STK11

I think that...

We need to study these in large trials, but we need to see, is this going to be better in PD-L1 negative, PD-L1 low, PD-L1 high? What combinations? Will this be able to specifically overcome STK11, keep one subsets where we see poor performance? So I think that we're just starting this whole process.

But let me ask you, actually I'm going to ask all three of you, let me ask you to sort of look ahead 10 years from now.

Are these biospecifics going to replace our current checkpoint neighbors, our current monoclonals that target PD-1 and PD-L1?

So I mean, we typically think about risk-reducing surgery for individuals at the highest risk for developing breast cancer.

And so most commonly, that is related to those with pathogenic variants in high-penetrance breast cancer genes, such as BRCA1 or BRCA2, and PALB2 for select patients, TP53, PTEN, CDH1, STK11.

It's quite a long list.

It's growing.

Next up is Peutz-Jager syndrome.

This is an autosomal dominant hamartomatous polyposis syndrome caused by a mutation in the STK11 gene.

These patients develop hamartomatous polyps throughout the gastrointestinal tract, especially in the small intestine.

The classic clue is mucocutaneous pigmentation, which are dark spots on the lips, inside the mouth, fingers, toes, or around the nose.

You mentioned RAS, the NT-RK, ROS1, MET.

NRG1, RET, STK11, and then you have PD-L1, PD-1.

Are there redundancies or are all of these independent in the patients? And what combinations do you see going forward for treating your patients?

Yeah, no, that's a great question.

And the hope is to do more testing of this assay in clinical trials or perspectives so that we can more confidently use this assay for other clinical decisions like that.

It also shares insights into a study evaluating the role of the zygocity of KEEP1 STK11 in response to checkpoint inhibition in patients with non-small-small cancer.

So this study is really interesting.

This is looking at the role of gene zygocity, and I'll explain what that means, for those two mutations, KEEP1, STK11, and how patients respond to immune checkpoint blockade or immunotherapy for lung cancer.

And the reason this is important is because these mutations, many other colleagues of ours have shown that if you have one of these mutations, they don't respond very well to immunotherapy.

There's been new work coming out of MD Anderson showing that if you have these mutations, but you actually double, you do dual checkpoint inhibition, you can actually rescue these patients and reverse that.

next-generation sequencing platform, and they've all been treated with immune checkpoint blockade.

So we wanted to look at the effect of gene zygocity of these two mutations.

They require a massive total abdominal colectomy with an ileorectal anastomosis.

Finally, Peutz-Jeghers syndrome caused by the STK11 gene, characterized by widespread hammer tomatoes polyps and striking mucocutaneous melanotic pigmentation.

They have a massive risk of small intestine adenocarcinoma and frequently suffer from intussusception.

We are moving into our final phase, colorectal cancer.

Most cases are sporadic, but familial syndromes exist.

Peutz-Jeghers syndrome caused by the STK11 mutation carries the highest relative genetic risk.

When you look at the somatic mutations inside the cancer cells, the P16 mutation is present in ninety-five percent of tumors.

What does P16 do normally?

No, but I completely agree with you.

I think that in these PD-L1 negative patients, and specifically if you dig deeper, such as on the Poseidon regimen or the recent data we saw from Dr. Scalides, looking at sort of the STK11 and KEEP1 co-mutant population, these are generally the low PD-L1 expressing patients.

We cannot use pembrolizumab alone in this population.

We do need to think about combination strategies.