Veracyte, Inc. ($VCYT)

Good day, and thank you for standing by. Welcome to the Veracyte Investor Call on ASCO Findings conference call. [Operator Instructions] Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, Kelly Gura Director of Investor Relations. Please go ahead, ma'am.

Good morning, and thank you for joining us today to discuss key findings from the 2026 ASCO Annual Meeting. Before we begin, please note that we will make forward-looking statements, including statements regarding our products, clinical evidence, commercialization plans, reimbursement, market opportunities and expected timing. These statements are subject to risks and uncertainties that could cause actual results to differ materially. Please refer to Veracyte's SEC filings, including its most recent Forms 10-K and 10-Q for a discussion of these risks. Veracyte undertakes no obligation to update forward-looking statements except as required by law. We will refer to slides posted on the Investors section of our website, and a replay of the call will be available there after the call concludes. With that, I'll hand the call over to Marc.

Thanks, Kelly. Today, we will discuss the exciting outcomes from the independent OPTIMA trial led by University College London, which provide what we believe are practice-changing results for patients dealing with early-stage breast cancer. We will also discuss results from the ENZAMET study analysis, which provides yet another level of insights for patients who are suffering with metastatic prostate cancer. Data from these pivotal studies were presented at ASCO over the weekend. We believe both provide strong level 1 evidence, demonstrating how our Prosigna and decisive test can uniquely guide treatment decisions. We're very happy to be here today to share these results with you and to discuss what they mean for patients, physicians and for Veracyte. Joining me from Veracyte is Dr. John Leite, our Chief Commercial Officer; Dr. Phil Febbo, our Chief Scientific Officer and Chief Medical Officer; Rebecca Chambers, our Chief Financial Officer, will join us for Q&A. I'm also honored to introduce Dr. Iain Macpherson, who is one of the principal investigators of the OPTIMA trial. Dr. Macpherson is a professor of Breast Oncology at the University of Glasgow and an honorary consultant medical oncologist at the Beatson West of Scotland Cancer Centre. His clinical and research work focuses on breast cancer treatment personalization, clinical trials and translational oncology. Dr. Macpherson has led and contributed to multiple national and international studies is widely published across peer review publications and is a recognized investigator in trials advancing precision approaches to breast cancer care. With that, I will turn the call over to Dr. Macpherson to walk through the OPTIMA trial results.

