End of Cycle Four and the Way Forward - After Cycle Three, Dr. Koeneke decided to call an end to the Carboplatin and Taxotere infusions. So Cycle Four consisted of the Phesgo injection only. The goal remains to root out any cancer cells that may have wandered away from their origin in her right breast and for Gloria to regain some of the 20 pounds of weight she has lost.

A Correction - In order to get all of the important aspects in a cycle into an update, it is necessary to wait until the cycle is complete. Then it takes some time to compose the report. While casting about for photos for the Cycle Three report, I inadvertently grabbed three that were taken during the early part of Cycle Four i.e., the cycle reported here. Those have been transferred to this update.

Cycle Four Commences - This cycle began on March 25 with a Phesgo injection into Gloria's right thigh. The only reaction noted over the next couple of days was a slight downtick in her level of energy and one incident of diarrhea.

A trip to Wisconsin had been planned for April 1, with a return on April 14. On April 16, our "German son" Tim was to fly in and stay with us until he returned to Berlin on April 21. Cycle Five would begin the next day.

The seven days prior to the Appleton trip were pretty uneventful in most regards. Gloria seemed to become more animated day-to-day as the time passed, but her weight stubbornly hovered between 116 and 117 pounds. Since we would be gone on Easter, we celebrated with Mariya, Miriam and Diana the Sunday before with one of my ham dinners. Gloria's contribution was a plate of deviled eggs - which we all forgot to bring out during the meal. Nonetheless, they were appreciated as an unusual dessert!

Gloria's April 24 column covered the events of both the Appleton trip and Tim's visit, and so I decided to plagiarize it for most of the update covering that period. After, I will discuss what Phesgo is and how it works as it was last mentioned in the 3 November update - now 6 months ago - and Phesgo was given little space compared to Carboplatin and Taxotere.

Gloria's April 24, 2026 Column -

Traditional Drugs - The chemotherapy drug Carboplatin had its origins in an experiment performed at Michigan State University in 1965. While looking at the effect of electricity on a particular bacteria, the researcher chose to use platinum electrodes as it was known to be a relatively inactive material and so unlikely to have an impact on the experiment. A better choice would have been gold, but the expense would have been much greater.

But the platinum wasn't passive enough, did have an impact, and formed a compound that hindered cell reproduction. This undesired and unexpected effect has now been used to treat cancer victims ever since.

Taxotere can trace its origins back to the 1960s when the National Cancer Institute began testing over 100,000 plant materials for anti-cancer properties. A compound that fit the bill was discovered in a West-coast yew tree.

The researchers involved in these efforts certainly deserve accolades for their powers of observation and diligence, but it seems a bit like looking for a home by wandering about in nature and seeing what you find. What was found might be thought of as a couple of caves - they work, but not very well. This is medicine from the era portrayed in the Flintstones cartoon.

Phesgo is Different - The drugs in Phesgo are quite different. They are much closer to a modern home where materials are selected and put together in order to achieve a particular effect.

In order for an animal to continue to live, dead cells or ones that are "over the hill" must be replaced. So cell reproduction is a good thing. But cancer is too much of this good thing! The problem becomes one of returning reproduction to an appropriate level- to turn it down, but not off.

An important part of the reproductive system for many body cells are the Human-Epidermal-Growth-Factor Receptor (HER) proteins. All breast cells have them. Each pokes through the cell membrane, so one end is on the outside and the other is on the inside. When a nearby cell detects the need for growth, perhaps due to an injury, it creates a protein called a ligand that finds its way to its neighboring cells. When the ligand reaches an HER receptor, a sequence of events is initiated that results in the receiving cell reproducing.

That's how it is supposed to work.

There are four types of HER cells, cleverly named HER1, HER2, HER3, and HER4. The HER2 protein is different from the other three, having no known ligand it responds to. Instead, it works as a sort of helper for the other three. So when HER1, HER3, or HER4 are activated by a ligand, it typically pairs with an HER2 to initiate duplication.

But an error in a cell can cause it to generate too many HER2 proteins. Those can then team up with one of the others in the HER family without the linking provided by a ligand or may even just pair with another HER2 receptor to trigger reproduction i.e., thereby producing uncontrolled growth.

