multiply faster than cells with the correct chromosomal pattern. It is those rapidly-multiplying cells with abnormal chromosomal structures that are cancerous.

Cancer experts can often identify tumor cells with incorrectly patched together chromosomes by means of genomic sequencing. But some breast cancer cases do not show this mutational pattern. A question then emerges as to the cause of these tumors.

The study authors, Peter Park and Jake Lee, analyzed the genomes of 780 breast cancers obtained from patients diagnosed with the disease. They expected to find the usual chromosomal disarray in most of the tumor samples, but many of the tumor cells bore no trace of this molecular pattern. Instead of the classic misshapen and improperly patched-up single chromosome, they saw that two chromosomes had fused, suspiciously near “hot spots” where cancer genes are located. These rearranged chromosomes had formed bridges, except in this case, the bridge contained two different chromosomes. This distinctive pattern was present in one-third (244) of the tumors in their analysis.

When the researchers focused closely on the areas of cancer-gene activation, they noticed that they were curiously close to estrogen-binding areas on the DNA. They found that these estrogen-binding sites were frequently next to the zones where the early DNA breaks took place. This suggested that estrogen might be somehow involved in the genomic reshuffling that gave rise to cancer-gene activation.

In vitro experiments provided more evidence of estrogen’s role. Exposing cells to estrogen and then using CRISPR gene editing to cut the cells’ DNA initiated a repair chain that resulted in the same genomic arrangement that had been found in the tumors whose rearranged bridges contained two different chromosomes.

Estrogen is already known to fuel breast cancer growth by promoting the proliferation of breast cells. However, the new observations cast this hormone in a different light. They show that estrogen is a more central character in cancer genesis because it directly alters how cells repair their DNA.

The findings suggest that estrogen-suppressing drugs such as tamoxifen, which is often given to patients with breast cancer to prevent disease recurrence, work in a more direct manner than simply reducing breast cell proliferation. The researchers propose that tamoxifen and other estrogen-suppressing drugs may prevent estrogen from initiating cancer-causing rearrangement of genomes within cells, thus preventing – or at least impeding – the onset of the cancer itself.

Whether the study could have downstream implications for breast cancer treatment or cancer testing is still to be determined. But it is an unquestionable advance in our understanding of the genesis of the disease.

Restoring natural killer cells in persons with obesity may help reduce cancer risk

Just about everybody recognizes that being obese is not good for our health. Persons with obesity are at significantly higher risk from cardiovascular disease and diabetes, and it’s not hugely difficult to figure out why this is so. However, it’s not so generally known that somewhere between 4% and 8% of all cancers can be attributed to obesity.

Obesity is a risk factor for several major cancers. These include post-menopausal breast cancer, colorectal cancer, endometrial cancer, and cancers of the kidney, esophagus, pancreas, liver, and gall bladder. Statistically, excess body fat results in an approximately 17% higher risk of cancer-specific mortality.

The specifics of the relationship between obesity and cancer risk are not totally understood, but (to quote a detailed review), it involves “altered fatty acid metabolism, extracellular matrix remodeling the secretion of adipokines and anabolic and sex hormones, immune dysregulation, and chronic inflammation.” (S. Pati, Cancers 2023 15;485) I am none the wiser.

But it does appear that a certain class of drugs, mostly used to treat diabetes, has another effect which may mean that these drugs could also be used in the treatment of cancer. The drugs are termed glucagon-like peptide 1 (GLP-1) agonists, meaning that they support rather than inhibit the action of that peptide. A peptide, by the way, is fairly simple molecule composed of amino acids. GLP-1 agonists improve control of blood glucose by signaling the insulin-producing cells in the pancreas to step up insulin release. They also slow down the digestive process a bit, which produces a feeling of satiety and reduces the appetite, which results in weight reduction.

Drugs in that class include dulaglutide (Trulicity, from Eli Lilly), exenatide (Byetta, also from Eli Lilly), semaglutide (Ozempic) and liraglutide (Victoza, both from Novo Nordisk). Weight loss varies with which GLP-1 agonist is used and also the dose.

One of the many unfortunate effects of obesity is that it appears to lead to a deficiency in natural killer (NK) cells. NK cells are a vital component of our immune system, and they have a number of functions. They can be taught by other participants in our immune responses to recognize not only invaders such as viral particles (as you surely remember, it was the NK cells that did the brunt of the work of getting rid of those COVID-19 virus particles), but also cancer cells.

Individuals who are obese have functionally defective NK cells, which have a decreased capacity to produce cytokines and kill cancer cells. Investigators suggest that it is plausible that changes in NK cell activity are contributing to the many adverse health consequences in obese persons. These include, as discussed above, a significantly increased risk of cancer.

A group of investigators from The Obesity Society conducted a study to determine whether therapy with a GLP-1 agonist might restore NK cell function in obese persons. In a cohort of 20 persons with obesity, the study investigated whether six months of once weekly treatment with semaglutide could restore NK cell function and metabolism. As measured by cytotoxicity assays and production of interferon gamma and granzyme B, the semaglutide treatment did increase NK cell function. The reported improvements in NK cell function appeared to be independent of weight loss. The conclusion of the researchers was that the restoration by means of GLP-1 therapy of NK cell functionality in persons with obesity may be contributing to the overall benefits observed with this class of medications. (The Obesity Society. Obesity 2023;1–11.www.obesityjournal.org)

In other words, treating obese individuals with those GLP-1 diabetes drugs that result in weight loss may also help reduce the risk of cancer that commonly affects obese persons. One more reason to think of obesity as a health risk.

