NeoGenomics, Inc. (NEO) Earnings Call Transcript & Summary

Good morning, and thank you for joining us for this morning's Breast Cancer Tumor Board. We are so glad to have you joining us today. A few housekeeping items before we get started. Should you have any questions for our presenters, please submit via the Q&A on the bottom tool bar. As always, shared cases are what makes this program successful, and we encourage submissions. Should you have a case that you would like to present at one of our tumor boards, please send an e-mail to [email protected]. The programming today is brought to you by the Medical Affairs Department at NeoGenomics, whose aim is to foster education and promote the understanding of cancer within the global scientific community at large through programs that enrich medical and scientific knowledge of cancer diagnostics that point the way to advancing patient care. In addition to our breast tumor board series, we also have a lung tumor board series. On your screen, you will see a QR code. You can take a picture with your phone and it will bring you to a registration link. Additionally, a link to register for the lung tumor board series will be provided in the chat shortly. Our host today is Dr. Fernando Lopez-Diaz, Director of Clinical Science at NeoGenomics. Dr. Lopez-Diaz, welcome.

Good morning, everybody. Good morning, Susan.

Thank you. Joining us on the panel today, we are very pleased to welcome Dr. Nhu Ngo, Director of Molecular Pathology at NeoGenomics. Dr. Ngo is Board certified in anatomic and clinical pathology as well as molecular genetic pathology. She has been practicing for over 20 years, including 15 years of hospital-based experience in anatomic and clinical pathology. Dr. Ngo, welcome. We're so glad to have you with us today.

Good morning. Thank you.

And we are so privileged to welcome back as our moderator today, Dr. Razelle Kurzrock. Dr. Kurzrock is the Chief Medical Officer at the Win Consortium for personalized cancer therapy. She is known for founding and building the largest Phase I clinical trials department in the nation and world, while at the University of Texas' MD Anderson Cancer Center. A central theme of that program was the precision medicine strategy. Dr. Kurzrock is from Toronto, Canada and has over 800 publications and has been named to the list of the most highly cited scientists in the world and the 25 world leaders in precision medicine. Dr. Kurzrock, welcome. We are so honored for you to join us today.

It's my privilege. Thank you.

Well, we have 3 very exciting cases to discuss today. So I'm going to turn it over to Dr. Lopez-Diaz to get us started with our first case.

Great. Thank you so much, Susan. We'll jump over our cases because there is a lot to be discussed. And I think that the aim of this session today was to highlight the molecular-targeted approaches in breast cancer therapy, and the [ visions ] have very rich set of molecular alterations. So can we -- I'm not in your slide, can you -- thank you. So the first case, and we've discussed cases before, it's a male person, 74 years of which presented with [ basal cell ] carcinoma of the breast. And -- please next slide, please. Yes. So interestingly enough, these patients have had a year to ERBB2 alteration, one of the most common alteration in the extracellular domain of the HER2 protein, [ 13 310 ] [indiscernible], and that's an [ accurate ] mutation. I also had an RB1 truncating mutation alongside with the third promoter alteration, which is also pathogenic, and a P53 truncating alteration right before the -- in the middle of the DNA binding domain. Interestingly enough, the patient is microsatellite stable that has a high tumor mutation burden. Tumor mutation burden, I believe it's around 15.3, if I'm not mistaken. We can review that in a minute. It has also PD-L1 expression. And it was tested by immunohistochemistry with a Pan-TRK antibody, and that was found to be expressed. And -- however, NGS testing has been performed as well to detect fusions for NTRKs, NTRK 1, 2 or 3. And none of them have been detected in this. No fusion has been detected among the more than 250 gene fusions that our laboratory tests and in its fusion assay for solid tumor. No abnormalities were detected either in BRAF [indiscernible] 2, EGFR, [ CKIT ], KRAS or NRAS, PDGFRA or PIK3CA. Dr. Kurzrock, I'll leave you the floor for the discussion of this case.