Thank you, Marc, and good morning, everyone. It's my pleasure to present the first results from the OPTIMA Phase III randomized controlled trial of test erected chemotherapy in patients with high clinical risk Estrogen receptor-positive, HER2-negative early stage breast cancer. OPTIMA is an academic trial sponsored by University College London and the data were first presented by my colleague, Professor Rob Stein at the ASCO Annual Meeting this past Saturday. Before diving into the results, I'd like to briefly provide some background for why Prosigna was selected as the molecular diagnostic to be used in the trial. The OPTIMA trial was preceded by a feasibility study called OPTIMA prelim which was initiated in 2012 for early-stage high-risk breast cancer patients. In addition to its primary objectives, it served as a head-to-head comparison, evaluating the value of information and performance of Prosigna and other genomic tests. Based on these analyses, Prosigna was chosen as the integral biomarker for guiding treatment decisions in the OPTIMA MAIN trial. The positive clinical outcomes of the 10-year OPTIMA prelim study were presented at the ESMO Breast Cancer Annual Congress last year. The findings suggested that Prosigna had enhanced prognostic accuracy in high-risk patients compared to the test that was initially used to assign patients to treatment groups. Importantly, Prosigna identified 22% of patients or roughly 1 in 5 as high risk of recurrence after they had initially been classified as low risk by the test used to assigned treatment. Unfortunately, those patients went on to experience adverse outcomes at a rate consistent with a high-risk status. These findings demonstrate Prosigna has greater prognostic accuracy, which provided early confidence for the OPTIMA MAIN trial. And these results have turned out to be very exciting for patients and for our continued understanding of breast cancer. Today, tumor gene expression assets are widely used to assist chemotherapy decisions, primarily in postmenopausal women with estrogen receptor positive HER2-negative early breast cancer with up to 3 involved acciliary lymph nodes. However, supporting evidence for premenopausal patient uses mix and current guidelines do not support test use and premenopausal women with any degree of nodal involvement. As such, typical treatment for high-risk premenopausal women has been both the course of chemotherapy, which can hub severe and lasting side effects and standard hormone tablets taken for 5 to 10 years. In addition, there's almost no prospective evidence for the use of gene expression tests in patients with higher levels of modal involvement, 4 or more involved nodes. OPTIMA was inspired by retrospective clinical analysis that suggested that gene expression assays in addition to providing prognostic information could also predict chemotherapy sensitivity. And this would mean that patients with tumors that have a low test score for risk of recurrence would not benefit from chemotherapy despite having a high stage related recurrence risk. OPTIMA had a bold and impactful trial design. We recruited more than 4,400 women and men aged 40 years and over, following surgical excision of their breast cancer. These patients were recruited across 6 countries from 2017 through 2025. Cancers had to be ER positive and HER2 negative, and there could be up to 9 involved auxiliary nodes. For node-negative cancers, there was a minimum tumor size requirement of at least 30 millimeters. The patient characteristics were well balanced. The median age was 56, 37% of participants were premenopausal, 31% of cancers were grade 3 and 46% were 3 centimeters or larger. 8% of participants had node-negative cancers, 73% had 1 to 3 nodes and 19% at 4 to 9 involved nodes. Eligible patients were then randomized between a control arm, which consisted of chemotherapy followed by endocrine therapy or to the Prosigna test directed arm where treatment was decided by the Prosigna risk of recurrence or ROR score. Notably, the Prosigna test was performed after the initial randomization occurred. Those with an ROR score greater than 60 received the same treatment as the control arm plus those with a score of 60 or below avoided chemotherapy and moved straight to endocrine therapy. For patients receiving chemotherapy, the randomization was blinded to both sites and participants, which was an important aspect of the trial design. All other adjuvant treatments, such as CDK4/6 inhibitors, bisphosphonates and radiotherapy were given as standard and the control arm also receives a Prosigna test, which did not impact treatment. Importantly, endocrine therapy included ovarian function suppression in all premenopausal participants, another key aspect of the trial design. This ensured that the confounding effects of chemotherapy-induced menopause were minimized, allowing for a clearer assessment of chemotherapy benefit. As a result, OPTIMA provides the first definitive predictive data for premenopausal women in this setting. OPTIMA used a non-inferiority design. The primary endpoint was invasive breast cancer fee survival or IBC which includes all invasive recurrences, new primary breast cancer and death from any cause. The primary analysis was of the test directed versus the control arm in the overall per protocol population. We were powered to demonstrate non-inferiority with the margin being a 3% absolute difference in IB CFS at 5 years, meaning to demonstrate that the test directed arm delivered similar outcomes within a 3% margin. A key secondary analysis was performed in the per protocol population with ROR scores of 60 or less. This is, in effect, a randomization between chemo endocrine therapy or endocrine therapy alone. And this is the analysis that really defines clinical utility. So OPTIMA met its primary and secondary endpoints for invasive breast cancer fee survival and showed that prosignigated treatment delivers equivalent outcomes while avoiding chemotherapy in a large portion of patients. The chart on the left represents the complete per protocol population and the right shows the low ROR score population. Of the more than 4,400 people who took part in the trial, more than 2/3 of participants had tumors with ROR scores of 60 or below, representing a low Prosigna score. For this group, the results showed that outcomes were incredibly similar, whether chemotherapy was given or not. The difference between these outcomes easily met the noninferiority margin objective of the trial. Our statistical test showed that at most only 2% of patients with a low Prosigna ROR score treated with chemotherapy will benefit from this treatment well within the threshold of no more than 3% required by the trial. This suggests that for patients with low Prosigna ROR scores, chemotherapy offers little or no additional benefits meaning many people can safely avoid it and its many negative toxic side effects, thereby ensuring a higher quality of life during treatment. These outcomes are consistent across all subgroups for patients with low Prosigna ROR scores, as shown on this forest plot. The data clearly demonstrates that the underlying biology of the tumor as elucidated by the Prosigna test is what truly drives outcomes. The Prosigna test is built on the PAM50 genomic classifier, a well-validated framework rooted in breast cancer biology which we believe underpins the consistency and strength of these results across subgroups. By measuring that biology directly, Prosigna is able to differentiate which patients will and will not benefit from chemotherapy, independent of traditional clinical risk factors. While this plot is a great summary of the subgroup analysis, the next few slides will demonstrate the Prosigna performance across the low ROR score population. As I mentioned earlier, the premenopausal population and the patients with higher nodal burden are of particular interest with very strong data shown in these Kaplan-Meier plots. So starting with menopausal status. There is no difference in the outcomes for premenopausal patients are shown on the left or post-menopausal patients, as shown on the right. Now looking at the Kaplan-Meier plots according to number of nodes. Again, there is no evidence of a differential effect in patients with 4 to 9 nodes as compared to 1 to 3 nodes. Further it does appear visually to be some separation of the cars for 2 years in the higher nodal group, these curves are not statistically different from the overall results. Another way of looking at patients with the highest stage related risk is by grouping by stage where Stage IIa includes all patients with 4 or more nodes as well as patients with 1 to 3 involved nodes and a primary tumor size larger than 5 centimeters, would be considered to have a similar stage related prognosis. As mentioned, whilst patients with 49 involved nodes make up 19% of the trial population, the proportion with Stage IIa tumors is higher at 29%. And again, we found no statistical heterogeneity across these subgroups. So in summary, the results of OPTIMA are clear and impactful with the trial successfully meeting its primary and secondary endpoints. Many clinically high-risk node positive patients may be able to safely forgo chemotherapy without compromising outcomes. Prosigna identified that more than 2/3 of high-risk node positive patients who previously would have received chemotherapy could safely be spared this treatment entirely without compromising outcomes or increasing their risk of recurrence. Results were robust across high-risk subgroups that matter most, including premenopausal women treated with ovarian function suppression and patients with more extensive nodal involvement up to 9 positive notes. Molecular biology, not clinical factors alone should guide chemotherapy decisions for these patients. OPTIMA now provides Level 1A prospective evidence by Simon-Hayes criteria, showing that the Prosigna test can accurately predict chemotherapy benefit and guide safety escalation across patient populations. And with that, I'll hand back over to the Veracyte team. John?

