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

[indiscernible] You'll be joining us for this morning's Breast Cancer Tumor Board. We are glad that you have joined us today. In addition to our Breast Cancer Tumor Board, we also do have a Lung Cancer Tumor Board, a link to register for the Lung Cancer Tumor Board will be provided in the chat section shortly. [Operator Instructions] As always, shared cases are what makes this program successful, and we do encourage submissions. Should you have a case that you would like to present at one of our tumor boards, please e-mail [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 a program set enrich medical and scientific knowledge of cancer diagnostics that points the way to advancing patient care. Our host today is Dr. Fernando Lopez-Diaz, a principal scientist in Research and Development at NeoGenomics. Dr. Lopez-Diaz, welcome.

Good morning.

And our moderator today is Dr. Razelle Kurzrock. Dr. Kurzrock is the Chief Medical Officer for the Win Consortium for personalized cancer therapy. Dr. Kurzrock is a world-renowned physician scientist leader in precision medicine and the development of novel therapeutic in the field of oncology. She has recognized for founding, developing and sharing one of the largest Phase I clinical trial departments globally, while at the University of Texas' MD Anderson Cancer Center. 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, we are still glad to have you with us today.

My pleasure. Glad to be here.

And we are so excited to have you -- we are going to start off with your presentation. So I'm going to turn it over to you.

Next slide. Just let me know when you're ready to go to the next slide.

Excuse me. Can you share the slide? Oh, they're coming.