So I think this is a very interesting patient. And what I'd like to start -- well, maybe what I could start with and we could come back to this is a few slides about men with breast cancer. So I think that this is very unique because breast cancer in women is very common. Breast cancer occurs in men, but it is a rare condition. Next slide. So breast cancer in men makes up 1% of breast cancers. And it is diagnosed generally at an older age than in women. Usually men are about 65 to 70 years old when they're diagnosed, women are about a decade younger. It is diagnosed more frequently in blacks. And it's diagnosed at a more advanced stage than in women. And I don't really know that, that's because it's more aggressive or because men do not think about breast cancer because it's so rare, while women have routine mammograms and looking for lumps and so forth. And probably because it's diagnosed at later stage, not surprising, and patients are older, not surprisingly, there's a higher mortality for men than for women with breast cancer. Next slide. So these are the symptoms of male breast cancer, not really that different from what you would think about with female breast cancers, lumps, nipple discharging, changes in the skin, [ redding ], skin dimpling, inversion of the nipple. And I think, again, my own experience suggests that men when they have a symptom, they don't really think of breast cancer, so they tend to postpone seeing a doctor, while women are very aware that if there's something that feels amiss in their breast area, they need to go to their physician quickly. Next slide, please. Risk factors for men with breast cancer are family history of breast cancer, BRCA mutations and Klinefelter syndrome. So as you know, Klinefelter syndrome is the 47, XXY syndrome, and people with Klinefelter syndrome do have an increased risk of breast cancer. Next slide. So what about hormone status? These cancers are often estrogen receptor positive, that's found in 80% of patients. One study showed that there was an increased incidence of prostate cancer in these men when -- in this study, 70% of with breast cancer develop prostate cancer. And one question that arose was could this be due to the use of aromatase inhibitors because aromatase inhibitors increase testosterone. Androgen receptor expression is found in about almost 63% of patients, and it's more frequent in estrogen-positive tumors, 85% of cases. Remember that androgen receptor is found in women with breast cancer. Probably about 30% of ER-positive tumors have estrogen -- have androgen receptors, not something that people look for, but I think it's something that should be thought about. And in general, breast cancer in men, the treatment is very similar -- the treatment recommendations is -- are very similar to the treatment for women. I think that might be the last slide, or we could go the next one, be sure. But if you want to -- yes, if you want to go back to the case, we can then have everybody looking at it and we can discuss the possibilities.

While we advance the slides, one of the things we checked on this specific patient was androgen receptor alterations that could have been detected. No SMBs or [indiscernible] in the androgen receptor gene were found. At this moment, we don't have currently expression determination capacity, although this is something that our laboratory is evaluating in one of the assets that performs RNA sequencing studies. But this is really something that we are not ready to -- I mean, it's not something that is readily available in the clinical setting nowadays in the state of the art of clinical oncology. But in this case, we don't have expression data from the patient, that's for sure.

Yes. So let's talk a little bit about this patient. We don't have the details of the history. So we're going to look and assume that the patient has had classic therapy. And we're going to focus on what we find at the molecular level and what are the possibilities for treatment. So the first thing we noticed that I think is pretty interesting is that the patient has an RB2 mutation and a S310F. This is considered a mutation that is sensitive to HER2 targeting. So I think there are several drugs that could be considered. One of them is lapatinib. And another -- the other drugs are drugs like Herceptin, ENHERTU could be considered. And in the large recent study of ENHERTU, patients with low HER2 responded. Low being 1 plus or 2 plus. But there are also patients with mutations that were responsive. So I think HER2 targeting would be an important part or -- of this patient's treatment. The other thing, which I think is very important here is that this patient has a high tumor mutational burden. And the PD-L1 is positive. It's detected. So the other therapy that would be possible is pembrolizumab, which has a tissue-agnostic approval for patients that have greater than or equal to 10 mutations per megabase. And -- so I think this patient would also be a good patient for immunotherapy. Now in our own Precision Medicine Clinic, we often do combinations. And a combination that I think would be very attractive would be something like pembrolizumab together with ENHERTU. There has been a study of -- in breast cancer, looking at -- I believe it was nivolumab, which, as you know, is another anti-PD-1, similar to pembrolizumab, with ENHERTU and didn't show any advantage over ENHERTU by itself in patients that were HER2 positive. But let me just explain why I think that study doesn't apply to this patient. So the study did not look at patients that were tumor mutational burden high and had an HER2 positivity. They just looked at patients that were HER2-positive. They did find that the 2 drugs together were safe, and they -- so that would be reassuring. And then the other thing I'll mention is that even though we don't have HER2 IHC on this patient, if I was to guess, I think the HER2 IHC would be negative. And the reason for that is that's what we usually find when there's an activating mutation. The mutation activates the kinase receptor, but it doesn't increase the expression of HER2. So these mutations are still very vulnerable to HER2 targeting, but the patient ends up being HER2 negative, and I think that speaks to how important it is to do the next-generation sequencing. Because if all you have is the IHC, that can be misleading. Now the last thing I'll mention is that -- I said before that 80% of male breast cancers have ER positivity. And if they are ER-positive, 80% of those are also androgen receptor positive. And so we don't know the status in this patient. But if the status is positive for ER, we would consider an anti -- an estrogen modulating agent. If the status is also positive for AR, I would not use an aromatase inhibitor because those inhibitors raise testosterone. So some other agent like fulvestrant or another agent could be used. And then the other thing to consider is that the patient is both AR and ER positive, an agent like -- such as Lupron, which has a more central effect, could be used to drop both the androgen receptor and the estrogen receptor levels. And then, of course, in a patient that had androgen receptor positivity but no estrogen receptor, there are many anti-androgen agents that are approved for prostate cancer that could be repurposed for this patient. So again, I think ENHERTU and pembrolizumab would be the center of the therapy. And then the other considerations might relate to hormone status. And I'm just going to pause there and address any questions.