Somewhat confusing results from a trial of Tecentriq plus Avastin in liver cancer

The particular subset of liver cancer patients at issue here are those who have had surgery for liver cancer (hepatocellular carcinoma) and were considered to be at high risk of recurrence. Hepatocellular carcinoma is one of the most serious cancers, with a five-year survival rate of about 17%. The trial in question, dubbed IMbrave50, enrolled 668 subjects randomly assigned either to combination therapy with atezolimumab (Tecentriq, from Roche) and bevacizumab (Avastin, from Genentech, which is part of Roche) or to active surveillance.

Initial results were announced at the American Association for Cancer Research’s 2023 annual meeting. The Tecentriq / Avastin combination reduced the overall risk of recurrence or death by 28% compared with active surveillance. However, in an early evaluation of the trial subjects’ life expectancy, the Tecentriq / Avastin combo was linked o a 47% increased risk of death. The presenter, Pierce Chow, Ph.D., from the Duke-NUS Medical School, pointed out that the overall survival analysis was “highly immature,” since it was based on the deaths of 47 patients, which amounted to just 7% of the total trial population.

In the first year of the trial, there were 27 deaths in the Tecentriq / Avastin arm, of which three were related to COVID-19. None of the 20 deaths in the control arm were related to COVID-19 in the first year.
The number of deaths caused by liver cancer recurrence was similar between the two arms, according to Chow. But two patients’ deaths (0.6%) were deemed related to treatment with Tecentriq or Avastin.
More broadly, investigators recorded a 24.1% rate of serious side effects for the Tecentriq-Avastin combo, including 13.3% related to treatment. In contrast, the surveillance group logged a 10.3% rate of serious side effects.

The overall trial design would likely make it difficult for Tecentriq to show an overall survival advantage at the conclusion of the trial. Patients in the control arm are allowed to cross over to receive the Tecentriq / Avastin combo after recurrence. Of the 133 patients in the control group whose cancer did return, 61% so far have gone on to receive the combo.

In addition to the safety concern, the trial was conducted mainly in Asia. Patients who are identified as Asian make up nearly 82% of the entire trial population, and about 62% of participants have hepatitis B, which, according to the Centers for Disease Control and Prevention, accounts for just about 15% of liver cancer cases in the U.S. Liver cancer does disproportionally affect Asians, in part because of viral hepatitis, which is more common in that part of the world.

The adverse effects data in particular could cause difficulties for Roche in securing FDA approval for Tecentriq for this specific form of cancer. Tecentriq already has FDA approvals for both non-small cell and small cell lung cancers, melanoma, and liver cancers not considered treatable by surgery.

A blood test can identify twelve different types of cancer based on single cells

The test has been developed by a Canadian outfit called Adela, formerly known as DNAMx. It looks for small pieces of tumor DNA that are released from dying cancer cells into the blood stream. These can be identified by analyzing the patterns of the molecules attached to the DNA strands that help govern which genes are turned on or off, a pattern called methylation.

The test was announced at the annual meeting of the American Association for Cancer Research (AACR) in Orlando earlier this summer. The findings were the result of a retrospective study based on an analysis of archived blood samples from about 4,000 patients. The different cancers included bladder, breast, colorectal, endometrial, esophageal, lung, ovarian, pancreatic, prostate, kidney, head and neck, and the liver, gallbladder and bile ducts.

Methylation patterns differ between cancerous and non-cancerous cells. These abnormal patterns can be key drivers of the continuous, unrelenting growth of cancer cells. Some of these patterns are common to several cancer types, but there are methylation patterns that are specific to the tissue where the cancer dwells.

Adela’s test aims to capture the methylation pattern across the entire cancer genome using a machine learning algorithm, without pre-treatment with chemicals or enzymes that may damage genetic material, and without needing to decode the entire sequence of DNA.

The company said its preliminary study results showed its test could tell the difference between blood samples that had evidence of cancer and those that didn’t 94% of the time, including all cancer types and stages. About half of the samples with cancer were in stage I and stage II, and were correctly spotted 92% and 95% of the time respectively. Stage III and IV cancers were identified at rates of 95% and 97%, according to Adela.

It should not be necessary to say that such a test would be enormously valuable.

A tentative conclusion?

No, nothing above qualifies as President Biden’s “Cancer Moonshot.” I don’t know if there will ever be a “cancer moonshot” – a single, unified, cancer treatment option that effectively “cures cancer.” I don’t even know if Joe Biden meant it that way; more likely what The Authorities are aiming for is a suite of treatment options that covers the entire cancer spectrum. Doc Gumshoe’s personal skeptical view is that cancers, being endowed with the unrelenting will to survive in some form, will always be with us – in some form. Our best hope is to subdue and control most manifestations of this infernally variable curse so that we humans can live out our allotted lives in health and felicity.

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Forgive me if this was too abstruse and insufficiently conclusive. I will try to make the next one a bit easier to digest. I am going to take another look at Lyme and other tick-borne diseases. The last time I took up that subject, I think I came to the wrong conclusions. Thank you for putting up with me. Best to all and stay well, Michael Jorrin (aka Doc Gumshoe)

[ed note: Michael Jorrin, who I dubbed “Doc Gumshoe” many years ago, is a longtime medical writer (not a doctor) and shares his commentary with Gumshoe readers once or twice a month. He does not generally write about the investment prospects of topics he covers, but has agreed to our trading restrictions.  Past Doc Gumshoe columns are available here.]