Okay. Thank you. And if you want to go back to the first slide, the other way, that would be great. So I wanted to say that this presentation is about a specific type of triple-negative breast cancer. I think as everybody knows, triple-negative breast cancer is a particular problem. And I thought we would give a little update on a subtype of triple-negative breast cancer called metaplastic breast cancer which is an aggressive subtype of what is already aggressive, that's triple-negative breast cancer. Next slide, please. So these are my disclosures. Next slide. So summary about what I am going to say is based on our experience in several situations, most recently at the University of California, San Diego where -- while I was there, I founded and directed a center for personalized cancer therapy. And this precision medicine, personalized medicine is, especially close to my heart. Next slide, please. And as was mentioned before that, I was at MD Anderson Cancer Center and founded and shared early clinical trials department that really became what was probably the largest in the world of its time. Next slide. And these experiences are really informed, some of the thinking about where we're going to go forward. And part of these experiences that experienced with over 21,000 patients that have had clinical grade genomic profiling, which I think next-generation sequencing is really part of the present and future of oncology. Next slide, please. So let's hone down on metaplastic breast cancer. It is a small subset of all breast cancers, usually triple-negative disease. It's higher in African-American women, and it's high grade, as I mentioned, mostly triple-negative, though there are exceptions -- it's a very resistant type of breast cancer. Most are resistant to neoadjuvant chemotherapy. And the 3-year survival for metastatic disease is about 15% as you all know things have gotten much better for metastatic breast cancer, but metaplastic is still a real challenge. Next slide, please. WHO self classifies this is about a metaplastic breast cancer into 6 different types, histologically and they are listed here: spindle cell, mesenchymal differentiation, mixed and adenosquamous, fibromatosis-like and squamous cell carcinoma. Next slide. What we've done is to look at the genomic classification or underlying alterations in these patients. And this is a publication from Palacios Group, looking at the electro features of medicine plastic breast cancer. And importantly, they found that P53 mutations, PIK3CA mutations and [ church ] alterations are really a hallmark of this disease in 3 of the subtypes of metaplastic breast cancer. This is really quite consistent with what we found as well. Next slide. So back during the time I was at MD Anderson Cancer Center, we developed what we nick named the Dr. [indiscernible], and this was early phase trials with [indiscernible]. So bevacizumab and temsirolimus, bevacizumab being anti-VEGF antibody, temsirolimus being an mTOR inhibitor. And we combined them with chemotherapy, d for Doxil, p for Paclitaxel and c for Carboplatin, and looked at a variety of patients. And one of the most interesting groups turned out to be metaplastic breast cancer because the response rate was about 25% across our regimens with most patients being heavily pretreated. And the responses have PI3 kinase pathway plus TP53 mutations as was noted more recently in that publications. And we think this is really interesting because the PI3 kinase pathway activates mTOR. So temsirolimus are targeted that and P53 mutations activates the VEGF, VEGFR pathway. And there is now data from several groups, [ ARs ] as well as Sloan-Kettering, a group at Europe that suggests that giving bevacizumab to patients with p53 mutations associated with a better outcome. So there were patients that had partial response to therapy. And we also had some complete responses. I personally had a patient that had a complete response that was ongoing at 4 years when I left MD Anderson. So this is definitely a regimen of interest for a subtype of metaplastic breast cancer. Next slide, please. And this is what I've mentioned before, some of the data suggesting that TP53 alterations whole life with response to VEGF, VEGFR inhibitors. And we did see that in metaplastic breast cancer. Next slide. So in addition, 25% was for these heavily pretreated, a pretty good response rate, especially with some durable complete remissions that really doesn't cover all patients. And more recently in 2022, just recently, we -- from the rare -- from the only therapeutics of our cancer committee that I chair at SWOG and CI, we have done a trial with immunotherapy within ipilimumab and nivolumab combined for metastatic metaplastic breast cancer and just published this in clinical cancer research, and I think the results are very interesting. Next slide, please. And so what we saw that was really fascinating was these all or nothing responses. So 3 of these 17 patients treated had responses, including one complete remission and 2 [indiscernible]. And the reason I say it was all or nothing is because the all 3 responsors are ongoing at 2 to almost 3 years. So these are really exceptional responders. And unlike most of the other studies I've done, we have the exceptional responders or nothing. The other 14 patients had nothing, they didn't even have stable disease. So of course, what we want to know and what we're working on now is can we use molecular features to identify who the responders are. Next slide, please. So this just shows you this all or nothing phenomenon. Next slide. And you can see in the waterfall plot, the 3 basically super responders. Next slide. And you can see that all 3 of them are ongoing at 2 or 3 years. Next slide. And then apart from these 3 super responders, what you can see is the other patients just had progression. They had no response whatsoever. And in my experience, this is barely unusual. This all or nothing phenomena, and it suggests that there is a targetable molecular defect in the 3 responders that we can identify and then pick those patients. Next slide. So the key questions are, we have now identified 2 regimens with activity in this very aggressive subtype of triple-negative breast cancer that is metaplastic breast cancer. One is Avastin Torisel together with either doxil, paclitexal or carboplatin chemotherapy. The response rate is about 25% with some durable complete remissions. And we believe that the markers are PI3 kinase pathway and TP53 alteration for these patients. And then we have a subset of patients that respond to a completely different approach, and that is combined immunotherapy with nivolumab and ipilimumab, and we don't know for sure, but we think it may be a different subset than response to the doxil, Avastin, Torisel type regimens. And we are now in progress of a deep interrogation of these patients with DNA and RNA sequencing to try and uncover who they are, and can we identify them. And if we can, if we put the 2 subsets together, we will be at about 40% response rate if they do indeed represent different subgroups. Next slide. So that wraps up what I wanted to say as a preamble to our tumor board on triple-negative breast cancer and happy to address the questions and my contact and Twitter handle is there for you. So I will pause there.

Perfect. And just as a reminder, questions are encouraged and welcomed. So please, if you do have any questions, feel free to submit via the Q&A tool. I will give them just a minute to see if we do have any questions, and then we can move on to the next case.

