Thread by @marklewismd

A RARE DISEASE NARRATIVE TWEETORIAL

Today, during an #ASCO20 clinical science symposium, I'm honored to comment as a patient-physician on the meaning of drug development for rare diseases

Inspired by @DavidFajgenbaum (but not half the man he is) I am going to share my own story

It started with a call from the embassy.

We were moving to the U.S. and needed chest X-rays to exclude TB.

My father's CXR showed no concerning cavitation, but his right hemithorax was mysteriously opacified 👇

Within two weeks of arriving in Texas we had secured a cardiothoracic surgeon and my father then underwent a right pneumonectomy. It was an R2 resection and we were told he would need radiation to "lung cancer" remnant in the mediastinum. XRT was brutal and led to esophagitis.

Three years later we were on vacation at Disney World, and my Dad developed back pain. We were in the "happiest place on earth" when we learned his cancer had returned with bone metastases. He began cisplatin/etoposide and nearly died of neutropenic sepsis in his cycle 1 nadir.

In what he would later call "a spine-tingling miracle of providential timing" @US_FDA had just approved filgrastim and my Dad's oncologist visited him in the ICU to administer the first dose of GCSF given to any patient in his practice.

I would later describe the moment thusly:

My father's white cells rebounded and he fended off his infection to live a further 3 years. At that point his metastases had become platinum-resistant and he had a Hail Mary treatment with paclitaxel. It was 1994 and the timing was now not so providential.

The taxane was not yet semisynthetic and was incredibly allergenic. He died from anaphylaxis after his initial dose.

It was my first experience of iatrogenic harm, and, despite a career founded on the precept primum non nocere, it would, regrettably, not be my last.

Strange tragedy continued to befall the family.

A few years later my father's brother developed bitemporal hemianopsia and was found to have a pituitary macroadenoma.

Upon its removal he developed hemorrhage leading to pituitary apoplexy and died post-op.

And then, just as I started my oncology fellowship, I developed abdominal pain related to hypercalcemia.

It was my Eureka moment. My Dad had suffered from high calcium too and I knew there were only a few conditions that would lead to that condition in consecutive generations.

I was the proband in a kindred of multiple endocrine neoplasia type 1.

Let me get on my soapbox here and say that FAMILY HISTORY IS SELDOM "NON-CONTRIBUTORY" (and that phrase typically signals either laziness or haste in taking the H&P)

Genetic testing confirmed my suspicion of MEN1. Here my timing was again providential, as the pathogenic mutation in my family had only been added to the index database in 2007. Had I been tested before that, I would have been told I was (falsely) negative.

There is still no truly targeted therapy for MEN1, but nonetheless being aware of my rare disease has empowered me.

As I wrote in an essay describing the process of self-diagnosis in JCO in 2011:

And sure enough, in 2017, my dominant PNET grew to the point that I needed a Whipple:

To date, I have been fortunate not to require chemo or radiation.

But I have gained the hardwon empathy for the patients with rare diseases, those whose hoofbeats are considered too esoteric to be heard when the horses of common illnesses are galloping all around us.

The truth, though, as @DavidFajgenbaum observed too, is that, as a collective, rare diseases are a massive herd, increasingly linked by driver mutations as we enter a brave new world of histology agnosticism.

@VivekSubbiah, for instance, is doing pioneering work on RET targeting

This is of massive clinical importance to patients with MEN2, not to mention a growing host of tumors whose oncogenesis relies on that proto-oncogene par excellence.

Tune in today at #ASCO20 to learn more about the marriage of genomics and targeted therapy bringing new hope.

I, for one, as a patient-physician and father of a child with a rare disease, could not be more grateful for my colleagues who have devoted their careers to studying the zebras, which are not nearly as uncommon as we once thought.

🙏