Thank you, Dr. Macpherson . And congratulations again on these important results. As the data shows, OPTIMA validates Prosigna in the broadest high-risk breast cancer population to date. This is critical as NCCN guidelines currently recommend all high-risk patients with extensive nodal involvement, those who have more than 3 nodes to receive chemotherapy based on clinical factors alone. For those with 1 to 3 nodes involved, NCCN guidelines recommend consideration of genomic testing to assess risk and guide chemotherapy use in both pre- and post metabolic patients. The optimal data -- I'm sorry, the OPTIMA data showed that more than 2/3 of high-risk patients, those with low Prosigna risk of recurrence scores can safely avoid chemotherapy. In this study, the test directed population achieved 5-year cancer-free survival rates of 93.7%, statistically non-inferior to the 94.9% achieved with chemotherapy in the control arm demonstrating that omitting treatment for these patients does not compromise outcomes or increased recurrence risk. One of the things that we really like about the OPTIMA trial is how the study design required ovarian suppression for all premenopausal women and stratify for other important clinical variables, allowing analysis of endpoints according to chemotherapy use. For the premenopausal group, over 70% are low risk by the Prosigna test and can safely avoid chemotherapy. The impact of patients of being able to avoid chemotherapy is undenied. In addition, Prosigna provides clarity to those patients with a high risk of recurrence score such that the chemotherapy, they are undertaking maybe even more beneficial to them than previously understood. This combination of strong clinical evidence and meaningful impact to patients supports our view that our Prosigna test should be the new standard of breast cancer care for all patients dealing with early-stage hormone receptor positive disease. Further, past trials such as Transit Act, directly comparing the performance of Prosigna versus other commercial breast cancer prognostic assay show poor to moderate correlation between suggesting these tests approach the same objective through different methods and have different cutoffs between high and low risk categories. Thus, extrapolation of the optimal results the other tests in Prosigna has not been validated and may lead to incorrect assignments of therapy. This means we expect Prosigna to be the only commercial test to benefit from the insights learned from the OPTIMA trial. Now let's talk about U.S. market opportunity. There are approximately 225,000 patients diagnosed with ER-positive HER2-negative disease every year and all are eligible and appropriate for Prosigna testing. OPTIMA demonstrates that Prosigna is the only test to predict chemotherapy benefit regardless of menopausal status and for patients with up to 9 positive notes. This builds on prior studies, which demonstrate Prosigna delivers great prognostic accuracy than other genomic assays, including in those negative patients. The robust performance of Prosigna in the OPTIMA trial provides the evidence to support Prosigna's use across the entire early-stage hormone receptor-positive breast cancer market, where a broader adoption will be supported over time. We also plan to provide access to our grid research-use-only database as part of our broader evidence strategy. continuing to lead with KOLs and collaborators that generate a steady cadence of new and innovative data and molecular signatures to advance the understanding of breast cancer in the same way that we have consistently done in prostate cancer. We look forward to launching Prosigna as an LDT in our CLIA lab on June 8, supported by our newly hired and highly energized commercial team. But as we know, evidence like OPTIMA is the fuel that drives the reimbursement, adoption and guideline inclusion for molecular diagnostics. The Prosigna test is the only commercial test built on the PAM50 genomic classifier, a well-validated framework rooted in breast cancer biology that we believe drives its strong and differentiated performance. A robust body of evidence shows that Prosigna test delivers greater prognostic accuracy than other genomic assays as particularly in the critical 5- to 10-year breast cancer recurrence windows. OPTIMA adds to that evidence base demonstrating that Prosigna is the only test proven to predict chemotherapy benefit in high-risk premenopausal women and patients with extensive noble involvement, including up to 9 positive notes. These findings have the potential to change clinical practice and are especially meaningful for many patients who may safely avoid chemotherapy and its lasting side effects without compromising outcomes or increasing their risk of recurrence. Beyond OPTIMA, we have a steady pipeline of additional studies underway that we expect will further reinforce why the Prosigna test stands apart. With that, I'll pass it over to Phil to walk through the data that was presented in ASCO from the ENZAMET study. Phil?