I have a question for you to discuss with us Dr. Kurzrock, there are certain metaplastic breast cancers that are spindle like. And so much has been done in the past, I would say, probably 15 years regarding the epithelial-to-mesenchymal transition and the conversion of myoblast itself and normal so that the ranging to the slow growth mode of cells that behave more as a -- such as a sarcoma tissue, but indeed, they can be rarely responding to therapies that target cell proliferation because they respond there slowly. And that might indeed be involved in specific pathways that are regarding or that are engaged into the [ E&P ] and the VEGF pathway would be one of those, and we've discussed many times about the VEGF-beta segment pathway. So what can you tell us about this type of phenotype and the responses in the studies you described?

Yes. So I think that's really an interesting question. We do know that one of the patients that I alluded to that achieved on Doxil, Avastin, [indiscernible] regimen prolonged complete remission had a single cell penotype. So I think your question is a really good one, and I don't know if there is a molecular portfolio that identifies this phenotype as well? Or if it was just a coincident that this single cell patient had best response. I think how the different histological subtypes will relate with the underlying molecular abnormalities is an area we really need to investigate. But I do want to mention that the best responder was actually single cell.

That's interesting. Maybe p53 and cytokeratin 5/6 could be markers that could help on distinguishing that very often, p53, over expression is one of the leading hallmarks of the spindle-like phenotype and other cell types. And I don't know if that eventually helps. And the other question you had the regimen with the [indiscernible]. And some of these patients were any of those spindle-like, I was wondering on that if there is this new wave of bivalent antibodies that can target the PD-1, PD-L1 access and then some of the other target, again, is one E&P targeting antibody that target TGF-beta in the extracellular compartment. I don't know what can be drawn from this point on that, but maybe there is some connection there.

Yes. So I think those are also really important questions. And we have a question in the chat box also, what are the super responders were so due to their main system with this show up in the case control sequencing study. And then you refer to the bi-specific antibodies that target PD-1 and CTLA-4. And I think that would be a really interesting approach to some of these patients. Some of the questions that we don't know are, these patients not nivolumab and low-dose ipilimumab, we don't know if they would have had the same response to nivolumab by itself. And my gut feeling is no, but I don't think that feelings are science. So that would be a question that would have to be answered. The other question is, are there genomic markers that would identify these patients. And as I mentioned, in collaboration with the National Cancer Institute and the [ CMAC ] group. We are doing a deep interrogation of these studies with genome of these patients with whole genome sequencing and RNA. The real question is, will it be so obvious because there's 3 patients that had super responders and 14 that had nothing, that would get results out through patients. It is difficult, but there might be something striking in there. And we do know that there are some striking factors that can predict response to immunotherapy. For instance, if all 3 patients had very high PD-L1 or if all 3 patients had very high tumor mutational burden. So there are some possibilities there, but we don't know the answer. I think what you're thinking is that these are different subsets, the immunotherapy responders and the Doxil, Avastin, Torisel responders are not the same subset of patients. We have some preliminary data to support that thinking. Again, we don't know for sure. But if that's true, that would be very important because that would bring, as I mentioned, the number of responders up to about 40% and the trip would be to identify those patients beforehand because you don't want the patients that are potentially responsive to Doxil, Avastin, Torisel to get immunotherapy and vice versa. So this is where genomic interrogation, I think, is the key to figuring out which patients belong on which therapy.

Thank you. Thank you. Very interesting discussion. Very interesting subset of breast cancers. And by reason through the literature, I couldn't avoid to note to the fact that there's very little incidence of the BRCA pathway being involved. So not many -- very low germline alteration. So that's also something to note about the specific type of disease or presentation of the breast cancer disease.

