Is it breast cancer or lung cancer? (12/6/24)

 Daryl Morey was the general manager for the Houston Rockets from 2007-2020. His approach to hiring NBA talent leaned heavily on the application of advanced statistical analysis, a skill he developed working in a consulting firm after studying computer science at Northwestern. I’ll let Michael Lewis take it from here:

“From his stent as a consultant he learned something valuable, however. It seemed to him that a big part of a consultant’s job was to feign total certainty about uncertain things. In a job interview with McKinsey, they told him that he was not certain enough in his opinions. ‘And I said it was because I wasn’t certain. And they said, we’re billing clients five hundred grand a year, so you have to be sure of what you’re saying.’  The consulting firm that eventually hired him was forever asking him to exhibit confidence when, in his view, confidence was a sign of fraudulence…A lot of what people did and said when they ‘predicted’ things, Morey now realized, was phony: pretending to know things rather than actually knowing things. There were a great many interesting questions in the world to which the only honest answer was, ‘it’s impossible to know for sure.’”

I think this perspective is extremely important as we proceed in the next steps of finalizing a diagnosis and developing a treatment plan—neither of which have been nailed down yet. As one of my cardiac surgical attendings would often remind me during difficult parts of an operation as a fellow, the worst thing you can do in a game of chess is to rush the next move.

This past week we finally received the final results on the Tempus genomic sequencing studies that were performed. The diagnosis rendered was metastatic moderate to poorly differentiated adenocarcinoma. Tumor origin prediction was also performed using an artificial intelligence model that provides a quantitative estimate based on gene expression. There’s a 51% chance that this cancer originated in the breast and a 42% chance that it came from the lung. Like the NFL playoff picture, there are other possibilities that are hypothetical contenders but not likely to be relevant after the first round of assessment (sorry Cowboys fans). Interestingly, each of the oncologists we have spoken with (be they breast or thoracic in training) lean towards lung as the primary. Mammary analog secretory carcinoma of the lung is probably the best guess, but as they say, “it’s impossible to know for sure.”

If you’re one of the blind men trying to describe this elephant, you’d likely formulate your opinion based on one of three different features. Estrogen receptor positivity (which was somewhat discordant between biopsies) occurs in 60-80% of breast cancers, compared with only 10-15% of lung cancers. PD-L1 receptor positivity, on the other hand, favors lung at 24-60% vs. 10-30% in breast. While the RET fusion mutation is only present in 0.7-2% of lung cancers, it’s even more uncommon in breast cancer. I brought up the question with ChatGPT and was informed that “the co-occurrence of all three in lung cancer is not well-documented and would be considered an unusual combination” and “while each of these markers can be present individually in breast cancer, their combination is not commonly documented in the literature.”

The only reason this even matters is that we need to make a decision about which treatment regimen to follow, and without a body of scientific evidence to map this to we’re basically shooting in the dark. There is an antidote for uncertainty, but it is not found in Bayesian analysis or genomic testing. Right now we must search for wisdom, and there's one really good way to find it. James 1:5 tells us: “If any of you lacks wisdom, you should ask God, who gives generously to all without finding fault, and it will be given to you.” This week we will be praying specifically for wisdom as we consider the following questions:

1. Which tyrosine kinase inhibitor will have the greatest efficacy against this cancer? The candidates are selpercatinib and an experimental drug that would require enrollment in a clinical trial at Memorial Sloan Kettering Cancer Center.

2. When should we start this new agent? We need to balance efficacy against toxicity.

3. Would it be wise to repeat imaging before changing the treatment strategy? Joyce feels that her lymph nodes are responding to the chemotherapy, so it might be helpful to know what the impact has been on tumor size before we switch treatments.

4. With three different molecular targets, would it be wise to go after this thing with more than one drug?

As Peter Drucker put it in The Effective Executive, “A decision is a judgment. It is a choice between alternatives. It is rarely a choice between right and wrong. It is at best a choice between ‘almost right’ and ‘probably wrong’ — but much more often a choice between two courses of action neither of which is provably more nearly right than the other.”

Our next appointment is on Tuesday to discuss all of these matters. We appreciate your prayers as we prepare to make the most important decision in our journey so far.