Thanks, John. As you know, at Veracyte, we've been focused on expanding our decipher prostate test into the high-risk biochemical recurrence and metastatic settings, contributing to one of our highest growth areas over the past few quarters. I am pleased to see that our evidence generation engine is continuing to advance the understanding of this devastating late-stage disease, providing new insights into how to better treat these patients. ENZAMET is an international randomized Phase III study conducted by ANZUP. The prespecified biomarker analysis included 634 patients with a median follow-up of 5.6 years. This study assess whether decipher prostate can predict the benefit of adding chemotherapy to standard doublet hormonal therapy in metastatic prostate cancer. In the study, patients with low decipher scores showed no evidence of benefit from adding chemotherapy while patients with higher scores benefited from treatment intensification with docetaxel chemotherapy. Patients with higher decipher scores who received this triplet therapy had significantly improved 5-year overall survival compared to those with standard hormonal therapy alone. These patients had more aggressive disease features, yet achieved comparable survival to patients with a lower decipher score on doublet therapy. The study provides level 1B evidence that decipher can identify which patients can safely avoid chemotherapy and which may be more appropriate for triplet therapy. This is a highly relevant clinical question in metastatic disease where the toxicity trade-off is meaningful and better risk stratification can improve treatment decisions. Prior studies such as STAMPEDE and CHAARTED helped establish Decipher's role in predicting benefit from adding docetaxel to androgen deprivation therapy, or ADT, for patients with metastatic prostate cancer. ENZAMET takes us the next step by addressing a more contemporary and important clinical management question, of which of these patients may benefit from triple therapy by adding docetaxel to ADT plus an androgen receptor pathway inhibitor or ARPI, such as enzalutamide. Approximately 30,000 patients are diagnosed with metastatic prostate cancer each year. This new evidence broadens Decipher's relevance across the prostate cancer continuum and further supports its role in guiding consequential treatment decisions from active surveillance through metastatic disease. With that, I'll turn it back to Marc for a few closing thoughts.

Thanks, Phil. The OPTIMA and ENZAMET data demonstrate the strength of the Veracyte clinical evidence engines, including for Prosigna breast and Decipher prostate. The OPTIMA trial expands on Prosigna's established prognostic utility in breast cancer and demonstrates that it can safely guide chemotherapy decisions in the broadest high-risk, early-stage breast cancer population study to date enabling more than 2/3 of patients to avoid chemotherapy without compromising outcomes. The ENZAMET analysis further expands Decipher's utility in high-risk biochemical recurrence in metastatic prostate cancer delivering predictive evidence that can help guide treatment intensification decisions in advanced disease. Together, these results highlight how high-quality practice aging data can expand the clinical utility of our tests unlock significant market opportunities and most importantly, improved care for patients by enabling more precise personalized treatment decisions while helping avoid unnecessary toxicity. I couldn't be more proud of these results which further our mission of transforming cancer care for patients all over the world. Before I close, I'd like to thank the more than 5,000 patients who participated in both OPTIMA and ENZAMET and the independent research teams who carried out these important studies. I'd also like to thank the Veracyte team, who have worked tirelessly to make our Prosigna, decipher and other tests available to physicians and their patients. Thank you again for joining us today. Operator, please open the line for questions.

[Operator Instructions] Our first question is going to come from the line of Subbu Nambi with Guggenheim.

Absent differentiation in NPC and guideline classification versus Oncotype, one concern would be that it will be a challenge for you to overcome incumbency buyers. What are your thoughts on how to address that? Or do you think will very clearly stated as Prosigna given Prosigna is the only study that's shown differences in premenopausal women and model status.

Subbu, you're breaking up a little bit. Did you ask effectively about the competitive differentiation? That's what I was ascertaining. But...

So I can repeat my question if it wasn't clear. Is the audio better now?

Yes, it's a little better now.

Absolutely. Absent differentiation in NCCN guideline classification versus Oncotype, one concern would be that it will be a challenge for you to overcome incumbency buyers. What are your thoughts on how to address that? Or are you certain that NCCN will very clearly mention that it's Prosigna that's shown all this evidence and that's why warrants being included in NCCN guidelines.

Yes. Thanks, Subbu. We got that question. Yes. So as far as NCCN guidelines are concerned, let me start and then I'll ask John to add in here. But I think if you go back to look at our previous diagnostics test, NCCN guidelines have been a catalyst for incremental growth, but they don't stop the growth engine working. So we actually -- while we're waiting for NCCN guidelines, which John can talk about our level of confidence around that. But while we're waiting for those, we believe that there will be some meaningful adoption over time. And then the NCCN guidelines will ultimately come and then like we saw in prostate put that into a new year. As far as the level of evidence is concerned, it's very compelling. John, do you want to talk about that?

Yes, I'll double down on that, Marc. We've obviously been having some very fascinating conversations here at ASCO. It's been a successful conference for us as a company and the OPTIMA trial result session, clearly generated a lot of interest and inspired some great conversations. I think there will be a cadre of physicians that will adopt in advance of the guidelines. And of course, there are those physicians that are more conservative that will wait for the issuance of the guidelines. We, of course, can never predict when that's going to happen over in what format, we feel confident that the data stands on its own. It is practice-changing by everyone that we've had conversations with -- it is, I think, ultimately, it will make its way towards guidelines in 1 form or another. I think we'll be fine to managing the language and how we position the performance claims of Prosigna in the market.

Another question is, no one has definitively actually shown that in Panopta women, there is no chemo benefit in low-risk patients. So thank you for that. Thank you for a very well-designed study. But crude evidence supported efficacy in 3 menopausal women support an up plus in NCCN guidelines from 2 way to 1. And in turn, what that looks like from a commercial perspective?