I think there is one question from the audience that might be perfect because you were mentioning at least tangentially, but there's a question -- somebody is asking to comment on the new HER2 low classification, if you could. And I think that you were tangentially commenting on the HER2 expression status and the possibility of therapies. Can you expand a little bit on that?

Yes, I think that was the -- and I don't know if you want to comment as well, but I think that there was a lot of excitement over the ENHERTU study that showed very significant effects in breast cancer with 1 plus or 2 plus on IHC. Generally, patients are considered positive at 3 plus. I think this was complete paradigm-changing study. And so one could ask why would patients that are 1 plus or 2 plus respond. And I think -- to me, this was really a genius study. ENHERTU is different than a lot of other HER2-targeting agents that we use like lapatinib or Herceptin and so forth and that it has a payload. And it -- so it's not just acting by inhibiting the receptor or mitigating the effects of this receptor, the way lapatinib as a small molecule kinase inhibitor would be acting or the way Herceptin, trastuzumab would be acting. ENHERTU does that, but it does something else. And it uses the receptor as kind of a Trojan horse to enter the cell and bring its chemo. Its -- essentially a chemotherapy payload with it. And so I think the people who thought of that study were -- it's really, to me, a really brilliant study. And we've begun using ENHERTU in HER2-low patients. We actually just saw a patient in clinic yesterday. She has a cancer of unknown primary, but we think it may be coming from the breast. And she is very similar to this patient. I mean, she is a she, not a he, but she has an elevated tumor mutational burden. She has HER2 -- an RB2 mutation, and we started her about 2 months ago on the combination of pembro and Enhertu. And she's tolerating it well, and she reports feeling much better. So I think this is a whole paradigm. And one of the questions, of course, will be does it apply to other cancers as well. What about low HER2 expression in other cancers? So I'll pause there. And I don't know if there's any other answers.

I'd like to make a couple of comments about the discussion thus far. So yes, this is an extremely interesting case. So as you mentioned from -- I'm talking from a pathologist point of view. So we're the ones who actually do the stains and the assays in the lab. So in terms of the HER2-low positive, right now, at least on the ENHERTU label, right, it's defined as IHC of either 1 plus. That's it. Or if the IHC is 2 plus, the FISH has to be negative. So those are the two ways to define low HER2 right now for ENHERTU. And as you say, most of these activating mutations in HER2, if you were going to do IHC, will likely be not 3 plus, but somewhere either 0, 1 plus, maybe 2 plus with FISH negative. And so in this patient, you would still want to get that IHC, right, to show that they are low HER2 based on that -- how that label defines them. The other comment is about the AR testing. There are a few places where androgen receptor IHC is done as a standard with breast -- in breast cancer. And it's usually done with the triple negative cases because, again, it does inform therapy, whether the patient's ER positive or ER negative. So I do know of a few places where, as part of the panel, they do ER, PR, HER2 and AR. And so that is something that's widely available. It's of an IHC. And then my comment about ENHERTU, which I find interesting as well, is that Trojan horse effect. I believe not only is the payload delivered to the cell, where the antibody binds, but there's a bystander effect as well, so that the payload is -- can permeate into neighboring cells. And so the death is not just delivered to that 1 cell, but to the surrounding cells as well. And in a way that will allow cells that may not express HER2 at all on the surface, so may not bind the antibody, but those cells will, too, get the chemotherapy payload. So that is another way because we know that tumors tend to be very heterogeneous.