Yes. And I think that's correct, even though I've seen several patients in their 30s, the average age, the median age is 63. But I personally have seen a few patients in their late 30s with the disease, but we couldn't identify a germline alteration. [indiscernible] you have to wonder if there's something that [indiscernible]

Thank you. Okay. So if there are no more questions, maybe we can -- on -- let's check if there is any other questions in the queue here. Okay. All right. So then we'll move on into our other cases. And we have I think that can you go back a little bit? Sorry. So this -- the following case is a case of a female person, 56 years old, that has been central laboratory for testing. And this is being reported as metastatic carcinoma, the tissue as a contracted from test all specifically for [indiscernible]. And the next slide, please. So we don't have a lot of clinical information of the patient, but we know that we are at diagnosis and it's an advanced stage carcinoma. And this is -- these are the results of the molecular profiling that we observed run on our genomic platform. So a BRAF, G469 to our alteration -- to arginine alteration -- sorry, an ERBB2 alteration, [ R678 ] alteration. And from taking alteration or stopping mutation in MSH6, PIK3CA alteration, both in the end terminals and in the kinase domain, the second one being one of the most prevalent ones. And pathogenic alteration in p53 in the sensation domain of p53-R175H, which is now to also be an oncogenic alteration, not only tumor-suppressing [indiscernible] that tumor suppressing activity of p53, but also an oncogenic aspiration. Patient presented a PTEN deletion by [indiscernible]. It was microcapitalized stable. It expressed PD-L1, and it had a tumor mutation burden of 8.7 mutations per megabase, an intermediate TMB value. No formalities were found in BRCA1, BRCA2 and estrogen receptor. Genes and [indiscernible] molecules were not detected by immunohistochemistry. Next slide, please. Okay. I think we can start the discussion. Dr. Kurzrock, its -- is your case, we have some additional information that you can use during our discussion here.

Yes. Thank you. So it looks like the PD-L1 is expressed here. But if you can just help me it's a pretty low level of expression. It's a 1% expression. Is that correct?

Yes, it is correct. It is a 1% expression. Of course, according to the guidance, that's a positive expression. And that's with the SP142 and -- that is a companion diagnostic for centric according to FDA. Interestingly, this case was also run 22C3 antibody, that is actually the companion diagnosis for KEYTRUDA. And the value came basically lower than 10. And basically, that's considered non-express for this antibody.

Okay. And to remind me, I don't know if you had tumor mutations burden.

Yes, TMB was 8.7 mutations per megabase. That's intermediate according to our assay and its intermediate according almost all other assays that other laboratories have.