Yes. So I think I understand your question. In the premenopausal patients population specifically, they are managed by the same physicians. I think the evidence is very, very compelling. I think the evidence, as we've said, is practice-changing. I think adoption there, there are a lot of eager patients and eager patients equally that want to see this test apply to them. I think this is going to be one of our main entries ones, Subbu.

Our next question comes from the line of William Bonello with Craig Hallum Capital Group.

I would agree what we heard was practice changing in terms of premenopausal and there didn't seem to be much question about that data. The response to the data on 4 or more nodes seem to be a little bit more cautious than the take on the premenopausal data. And so I'm just curious in terms -- well, 2 things. One, in terms of what you're doing on further studies that may demonstrate or maybe even segment the effective of the test in patients with 4 or more nodes. And then secondly, how significant of an opportunity and maybe a share shift driver is nodal status compared to menopausal status.

Yes, Bill, thanks for the question. I'll start and then others can weigh in. But the way to think about this is the market opportunity here. The patient population that Prosigna addresses is the ER positive, HER2 negative patient population, which in the U.S. is the 225,000 patients per year new incidences. Whether it be the premenopausal or the high risk, high nodal status, entry points or even just physicians starting to use Prosigna for no negative patients. Those are just kind of like the entry points. We actually think that the entire market starts to adopt Prosigna in some level in some fashion over time for their patients in general. We don't see it kind of bifurcating like Prosigna gets used for only those patient populations where OPTIMA has demonstrated a clear distinction. This just increases the overall level of utility, both prognostic and predictive for Prosigna across the entire 225,000 population. As far as the falling line is concerned, if you want to discuss that Phil and talk a little bit about that [indiscernible]

Yes. So like with the Decipher now that we're kind of launching Prosigna as an LDT, we already have a broad funnel of studies in line to kind of further expand the evidence. And we are -- we do understand that some areas, there'll be a particular concern about the outcomes of these patients. And certainly, a higher node population. And we've been getting questions about what about even further nodes. I think it's quite interesting that some of the discussion around node positivity and Iain love your comment on this is node positivity and the amount of node positivity does not seem to be reflective of tumor biology as much as the Prosigna test, right? It's a clinical stage. And forever, we've had these cutoffs at 4 or 9 or more what we saw in this study and the optimize that really breaks down. And it's really the biology trumps the number of nodes. We can get back to you with the specific trials that we have that add to our portfolio and increase the confidence in that 4% to 9%. But Iain, maybe you can comment on that.

Thank you. Yes, I mean I would absolutely agree with that comment. I think the fundamental point here is this is about breast cancer biology, and there is no particular preexisting data to argue that the biology differs according to the number of involved nodes. So we feel these data are robust. It is a subject of the overall population. As I showed in my presentation, we can increase the size of that subgroup by looking at patients with very large cancers and 1 to 3 nodes. They're grouped together in TNM staging, they have the same prognosis. And that helps us increase the precision of that estimate. And we really have no suggestion of heterogeneity across these subgroups.

That's helpful. Can I ask just one follow-up to that. Just again, I wasn't thinking that physicians would segment which tests they use depending on menopausal or nodal status. I was thinking more that the premenopausal data is a significant reason for physicians to shift from one test to the other. And so I'm just curious let's say, beyond that, how important you view the nodal status as being a driver for that shift? Or is there anything else you'd highlight in the data that would be a driver for that share shift?

I think the OPTIMA results in general are a driver for that shift, including in the 1 to 3 nodal status as well because of both the combined performance of the OPTIMA results and also OPTIMA prelim. I think overall, what it demonstrates is that so many patients to both can avoid chemotherapy, and that's not just supranoposals. So yes, I think there's nothing else to highlight. I would take the OPTIMA results in and of themselves. and that just reinforces the predictive capabilities on top of the prognostic. Anything you want to add?

Yes. I would just add that the nodal status or high nodal burden and premenopausal canonical clinical challenges that have existed now for years, the OPTIMA trial is essentially a robust demonstration of the performance of the test with the best design trial and with the most compelling and latest results. I think those are compelling enough reason to convert.

That's perfect. That's what I was looking for.

Our next question is going to come from the line of Kyle Mikson with Canaccord Genuity.

Congrats on the great data. Just first on OPTIMA, I guess following up on the previous question. I think this is the first study with 100% ovarian function depression for premenopausal women. Could you just talk about how meaningful that is. And if a competitor could do like a similar study in the near term. And if someone did have similar data with at that 100% metric, could that depression fees kind of set you pretty far apart? Just kind of give some context there.

So I congratulate the research team on that design here. I mean, it was absolutely elegant and they did absolutely the right thing as far as the premenopausal is concerned. And this has been years and years in the making. I mean the study design goes back multiple years, and it's taken many years to collect the data. and produce the results. And so I think -- and it actually what it does, in my mind, is that it corrects some limitations to the previous studies, too. And so I think that's super important. And so yes, it would -- there's nothing to stop anybody else trying to do that in the future, but it would take a lot of time. I don't know if you want to add anything. Anything Iain you want to add.