Yes, I think that -- Yes, well, two comments to add to that. And thank you, Dr. Ngo for your brilliant comments. Those are pretty much appreciated. Regarding the ENHERTU, definitely, although the trastuzumab deruxtecan drug, basically, it uses HER2 to enter the cell. So the one thing, just to remind, is that there is, indeed, a mechanism for end of endocytosis, so called, of the drug. Basically, the drug is going to enter the cells by the HER2 protein. But that does not negate at all the bystander effect as the drug becomes attached. And first, it changes the pharmacodynamics of the drug, basically, in the tissue, as Dr. Ngo explained. The other comment -- thank you for making the point of AR expression by immunohistochemistry, that's very important. I think that -- maybe the one part I was referring specifically was just RNA expression because one of the things that has been also widely considered is amplification of AR in breast cancer -- male breast cancer patients and the expression on -- by RNA levels, basically. And I think that this is slightly [ different ]. So we also need to remember, all of us, that we have DNA, RNA and protein. And very often, one can basically be speaking about one specific biological process that refers to a given gene or it's protein, but there are different layers. And I think that the ideal situation is to know, well, if there is an amplification, is there any RNA being expressed, and if so, is there any protein being expressed, which in the end is the, probably, one that is going to lead to the biological activity. And this goes maybe to next question, to our proposal before we move on. Somebody asked us that, well, does the [ Pan-NTRK ] express have any impact on treatment? And this is an immunohistochemistry assay. And it will tell us whether there is expression of any -- it's -- indeed, it's a [ Pan-paraffin ] receptor kinase. This is not really a very specific antibody. And this is why, typically, once a patient is detected positive, it's reflex to another assay, to compare if there are fusions on NDS or eventually can be reflected to perform immunohistochemistry with specific [ antibodies ]. So can you comment on that?

I...

No. Doctor, you go ahead. This is your [indiscernible].

Yes. So the Pan-TRK IHC is actually a screening assay, it is not meant to be a predictive assay for therapy. So not everybody uses that. So what the Pan-TRK IHC does is it's -- again, it's very specific, but not -- sorry, very sensitive but not very specific. So it will pick up NTRK, either 1, 2, 3, expression on the cell surface. However, when you get a positive test, that is not the last step, then you reflect that to some sort of assay, whether it's FISH or RNA sequencing, to show that there is an NTRK 1, 2 or 3 fusion rearrangement because those are the -- it's the fusions that respond to NTRK therapies. It's not the expression. So I would not use that alone as an indicator of NTRK fusion status.

So I do want to make a comment on that as well because it's a little bit of a puzzle. You would think that the protein, which is a mediator, is the effector, would be more important. But it turns out that it's the presence of the NTRK fusion, which is at the genomic level, which predicts response to NTRK inhibitors, and the end results of the NTRK fusion, we believe, is expression. But as our pathologists mentioned, the Pan-TRK expression is not a good predictor of response while the gene fusion is a good predictor of response to NTRK inhibitors such as larotrectinib or entrectinib. And this is not just a phenomena that is for NTRK, with the exceptions of estrogen, androgen and HER2 status. We did a meta analysis on the impact of gene abnormalities versus protein abnormalities on the ability to match patients and predict the response. And this was about 35,000 patients we've downloaded from the literature. And it turns out that proteins are predictive, estrogen, androgen being the examples. But they have about half of the predictive power as genomics does. So the genomics is much more predictive. And to me, this remains a significant puzzle because, biologically, I think the protein should be more predictive than the gene abnormality.

Yes.

If I may add a comment on that to kind of help understand why there is a puzzle in this, is that one of the key point of immunohistochemistry -- I would say probably the only easy-to-recognize witnesses of an IHC is as good as the antibodies that we have available for the targets. And basically, in the case of tyrosine receptor kinases, those antibodies are not really specific for any specific kinase, so you might have a tyrosine receptor kinase being overexpressed, that doesn't -- because the domain -- basically of the tyrosine receptor kinase domain, they're common across a number of kinase. But you might know which one. So given a specific therapy, it might not be [ that kinase ]. And overall, in general, that's also true for almost any antibody. The example could be even like PD-L1 antibodies. There are different antibodies for PD-L1, and each of them have different predictive power with different drugs. You have the one that was developed for [indiscernible], the one for pembrolizumab, they are not really the same antibodies. They don't show the same positivity, and that may be -- and you cannot really distinguish. Once you're doing it, it's not really very precise, specifically for those proteins that do have [ isoform ] that may be co-expressed, PD-L1 being an example, it's PD-L1 and PD-L2, both of them, both proteins family members highly, highly isomorphic and basically overlapping, so can give proper activity. And the cases expand. The genomics [ typically ] are more specific in this regard.