So if you want to just go back to the alterations and I'm happy to discuss -- this patient has several alterations that are potentially targetable and I want to discuss the possibilities. So one, I have a tendency to favor immunotherapy if it's a possibility because I think as a clinician we've all seen these dramatic responses in a subset of patients. And so I would consider a checkpoint blockade molecule. And here are the caveats. The PD-L1 is positive, but it's low, but it's low positive. The tumor mutational burden is elevated, it's intermediate but it's not very elevated. And it's very interesting because the patient has a mismatched repair gene defect, MSH6 which actually qualifies the patient for pembro because there's a mismatch repair gene defect. Usually, when there's a mismatch repair gene defect, you get microsatellite instability. But this patient is microsatellite stable. So I think there's a lot of room for debate if this patient should get immunotherapy. But from my point of view, again, because we have -- we favor immunotherapy. I would consider a trial of something like pembrolizumab for this patient. Now the patient has several other targetable alterations, and I want to walk through them. The patient has a BRAF but it's not the typical BRAF. What we do know is that these A typical BRAFs do respond to MEK inhibitors like trametinib. And they don't respond that well to BRAF inhibitors. So that is a consideration. The patient has an ERBB2 mutation and I think this is important. So there is a subset of patients that respond to ERBB2 inhibitors that don't have HER2 overexpression. And this patient, to my knowledge being triple-negative, doesn't have HER2 overexpression. So what happens when you have a mutation? When you have a mutation, it activates the kinase region of the receptor. So you've got an enzyme that's active, overactive, but you don't get high levels of expression because the gene is active without being over expressed. And this might be the reason that patients with mutations respond to ERBB2 or HER2 inhibitors and also be the reason why there is some responses of breast cancer patients to HER2 inhibitors even without overexpression. So the other alterations that the patient has that I think are the most relevant is the PIK3CA mutation. The patient has 2 alterations in the PIK3CA region, the H1047R which is very common and then the R88Q, which is less common, but the patient also has a PTEN deletion, which also activates the pathway. So for the PIK3CA mutations, we could consider a drug like Alpelisib. But I would not choose Alpelisib. And the reason I wouldn't choose Alpelisib is because the patient also has a PTEN deletion. And in the presence of the PTEN deletion, you have both the alpha and the beta PI3 kinase subunit that is activated. Well, Alpelisib impacts only the alpha unit. And so you might expect to get resistance through the beta unit. So I would say that with the presence of both the PIK3CA mutation and the PTEN deletion, you need to go farther down the pathway and do an mTOR inhibitor like everolimus. And then the final alteration is in TP53. p53 is very common in cancer, does a lot of different things. One of the things, as mentioned during my presentation is that it activates the VEGF, VEGFR access. So you could consider a VEGF, VEGFR inhibitor. It wouldn't be my first choice because this patient has so many other targetable alterations. But I would think about immunotherapy, but possibly combining it with an ERBB2 -- with a HER2 inhibitor such as lapatinib and possibly combining it with a drug like everolimus because of the 3 alterations in the PIK3CA pathway. And then I make one other comment although we have been doing customized combinations for these patients. One area that has remained a huge challenge is patients that have activation of the [indiscernible] MEK through BRAF and activation of the PI3 kinase pathway. This unfortunately occurs commonly, but what we and others have repeatedly found is that if you combine MEK pathway inhibitors with PI3 kinase mTOR inhibitors, you get toxicity even if you reduce the dose. So you have to choose one pathway or the other to target. In this patient, I would choose the PI3 kinase pathway because there's 3 alterations in that pathway that suggests to me that tumor thinks that pathway is pretty important. So we don't know for sure if multiple alterations in a pathway mean it is more important but it might be a reasonable assumption. So I will pause there, and if there are questions or comments I need to address now.

Okay. There is indeed one question from the audience. So we'll try to attend that one and see then if there is any other one that wants to follow up or anything. So the question is, if you treat with immuno with an immuno-oncology therapy first, could you then go back with a targeted therapy if the immuno-oncology or immunotherapy does not work. Would a targeted therapy be less effective if immunotherapy treatment is used first versus after the targeted therapy?

Yes. So that's a really good question. I don't think we have any evidence that if you use an immunotherapy first, and then the patient fails that, that targeted therapy would be less effective. We do have some of our melanoma doctors that have suggested that if you use targeted therapy first, immunotherapy might be less effective. I don't really know that, that observation is on solid ground. But reverse using immunotherapy first, I don't really think that there is solid evidence for that. But one other possibility would be to try and combine them, and to use immunotherapy and combine it with, let's say, everolimus and lapatinib or do some combination like that. And then we've done a lot of these combinations. We've published this recently with our IPREDICT study in nature of medicine and then a second paper in genome medicine. The combinations can be done safely. If you initially reduce the dose, for the patient and then titrate to tolerance. And then some of these patients do very well on reduced doses and the drugs are active even though you reduce the dose. So personally, I would start out with the combination. As attractive as immunotherapy is, I don't know this patient has the MSH6, the mismatch repair gene abnormality has some PD-L1 expression, but the tumor mutation burden is only slightly elevated and the PD-L1 is not all that high. So I think immunotherapy should be part of the regimen, but if it's the only drug in the regimen, I don't know if we'll get a response. And that's why we suggest targeting, combining the targeted therapy with immunotherapy approach.

Just to add on to the question and thank you for the great response you provided. I think that maybe one of the fears in general is, well, choosing one therapy versus the other one, first can negate the afterwards therapy. But I think that maybe you can weigh in the considerations of time and in different diseases, how these might be more relevant than others, like stage 3 or 4 lung -- line of tumors where the choice of 1 therapy versus the other one, if you like a targeted versus an immunotherapy, it might mean not necessarily a change of responses, but a time line for the patient.