Both of these actions must be blocked to stop cell proliferation. Phesgo has two chemical components, one targeting each. Pertuzumab (per-TOO-zoo-mab) blocks HER2 proteins from pairing with other HER family members and trastuzumab (tra-STOO-zoo-mab) blocks an HER2 protein from pairing with another HER2 protein.

Immune System Similarity - In many regards, the Phesgo drugs act much as a person’s immune system does to defeat a disease.

Whenever the immune system detects an invader, it looks for some molecule on the rascal's surface that is unique to it. It then creates what are called antibodies. These are little Y-shaped proteins about one thousandth the size of a red blood cell. Both upper legs of the Y have molecules that are the mirror opposites of the unique surface molecule found on the invader. If while circulating in the blood, one of these antibodies encounters an invader, one of the Y legs will stick to that unique area.

This generally blocks the invader from doing whatever it normally does, such as invading a healthy cell.

After a successful invasion is repulsed, the excess antibodies may stay in the body for years. If a person ever encounters the same pathogen again later in life, the immune system reacts swiftly as these antibodies are already on duty. For a healthy adult, the accumulated antibodies of a lifetime of fending off threats account for about 1 percent of the blood volume or about the weight of 10 nickels for an average adult human.

A response will come more slowly for an invader never before encountered due to the need for the recognition, antibody-creating, and duplicating phases to first complete.

Pertuzumab and trastuzumab are called monoclonal antibodies. They are antibodies designed to recognize and lock on to different parts of the HER2 protein. Pertuzumab blocks HER2 from pairing with the other three HER receptors, while trastuzumab blocks it pairing with another HER2 receptor.

The accumulation of antibodies at any location invites an attack by the immune system's four types of "clean-up" cells by, in effect, poisoning and engulfing the cells targeted by the antibodies.

Where the Rubber Meets the Road - It's a big jump from theory to an actual therapy. Ignoring all the subtleties, the principal problems are to develop the antibodies pertuzumab and trastuzumab - also called Perjeta and Herceptin - duplicate them by the billions, and figure out how to deliver them.

There are about 120 different known atoms, but only 94 occur naturally. Of these, 20 are common. It only takes 11 to make up 99.9 percent of the human body. The proteins which make up the bulk of our being are created by chaining these common ones together like LEGO pieces. Pertuzumab - trastuzumab is similar - has about 10,000 hydrogen atoms, 6,500 carbon atoms, 2,000 oxygen atoms, 1,700 nitrogen atoms, and 40 sulphur atoms, for a total of about 20,000 atoms. Even if we knew how to do it, the process of "building" such a protein atom by atom would be excruciatingly slow.

Since the only important differences between various human antibodies is the binding head at the Y tips, that is where the effort is focused. In other words, we'll modify existing antibodies rather than build wholly new ones.

This part, as the Brits say, is a little "fiddly." It involves looking at the target cell's DNA and finding the part that generates the target part of the HER2 protein. Then the mirror image of the structure is created and, in effect, tacked to an existing antibody whose tips have been removed.

Now we need the resulting protein in large numbers. It is more than a bit ironic that the device used to achieve this end is a myeloma cancer cell! But it makes sense. Cancers are efficient copy machines and that is exactly what is needed.

A typical Phesgo injection contains 0.6 grams - the weight of about 10 percent of a nickel - of each of the two antibodies. These will be injected in the patient's thigh where they will join the body’s normal 50 grams of antibodies that have been collected over a lifetime of doing battle with diseases. The two active ingredients are dissolved in 10 milliliters of water containing an agent that facilitates absorption.

This is admittedly very clever. In some cases, tumors that were inoperable have been shrunk to the point they can be surgically removed. Others have vanished altogether. But there is a price to be paid.

Cancer cells are not the only ones with HER2 receptors and the Phesgo antibodies do not distinguish between the desired and undesired cells. One organ that relies on healthy HER2 operation is the heart. So, once again, there is no free lunch and a balance must be struck. Phesgo treatments come with the necessity of monitoring its effects on the heart with a possible need to curtail treatment.

And, of course, there is a dollars-and-cents price tag, although it is more dollars than cents. The price tag for all this clever chemistry? About $10,000 per injection, or a quarter for every minute between normal three-week injection cycles.