But I think it actually has to do with the mechanisms of the targeted therapies that we're talking about. So -- if you're looking at -- so all the drugs that we have do target a protein, right, whether it's a monoclonal antibody or a tyrosine kinase inhibitor. So those are the 2 major kind of classes of targeted therapy that we have. We have antibodies that recognize a protein on the cell surface. And we have tyrosine kinase inhibitors, which are small molecules that actually enter the cell and attack the kinase domain, okay, of the receptor. Now so -- when -- so when you have a mutation or a fusion, that can result in 2 different things, right? Typically, it results in activation of the kinase domain, but that doesn't necessarily mean there's overexpression of that protein on the cell surface. It means the kinase domain, which is inside the cell, is constitutively activated. And so those types of genomic findings are best targeted by kinase inhibitors, which enter the cell and bind to that kinase and stop it from being consistent with activated. If you're looking at the protein level on the cell surface for overexpression, like HER2 overexpression or EGFR overexpression, now there -- usually, the mechanism behind that is amplification of the gene, not necessarily an activating mutation. And so in those cases, drugs like HER2 work very well because they're actually targeting that overexpressed protein. So a lot of the discordance is actually what are you targeting, what is the genomic basis of what you're targeting. So if it's an amplification process that creates more expression on the protein surface of the normal molecule, then an antibody may be best. But if it's a mutation or a gene fusion that causes the kinase domain to be activated inside the cell, then it's typically a kinase inhibitor that would be more effective.

Yes, absolutely. Thank you, Dr. Ngo. And okay, we could probably discuss a lot with this case, but let's move on into the following case, please, for the sake of time.

Next slide, please. And well, this is a relatively young. It's an actually young female patient, 56 years old. And this patient presented a metastatic carcinoma of the breast. Next slide, please, and we'll discuss the molecular biomarkers, and we can see here the ER status is a triple-negative case with high KI-67 compression of 79%. Next. Yes, here it is. In this case, we can see a BRAF alteration in [ glycine ] 469 to arginine. This is an activating alteration in BRAF. Here, we see, again, an ERBB2 activating mutation, R678Q, which is also activating, as I say. And it's [ H6 ] truncating mutation at the -- I mean, this is a complete loss of ] is completely truncated gene. And PIK3CA mutation position arginine 88 alongside with a common alteration incited in histidine 1047 arginine and P53 inactivated mutations in -- inactivating and activating at the same time, mutation for the oncogenic capacity of P53 in arginine 175. The patient was presenting a [indiscernible] result for P10 deletion, was positive for the deletion. It's MSI is stable. It has PD-L1 expression. Here, we see one of the examples of different antibodies being used for a specific biomarker. And it has a tumor mutation burden intermediate. We can see the expression of the PMB status. I think, it's 8.5 or 8.6. And it's not expressing NTRKs basically or tyrosine receptor kinases and no abnormalities in BRCA1, 2 for estrogen receptor 1. Next slide.