I really I would agree with that statement. We -- a long time ago, decided to mandate severe function suppression, and that turned out to be a very important decision, particularly when we saw the results of some other trials that did not abate interpretation very difficult. So certainly, we've shown in the context of a variant function suppression that we can safely avoid chemotherapy, specifically based on the Prosigna test. And I think that these are robust.

Okay. And then on the decipher and that look great. But I just wanted to talk about this poster presentation. but essentially compared decapepostate head-to-head with emerging AI digital path, prostate test and the Singapore population. I think both were significantly associated with NSS with Veracyte free survival. Both are prognostic tests, but is there any other takeaways that you guys saw from this head-to-head study that we should focus on in fact the commercial landscape.

John?

Well, I think what we'll see, and we're certainly supporting a lot of evidence generation looking at the comparative performance. I mean I think there's incredible enthusiasm for Decipher as we grow our portfolio. There's been interest in digital pathology and looking at the prognostic potential there. What we're seeing in comparative analysis is where there can be isolated studies where wind controlling the slides, controlling the scanning and controlling the analysis, you can find a robust and reproduce full association with prognosis. What we're finding in our studies when that goes into the while when we go to practice, there's been some challenges as far as physicians experience where we now have multiple studies showing that in real use. Patients are -- can be found with very low risk using TPAI methods, whereas decipher is high and decipher has much more evidence supporting it. So we'll see over time. I think ENZAMET is the type of study that demonstrates that the decipher score is strongly associated with chemotherapy benefit. Those tests are run like any other tests sent for testing within a very controlled environment. And we see reproduceful associations through ENZAMET and preceded by CHAARTED and preceded by STAMPEDE. So I think it really takes -- the burden is on each test. These tests are different. They have different strengths. They have different performance when they're used by physicians for their patients. And we're very confident that the cipher consistently shows a strong association with endpoints both prognostic and now with this dose tax in prediction.

Our next question will come from the line of Mason Carrico with Stephens Inc.

As you kind of think about commercial adoption of Prosigna, how important is workflow integration relative to clinical evidence, where do you guys stand, I guess, on EMR connectivity and maybe electronic ordering? What investments are really required from here to make Prosigna as easy to order as the incumbent assay?

Yes. Thanks for that question. Let me start with -- actually, I couldn't be more proud of our team for having put together that workflow integration and order cash process so we're ready to launch this test on June 8 just a week after the pit data was presented at ASCO. John, maybe you can talk a little bit about your commercial teams approach and Rebecca you might want to talk a little bit about the infrastructure we've built for this.

Yes. So I'll start with digital ordering. As part of the development efforts to make us commercial ready for Prosigna as a laboratory developed test on next-gen sequencing -- we took a look at our entire logistics and ordering workflow. As part of that, it was decided that it was time to build a brand-new portal platform with a brand-new interface, looking to see -- how can we make the ordering process is seamless. And as -- I'm just going to say it, it has to feel familiar to what the office staff is doing today. And so just from that perspective alone, a lot of work went into making it as familiar and look like home to one of those office workers. Our goal here is to transition the test into practice workflows as seamlessly as possible and EHR is a big part of that, and that's a large part of the investments.

Yes. Thanks, John. I would say to you, a lot of the investments have already been made at head count being added over the course of the last 12 to 18 months and work that's been done to get ready for both today and for next Monday. As we progress through penetrating the Prosigna opportunity as well as the MRD opportunity, that expenses now in our run rate. I don't expect it to go anywhere. But I don't necessarily foresee outside of adding incremental commercial heads a big incremental step-up for additional spend being associated with the order to cash workflow from an EMR integration standpoint, we have been also investing on that side of the equation, and we will continue to do so, and that will be important, again, full for Prosigna and for MRT. All this is contemplated in our guide of adjusted EBITDA for 2026 as of that 26%.

Thank you both. And one of the important thing to point out is, I think we said this before, people are aware of this, but just worth punctuating. This as this test is run on the same platform that we have developed for Afirma that we recently launched at the back end of last year and that is performing extremely well in the lab, highly scalable. And so it's somewhat of a plug into that existing platform.

Got it. And then one more quick one for me. Does the strength of OPTIMA change your prior view that Prosigna is a 5-year share gain story rather than a near-term revenue contributor?

Yes. Prosigna is a multiyear, like any new test when you launch it, it's a multiyear story to kind of grow and gain share. The big distinction here with Prosigna versus when we launched, for example, a firm and even decipher. In most cases, we were trying to change practice in the context of convincing physicians using evidence as you always do, that they need to enter the molecular diagnostics into their workflow. That work has been done in breast cancer. And so now it's a question of, again, using the evidence to encourage appropriately positions to use Prosigna in their workflow given the predictive capabilities in addition to this prognostic. So it's a slightly different approach, there's not really a good analog for that, frankly, Mason. So we'll see how that goes. But -- some components are bear obviously easier. And obviously, when you enter a competitive space on components could be harder. Overall, when I take a step back, I feel like this should be -- especially with the strength of the evidence this should be a relatively straightforward prospect for us and our sales team who, by the way, are fantastic. And so we look forward to seeing how it pans out.