These are critical questions. One of the questions that has -- so we've really gone after the combination approach. And the combination approach is to really cut off as many avenues as possible in the tumor. Now one argument is that really in the end better than if you do the therapy sequentially -- are you buying a longer overall survival by hitting everything at once. Our preliminary data suggests that we are because the overall survival is longer, but it's not a randomized study, and that's the caveat. The other reason I think it's better to hit everything at once is because when you do one therapy at a time, not only are you not impacting the other alterations that already exist. But biologically, you probably drive the formation of new alterations. But I think that, that do you combine it at the beginning and just try to really hit the tumor -- or do you do sequential therapies. That -- even though I prefer the combinations, I think that's still a scientifically open question that needs to be addressed.

Okay. Thank you. So thank you so much for the discussion on this case. I don't see any other question maybe on the interest of time. We would move into the next patient. So -- and this is another female this time is single 73 years old with a metastatic lobular carcinoma, so far triple-negative case as well. And these are the molecular alterations. It's basically a mutation that removed the initiating cadherin on [indiscernible], the CDH1 gene. It has an activating mutation on the ERBB2 gene in the kinase domain and also activating mutation of PIK3CA, the same mutation that we saw in the other patient, which is one of the most common alteration for P3 -- PIK3CA has also been detected by phase at PTEN deletion. And this patient is also microsatellite stable. It has PD-L1 expression by the SP142, and the tumor mutation burden is low, not expression of [indiscernible] by IHC and no known abnormalities in BRCA1, BRCA2 and estrogen receptor 1. Next slide. These are the sustaining results for the patients. And these patients had a 1% expression based on the criteria for CNBC, and it was not tested by the 22C3 antibody, and you can see here that the [indiscernible] is negative. Okay. Can we go back to the previous slide, please? [indiscernible] into mutation. Thanks.

Yes. So I think that this is another very interesting and impertinent patient. And let's go over some of the alterations. So this patient has, like the other patient, a PIK3CA mutation, not the most common one, but still a pathogenic mutation and PTEN deletions. And like with the other patient -- because of the PTEN deletion, we -- even though Alpelisib is a good drug for PIK3CA mutations in the presence of the PTEN deletion we would not give Alpelisib because it targets the alpha sub component of the PI3 kinase, but doesn't target the beta and allows upregulation of the betas of resistance mechanism. And in the presence of PTEN deletion, you get upregulation from the beginning of the alpha and the beta component so we wouldn't go with Alpelisib. Now the report doesn't mention an interesting drug that I neglected to mention before, and that's [indiscernible]. So [indiscernible] an approved -- FDA-approved PI3 kinase inhibitor, its not approved for breast cancer, but it's a very interesting drug. It has been branded as certain gamma delta, I believe, inhibitor, but it's actually a potent pan-PI3-kinase inhibitor and through the alpha, beta, gamma and delta. And so that would be a real possibility. I think the other drug, again, is everolimus that is approved for breast cancer and is further downstream. It's an mTOR inhibitor and I think it's a potentially important drug. The second thing that this patient has like the first patient is ERBB2. And a patient has an ERBB2 mutation. And as we mentioned, with the first patient. The patient doesn't have elevated HER2, but the patient has a mutation that would biologically drive the tumor in the same way that an elevated HER2 might drive the tumor. And that's because the mutation activates the receptors enzyme and therefore, becomes a driver. So again, this patient would be a very good patient for HER2 inhibitor and drugs like neratinib, afatinib, and a [indiscernible] has shown that this particular mutation is sensitive to those drugs. So, so far, we have an mTOR inhibitor like everolimus, which is approved for breast cancer or alternatively a PI3 kinase pan-PI3-kinase inhibitor like [ Buparlisib ], which is approved for other indications as a possibility. And we have a certain ERBB2 inhibitors like neratinib, afatinib, dacomitinib that are also possibilities in this patient. The other important issue here is that this patient is MSS stable tumor mutational burden is not elevated. PD-L1 is expressed at albeit -- they're at a pretty low level, but it's expressed. So I would not rule out a checkpoint inhibitor in this patient, but I wouldn't give it by itself. I would combine it with the ERBB2 inhibitor and the PI3 kinase inhibitor. I think the chance is that a patient responds to a single agent checkpoint inhibitor are slim, but it still could be an important component of a combination regimen. Now the last thing that I wanted to address is the CDH1. So there isn't a great way to target CDH1. But this particular CDH1 variant has been associated with hereditary cancers. And I think this patient needs a germline molecular assessment with one of the -- I mean, we usually use in [indiscernible] or Ambry, but there's a whole array of different companies that do germline assessment. I think that this requires a germline assessment.