If I could go back, I'm happy to discuss the -- what are the possibilities. Another really great case actually. A very, very interesting patient. So this is a woman, 56-year-old woman, with triple-negative breast cancer. And she has a lot of targets. And so that's the first thing that we need to realize, that we're coming into a new era where we really see that because of the power of genomics and all the tools that we have available to us that patients have more than one target and that what we've been doing is these customized combinations. But I want to address all the different targets that she has. And also, some of the things that we need to think about, and I'm going to start with the fact that she has a mismatch repair gene abnormality. She has an MS Stage 6. But in spite of that, she's microsatellite stable. She is PD-L1 positive. Her TMB is a little bit elevated but not a lot elevated. But based on the mismatch repair gene abnormality, she could be eligible for pembrolizumab for immunotherapy. And we -- I often favor, if a patient is eligible, to give them immunotherapy. The reason I like immunotherapy is because, occasionally, these patients, even with advanced metastatic disease, are cured. Of course, most of them are not cured, but there's very few therapies that offer even that possibility. I also want to mention that it might be worth a rebiopsy in this patient. And the reason I say that -- and I'm just going to give an example from our clinic, we have a patient -- again, patient just saw yesterday, 41 year-old woman with adrenocortical cancer. And you can imagine that, that's a very lethal cancer, actually much more lethal than breast cancer. And she had -- very similar to this patient, she had a mismatch repair gene abnormality, MLH1, in her case. And her tumor mutation burden was almost the same as this patient, 8.5. And she was found to be microsatellite stable. We biopsied her. We decided to start her on immunotherapy because adrenocortical is so miserable. But we -- at the same time, rebiopsied her, and we did a biopsy for liver metastases. And it turned out that, that biopsy, which was a different region, showed a high tumor mutational burden of 24. And in that biopsy, there was microsatellite instability. So I would give this patient the benefit of the doubt, and she does have a mismatch repair gene abnormality. So I would -- and PD-L1 expression, I would favor thinking about pembro in this -- pembrolizumab in this patient. And I would also think about another biopsy of the metastatic disease. Now, she has a lot of other targets, similar to the man with breast cancer. She has, as Dr. Lopez noted, an activating RB2 mutation, which may confer sensitivity to HER2-targeting agents, so drugs like lapatinib. And I'm going to, again, come back to ENHERTU. She could have HER2 immunohistochemistry to see if she is expressing low levels of HER2. The label for ENHERTU is for low levels. But ENHERTU, I think last week, was also approved for lung cancer with activating mutations. So we know that in lung cancer, it's active in patients with these activating mutations. So I would consider ENHERTU, and my favorite regimen would be a combination of immunotherapy and ENHERTU in this patient. As with the previous patient, I mentioned that nivolumab, which is very similar, as you know, to pembrolizumab, has been given with ENHERTU and did not show an increased benefit over ENHERTU itself in breast cancer. But the caveats are that patients were not selected for high TMB or for mismatch repair gene abnormalities. They were only selected for low -- for expression of HER2. So I think that, that study conclusion does not apply to this particular patient. Now the patient has other targets as well. So in that way, it shows the complexity of what genomics reveals and then the complexity of decision making. So she has an unusual BRAF mutation. It's not the Type 1 activating mutation. This is a different BRAF mutation, actually may be inactivating. But what it does is it activates the [ neck ] pathway. And about a year ago, we published a paper that -- and there's other data presented recently at ESMO as well that showed that these unusual BRAF mutations respond to MEK inhibitors. They respond to trametinib. And we found that, that was a tumor-agnostic responsiveness. And I believe that's what other people are finding, too. Now the other thing that she has is she has 2 PIK3CA mutations. And -- as we know, drugs like Alpelisib are approved for PIK3CA-mutant breast cancer, but I would not choose Alpelisib in this patient. And the reason is Alpelisib inhibits the alpha subunit of PI3 kinase. She has a P10 deletion, and the P10 deletion activates both the alpha and the beta subunit of PI3 kinase. So I would expect her to be resistant to Alpelisib. And if we wanted to target that pathway, I would think that everolimus, which is an mTOR inhibitor, which is downstream of PI3 kinase action -- PIK3CA mutation action and downstream of the effects of P10, would be the drug to choose. So again, my first inclination would be ENHERTU with pembrolizumab. But other possibilities include everolimus and MEK inhibitor like trametinib. Now I'm going to make one other comment, in case somebody wanted to think about the type of customized individualized combinations that we've been doing. And that's the fact that trametinib cannot be given together with everolimus. So unfortunately, the MEK pathway and PI3 kinase pathway are frequently co-activated, not just in breast cancer, but in many cancers. And with the currently existing PI3 kinase pathway inhibitors and MEK pathway inhibitors -- we've published on this, but there's been a lot of studies with a lot of molecules by other groups as well. If you co-inhibit both pathways, it's toxic. And you really have to go down to very low doses. So we haven't found a good way to co-inhibit both pathways. One question that has come up in our clinic is if you have, for instance, KRAS -- a G12C molecule, and you want to use Sotorasib, and would that -- could you give that with a PI3 kinase inhibitor? And the answer is maybe because Sotorasib is specific for one KRAS, and it doesn't inhibit the entire MEK pathway. So I'm going to just stop there and pause, but I think there's really a lot of things to be learned from this patient and a lot of possibilities here.

Thank you, Dr. Kurzrock. And just -- the only comment I would do while we wait for more questions is, this eventually shows how we can be easily, I would say -- we need to be careful not to be full when we have possibilities of test that would give us a direct answer for -- as a combined diagnostic, even for instance, for certain drugs. As Dr. Kurzrock mentioned, this patient hasn't PIK3CA alteration that could be easily detected on certain tests for Alpelisib, that -- our companion diagnostics for Alpelisib. And you'd be missing if you only stood there and thought that this was the only thing that you needed to know about this big case. You don't know the BRAF alterations, the ERBB2 alternations that will be present. Anyways, is any question from the audience, please don't be shy. And Dr. Ngo, do you have any additional comments?