Our next question comes from the line of Puneet Souda with Leerink.

You have Michael Sante on for Puneet and congrats on the results. My first question has to do is if you have any estimate on the size of the premenopausal or high node positive population just to get us a sense of maybe the initial commercial traction for the launch.

Yes. We actually do. I mean -- and again, I would encourage investors to think about those as maybe some landing point, not the only, but landing points and entry points, but the node positive patient population is about 75,000 of the 225 and is split roughly 25 premias or 50 post manifolds and the total premenopausal is also including the negative. But again, those I would think of is not the market opportunity here. The areas where we have through OPTIMA and distinct evidence.

And maybe, John, you want to talk about kind of the go-to-market approach from a KOL-driven perspective because I think that does it to say how the entirety of the market is available.

Yes. So as we mentioned earlier, a publication here will follow following the publication. We imagine guideline inclusion. As we've stated, even for our prostate test, guideline inclusion has traditionally been a catalyst of growth. But in the meantime, we're not staying still. And as I mentioned, many of the key opinion leaders, thought leaders, researchers, clinicians who happen to do research as well are all attending ASCO and we're having very enthusiastic conversations, and it's clear that there is adoption potential in the early go prior to those events. And then those that are more conservative and guideline following would start to consider the test post that. So part of our commercial strategy has been and always will be. to start with key opinion leaders with our strong influencers who really understand the data, start to use that data to start to tailor and drive new practice workflows that then other physicians can follow in the community. And we'll follow that flow.

Great. That's helpful. And then I was wondering if you could offer any time lines or milestones for getting pricing and reimbursement set for Prosigna?

Yes. So the coverage policy has been set from the historical Prosigna test. We are in the process of reviewing the tech assessment with MolDX. We expect that imminently. And of course, as we've mentioned in prior calls, we don't control those time lines. We simply respond to the questions from MolDX but we have a conservative confidence that this will read out imminently. From a pricing standpoint, Rebecca, do you want to take that?

Yes, happy and happy to do so. Our belief is that we'll be able to cross walk hopefully to be a pharma [indiscernible] and that will be something that comes to bear in time. Historically, we've gotten paid around $2,500 for the IBD. And so when I think about it, our errors are in between that $2,500 and $3,300 price perspective. From the get-go, while we wait for Medicare coverage, we actually do have a number of commercial payers that are already covering Prosigna with varying coverage depending on different characteristics of the patient, but we're pretty excited here to actually launch next week, and we'll be doing so without Medicare reimbursement, but we can do so is because of those commercial contracts that already exist. And so we're pretty comfortable that from the get-go, we'll be able to at least cover the cost of the test in terms of the reimbursement and once Medicare comes in, it's even better. So we're optimistic here and excited. And obviously, all of this is contemplated in our spend guide. We don't have contemplation of the revenue contribution, but the impact is included in the adjusted EBITDA.

Our next question comes from the line of Keith Hinton with Freedom Capital Markets.

Just a couple of commercial questions. Number one, just when I think about the fact that you're launching before you have MolDX reimbursement, should we kind of interpret that as evidence that the sort of early effort here is going to be more in the premenopausal patients since those are more commercially insured. And can you just talk a little bit about the treatment of early breast cancer patients in the community versus academic settings? And then I have a quick follow-up.

Yes, John, do you want to handle that?

Yes, I can take both of those. So our -- you're absolutely right. Our historical practice has been to launch after Medicare reimbursement. This is a unique scenario in the sense that we had already enjoyed both coverage and reimbursement for the Prosigna test. And so the left over to do are acceptance of our tax assessments, which we've already submitted. That tech assessment essentially covers our validation effort from transitioning from the -- or the [ nCounter ] product to the NGS product. And as such, it reflects our, like I said, our cautious conservative optimism that's going to pan out imminently.

And to be clear, just to clarify, we will -- that will affect our go-to-market strategy 1 bit, whether it be premenopausal or postmenopausal doesn't matter. We will be addressing patients and customers across the entire category hit.

Yes. And so as Rebecca mentioned, it's less about will we get reimbursed. It's just ensuring that we have the reimbursement price that. On your second question with regards to early stage patients in premenopausal or postmenopausal setting in academic or community, as I mentioned, we're going to be pursuing our key opinion leader and collaborator stakeholders first. Generally, that is a sale that is very top down, meaning you start with these researchers who truly understand the impact of the data, what it does in terms of impacting practice workflows. That has a general effect of creating influence and peer-to-peer demand generation, and that will trickle down into the community. And we'll be able to follow that as it happens on a region-by-region basis. And that's the reason why we're able to build our sales force in a steady manner to follow this flow.

Okay. Great. And then the second question is just at a very high level, when you think about the OPTIMA data versus your internal expectations going into ASCO? How did this data match up with sort of your base or your bull case? And how is that informing the size and strategy behind the early launch investment?