Let me add on. I forgot to mention that indeed that alterations present in -- although this test has been performed on tumor tissue, so cannot be considered by any means as an indication the frequency of the mutation. So the mutant alive frequency, it is coherent with that. So it will further push for a germline test on the patient, it's 58% [indiscernible].

Yes, pretty high. And would indicate a germline test. Now you did say that the patient, I don't remember the age. It wasn't a young patient, it was...

73 years.

Yes. So we don't know the family history and CDH germline mutations often predisposed to pretty young cancers. You can see them in gastric cancers. I've seen a couple of patients with these diffuse gastric passers that are in their 20s. But I will tell you that from experience, not all these mutations read the books that I've seen patients that are elderly like this patient that have never had a prior cancer and don't have a particularly suspicious family history. And then you look for germline and it's germline. So I think that there are many exceptions to the idea that if you have a germline cancer, you're going to get cancer when you're young. Even if you have a BRCA mutation, 87% of women with a BRCA mutation will -- that is germline, will get breast or ovarian cancer. But it tells you that 13% won't, and that means that there's also a subset that don't get it until they're older. So 13% won't get it at all by the time they die. And subset are likely not to get cancer until they're older. So I would not take an older patient and say, we don't need to do germline because you're older. I think that that's mostly correct, but not always correct. And certainly, if the patient wants to know for their family, I would definitely do a germline in this patient.

Besides that, you specifically mentioned that there are no specific therapies for CDH1. And just to clarify, so [indiscernible] is a protein that stays on the cell surface of the tissues and holds the tissue together. When it's disrupted, not only itself can become loose, but at the same time, it's absence triggers the activation of the wind Wnt/beta-catenin pathway has been any progress in the development of beta-catenin targeting patients in the centers?

I think that you bring up a very important point, and this is an area where there are clinical trials, but I think it's still been very challenging for patients that have alterations in the Wnt/beta-catenin pathways. There are some drugs that report purposed and a name that do have Wnt inhibitory activity, drugs like sulindac, celecoxib. There is an anti-worm parasite drug called mebendazole, that we have used actually in a couple of patients with pretty good responses and there's anecdotal responses in the literature. So this is repurposing drugs that have been developed for 1 indication for another indication. And there's also some -- a very nice literature, a couple of papers in the literature that suggests that sorafenib -- these are preclinical papers, can inhibit this pathway as well. And -- but all in all, this pathway is hugely important. And we don't have the breakthrough that we've had, let's say, intra pathways or even Ras pathways that we previously considered undruggable and now we have drugs for certain alterations.

Okay. We welcome questions from the audience. And I'll trigger one last question from my end to incentivize the discussion. You mentioned in previous case and in this one, an activating alteration on the ERBB2 gene, non gain-of-function alteration. However, we know that most HER2 targeting therapies are based on another type of biomarker, which is HER2 overexpression. What you think is the evolution that we should expect in terms of FDA approval for basically therapies that we know the alteration is activating. We know this, we understand very clearly the biology, maybe neither in other context or in other presentations, the drugs would be approved. How quickly can we expect seeing FDA and/or even the drug developers pushing for trials to demonstrate the efficacy of the drug in these other centers? Because you're mentioning the fixation under clinical trials and eventually off-label. What can you tell us about that?