I do. So I think it is a great point to say that there are 2 major pathways that are very important to cell proliferation that a lot of our current available targeted therapies target. So it's either the RAS, RAF, MEK pathway or the PIK3CA aka the mTOR pathway. A lot of our current targeted therapies target one of those pathways. And so when we're looking at something a report like this, at first, it looks like, "Oh, great, we have all of these options." But again, we have to be really careful about the pathway interactions. So what I see in this case is, yes, it's nice that you have BRAF. This is a Type 2 -- Class II BRAF. So it is activating but slightly less so than V600, and these will respond to RAF inhibitors as well as MEK inhibitors that are not vemurafenib, which is specifically for V600. But then at the same time, you have this RB2 activating mutation or potentially activating mutation. And that's kind of in a similar pathway. But that interferes actually with the PIK3CA activating. So in other words, you have these inter-pathway interaction. So it may be that even if you went after -- let's say you decided to target the HER2. Having the PIK3CA activation actually would confer some resistance to the HER2 therapy. And so again, I think it's really important that -- Dr. Kurzrock is looking at all the options together as a profile as opposed to a variant-by-variant interpretation, which is how we started out with genomic therapy, where we looked at individual mutations. And that's why now we try to call this a profile because it truly is. You have to look at all the interactions as opposed to each individual variant by itself. The other thing I would comment on is, it's interesting that you bring up immunotherapies in combination with these targeted therapies because in the level cancer world. There are guidelines -- the NCCN guidelines would say that if you have a targetable kinase activation or EGFR or [ ALK ] or any of those, to not go with the immunotherapy upfront, but to target those because those patients may not respond well to immunotherapy. And right now, the recommendation is not to do the combination. And so I'm curious, Dr. Kurzrock, it sounds like in the breast cancer world, you seem to be much more willing to consider the immunotherapy upfront in combination with the targeted therapy.

Yes. So I think you bring up a very good point, and let me reply to it. So I think the point here is what people have been doing is giving immunotherapy with everything. Immunotherapy became the favorite child. And I really could understand that. It's because it's like gambling. If you're going to hit the jackpot once in a while, there's something that makes you very addicted. And we've all hit the jackpot in some patients with immunotherapy. I mean, I have patients that were ready to go to hospice, that I treated in 2015, 2016. And one patient back in -- probably about 2008, in a clinical trial, and they're cured -- or at least they're more than 5-plus years. And these patients were on death's door. So we all want that positivity. But I think the problem with the trials in lung cancer is that they added immunotherapy to everything without thinking about does the patient have any markers for immunotherapy. And I tried to emphasize that when I talked about the nivolumab and HER2 study that did not show any anything better than ENHERTU. But they didn't select the patients that had both RB2 and a marker for immunotherapy. So in these 2 patients, the man had high tumor mutational burden. And this woman has a mismatch repair gene defect and PD-L1 positivity. So they have a reason to get immunotherapy. It's not just random adding immunotherapy. And I think that, that type of study has not been done. So the NCCN guidelines, in my view -- and I love NCCN. I've been -- I was for 8 years on their Board of Governors and voted on their executive committee, I think, they're wonderful. But I don't think the guideline applies to these particular patients because they have a biomarker for immunotypapy. And I'll go -- and then I'll mention one more thing. In some cases, even to make your point stronger, like EGFR alterations, EGFR mutations in lung cancer, they are a marker for immunotherapy resistance and even hyperprogression. We found that about 20% of patients with EGFR will hyperprogress on immunotherapy, and then the rest of them mostly are just resistant. So I'm totally against giving immunotherapy across the board. But the difference here is that I'm suggesting that these patients have specific markers that I think would benefit from immunotherapy.

I don't want to cut the beautiful discussion, and this is addressing a very important point, but we have one more patient. And I think that to leave this today [indiscernible] more with also a note of hope for our treating physicians and for patients. I think that this is a case that deserves our attention. Dr. Kurzrock?