Yes. So I think it's actually a very challenging area because what somebody needs to do is look at the individual alterations and which should be several drugs that we have available, lapatinib, afatinib, neratinib, dacomitinib and so forth, best impact each of these mutations. And one mutation may be susceptible to one of these drugs, but not susceptible to another drug. And the same for antibodies, although I have the impression that antibodies may be more problematic with some of these mutations. But that may not be across the board. I don't really think that we're really there with the individual mutations in the HER2 sphere. And this is an area that is actually very important but you're talking about very small subsets of disease, and that has not been adequately explored. Now on the other hand, you have things like intra-fusions, which make up very small subsets of disease, and there's 2 FDA-approved drugs. So that means that targeting these alterations can lead to successful approval, sometimes pretty rapidly if you have [indiscernible]. But I don't think enough is being done in that sphere. There is a question.

Yes. There's one more question. In addition to PI3 kinase what's the interest on AKT and [indiscernible] inhibitors or [indiscernible] in other breast subtypes. I'm trying to get some additional callers, if you can start from the broad sense commenting on this question.

Yes. I think all of these are of interest, and I really look at it from a molecular point of view. I think mTOR inhibitors are already FDA approved, and there's a lot of potential for them in disease subsets that have activation of the PI3 kinase or AKT pathway. The same with AKT inhibitors, where you have PI3 kinase more AKT alterations, I think both of them have a lot of potential there. When you get to CDK inhibitors, there are several CDK4/6 inhibitors. And so far, in breast cancer, there's not any firm data that the patients that have CDK4/6 alterations actually do better with the CDK4/6 inhibitors. On the other hand, we've recently published data that when you look at the pan-cancer setting, some of the CDK4/6 inhibitors definitely do better when you have alterations in the pathway. But there is a caveat, and it's a very important caveat. It's this matching of patients with drugs like palbociclib or abemaciclib that our CDK4/6 inhibitors with alterations in the cyclin pathway does not work very well when you use the CDK4/6 inhibitors as single agents. You have to use them as part of a matched combination. So for instance, we published in Clinical Cancer Research that if we have alterations in the cyclin pathway and alterations in the MEK pathway and we target both pathways then we get responses. But if you target one of the pathways, you don't get very good responses. And I think the reason is because alterations in the cyclin pathways often coexist with very important co-drivers. And unless you hit the co-drivers, you just don't get a lot of mileage out of the CDK4/6 and pathway inhibitors when you match them. So it's a little different than, let's say, EGFR inhibitors or NTRK inhibitors, where you still get good responses even with single agents. With the CDK4/6 inhibitors, we found that you really -- given as single agents, even in patients with alterations in the pathway, we don't get a lot of mileage. But if we co-target the coexisting drivers than in a combination, then we do see some very nice responses.

Okay. Thank you so much for the question. I guess, it relates to targeting cell proliferation and cell resistance, what drives the best effective therapies. I'm imagining that's where you're getting. I think we are just in time to some please.

We are just about out of time. So I do want to say thank you to everyone for attending today. Our next Breast Tumor Board will be on April 13. We also have a Lung Tumor Board on April 6. There is a link in the comment section. And we also would like to extend to you guys a very special invitation on May 10. Dr. Kurzrock will be joining us for a diagnostic symposium on co-targeting driver pathways, efficacy and safety. It will be hosted by Dr. Derek Lyle. And so we want to extend this special invitation to you all to join us for that. We do have a link to register in the comments section, if you need it as well, please feel free to e-mail us at tumor [email protected]. And with that, we are over time. So thank you again, Dr. Kurzrock Dr. Lopez-Diaz. As always, and thank you to everyone who joined us today. Have a great day.

Thank you.

Thank you, Dr. Kurzrock.