Yes. So this is a patient of ours. And the reason that we're presenting her is because she's a medical mystery to us. And I think we talk about bed side to bench. But in the case we have a mystery in the bench -- I'm sorry, we talk about bench to bed side. But in this case, we have a mystery at the bed side, and I wanted to bring it up because maybe we can learn some from her. So specifically, this patient achieved a complete remission. And we don't think she should have, based on her panel. And so that means that the science isn't perfect and that we can learn for from it. So to go over it, this is a 44-year-old women with estrogen receptor positive, HER2-negative ductal carcinoma of the breast. She, interestingly enough, had tamoxifen in the past and letrozole in the past, and she didn't do well with them. And immunohistochemistry showed an intact P10. And then she had NGS of tissue from the left breast at the time of diagnosis, and it showed a P53 mutation and amplifications in the cyclin pathway CCNE1, which is usually considered a resistance pathway, IRS2 and MCL1. And you can see the PET scan before and after therapy, she has a complete remission ongoing at 9 months. And in my view, she has no business having a complete remission because it doesn't make any sense. So obviously, we're just learning. First of all, she was put on [ XMS stain ], an aromatase inhibitor, but she already had tamoxifen, which is not an aromatase inhibitor, but she didn't have letrozole, and it is an aromatase inhibitor. So we could postulate that it's the aromatase inhibitor that's doing it because she's ER-positive, but I really don't understand why when she failed tamoxifen and she failed letrozole. And then she was put on everolimus, and she doesn't have P10 loss, she doesn't have a PIK3CA mutation. She has P53 and CCNE1, which, if anything, should make her resistant. And then she has IRS2 and MCL1. And Dr. López postulated, while we were discussing this case, that IRS2 and MCL1, there is data that it is upstream of PIK3CA [indiscernible] mTOR and therefore, maybe that is why she responded, which is an interesting postulate. But I didn't want to present this because I want to show that we certainly don't know everything. And I'm happy to have any other comments that people have about why this might have happened.

I think that this event -- if you can move two slides, jump straight to why we are thinking that it is possible -- next slide. There is an [ ongoing ] comment that we can make at this point is just a speculation. There is a wealth of preclinical data. And I'd say that the IRS2 amplification specifically, it's interesting because it relates to the insulin pathway and ensuing growth factors pathway, which has been linked to cancer for decades. And there is a wealth of information inferring that there is an involvement of this pathway being activated specifically in breast cancer. But there's not a lot of clinical data. And your case is kind of one that might be providing that bed side tool. So the patient -- when you have IRS2 amplification, what -- all these very complicated slideshow, but can be resumed in the end, there is an activation through AKT pathway of the cell proliferation protein synthesis, and that might be the link to everolimus. And interestingly enough, the [ MCL1 ] alteration, which is a cell survival pathway, it's not proliferation, but its survival, it also acts to AKT. And there isn't much -- there is a little bit less information on how exactly it does, but it's been shown that the mTOR inhibitors can actually be affecting this pathway, specifically when you use an inhibitor in triple-negative breast cancer. So this is something that we can leave it up there because it's -- we're 1 minute passed by. But it shows that the science still needs to advance. We still need to understand much more, and this is why there's a circle between the base we serve, the preclinical, the clinical studies back to the bench to keep learning about how we can improve therapies and how we can improve precision oncology for patients. With that, I think we'll leave it for a closing remark by Dr. Kurzrock, if you want. And if not, I think that, Susan, we can just close the session in [ favor ] of time for today.

No. I thank you for having me as discussing. I think these are phenomenal cases. I love these cases, and we can learn so much. And I really enjoyed the questions. The doctor knows a pathology analysis. Dr. López, I know you well from UCSD and really enjoyed your analysis, especially of the last patient. So thank you for having me, and I hope we answered -- we couldn't answer all the questions, but I hope we answered some of them.

[indiscernible], Susan?

Thank you so much. Thank you, Dr. López-Díaz, Dr. Ngo, and especially Dr. Kurzrock, for this wonderful informative discussion on breast cancer. Next month in celebrations, if we want to use that term, of Breast Cancer Awareness Month, we will be having 2 breast cancer tumor boards, October 5 and then October 12. So we invite you to join us for both of those. In addition to our breast tumor board series, we do have a lung tumor board series, which we'll resume in November. And we invite you to join us for that as well. As always, if you have any questions that weren't answered during the tumor board, please feel free to e-mail [email protected]. Or if you have any cases that you would like to discuss at the upcoming tumor board, we welcome any cases. Again, just e-mail [email protected]. And to register for our lung tumor board series, you can just take a picture of the QR code that is on your screen now. And again, thank you so much to everyone for joining us. And a big thank you, again, to our panelists for the discussion today. Have a wonderful rest of your day. Bye-bye. Thank you.

Thank you, everybody. Goodbye.