Maybe I'll give my answer and I want to others too. But for me, I mean, pristine outcome, I would pull it up the those curves and the results and the fact that 2/3 of patients can avoid -- safely avoid chemotherapy is -- the outcome we were hoping for that outcome, is a noninferiority study. But the reaction to the outcome has been even more profound than I probably expected myself. I don't know if you would agree with that [indiscernible]

Yes. I would love to say that it all went to plan, but it was better than what we expected. I will -- the only thing I will add is that when we decided to start the development work, on the rollout of Prosigna as an LDT, it preceded our understanding or knowledge of what was going to happen with the trial. So we made a bet, and it worked out well. For us, the risk of not having this test available if this data read out positively, knowing what it could do for us was just too big to bear. So we thought this was the prudent thing to do.

Our next question is going to come from the line of Mike Matson with Needham & Company.

This is Joseph on for Mike. Congrats on the data. Maybe just a quick one to confirm on the launch strategy and sales force expansion. It sounds like you guys have already done a little bit of hiring over the past 18 months or so. And it does sound like maybe the launch strategy you guys are targeting KOLs at first and expanding from there. So could you maybe just add some more color on that just in terms of the territory expansion for Prosigna, should we think of this as like a multiyear project? Or is it maybe a little bit more aggressive on that? And then I have 2 follow-ups after that.

Yes. I'll let John talk about the approach there and the work that's already been done in his commercial team. What I would say is we retain full optionality we can dial up and dial down as needed, but most likely dial up, frankly, depending on how this goes. Our investment in the commercial activities here, and we're poised, ready to do that. As John tells us, he needs that investment, John?

Yes. I mean one of the things I'm exceptionally proud of is just the team that we've built to start. Every 1 of these folks that we've brought in quite purposefully has been exceptionally seasoned, very clinically and technically knowledgeable so that they themselves are player coaches. And so the rollout of this team always had in mind sales force expansion. And there's a very prescriptive process that's very data-driven where we know exactly how much revenue in a region requires us to then split that region and bring on more headcount. So we'll do that in a very prudent manner in accordance with the best practices that have been set in the other business units.

Okay. Yes. That's clear. And then if we can maybe go back to , I think you have a Slide 16, just outlining the clinical evidence in the future. an ongoing studies. I'm just kind of wondering exactly what the bars mean. I guess each bar is a study, but just in terms of the different categories, the test comparisons looks like you have there 1 ongoing and 1 in analysis. I'm just wondering maybe when would those read out. And then similar question for the predictive -- clinical predictive. Can you maybe walk through which of those therapies are included in there? Obviously, you have chemotherapy with OPTIMA and maybe some other studies. There's radiation therapy. I guess, these studies are that outlining predictive benefit, but are there other classes of therapies in that section. And then just last question. How do you guys expect the 10-year data from the OPTIMA trial, I guess, more or less 5 years from now, to be taken? Do you think that could be another inflection point just given the 10-year data available from, let's say, Oncotype.

Yes, great questions. And I'll start with like a high level on the evidence, Joe and then I'll hand over to Phil to get into a little bit more specificity. And then Iain, if you don't mind handling the 10-year outcome data there. So this is a grid that we share for or a child that we share for all of our tests, we have one for decipher. And we've recently been doing one of these for pharma as well, and it seems very appropriate to show the role of evidence as we call it. for the Prosigna test where OPTIMA fits in and how much is in progress outside of the already published studies. And I think one thing to rarely remember here Again, this is our same platform as a Afirma. So we're going to be able to provide, as John mentioned in his prepared remarks, access to the research grid tool, which, again, it fuels a better understanding of disease it fuels the generation of new studies and evidence and then that ultimately gets that flywheel turning. Phil, do you want to talk about specific maybe what's on the download here in the future?

Yes. So as we discussed in the beginning of the call. Prosigna is not a new test. It's been available as an IVD and there's been keen interest in -- including it in clinical studies. And what you see in the kind of evidence, I would say, reflects the strong history of studies supporting the prognostic strength of Prosigna across different indications, whether it's lymph node negative, lympho positive, premenopausal, postmenopausal. We've also had studies that look in the neoadjuvant setting as increasingly for higher-risk patients. People want to institute therapy prior to surgery. And the slide reflects our ongoing portfolio as now we're moving towards running those trials through our laboratory and presignasrun on our transcriptome, and that will further add to the information. The portfolio reflects studies that will be coming out over the next few years. As with all this work, we have a cadence and look forward to making meaningful contributions to San Antonio, ESMO Breast, ASCO and we can review with you the specific output. One thing I did want to mention and a little bit of a follow-up to the prior question, and it was discussed previously like we are now also launching into another large prospective trial with OPTIMA Young that's being run by unit cancer and it has to do with continued interest in really understanding the full benefit for premenopausal women. That does include up to 9 nodes so that will add further evidence to the use of Prosigna to identify women who can safely avoid chemotherapy provided they have a low risk of recurrence. And I also think part of the portfolio of studies that will come out will be the continued follow-up of the OPTIMA study as this was a time-dependent analysis that met all criteria. But Iain, maybe you can talk to what your expectations are as we see over the next 2 years and as we get towards 10 years follow-up for that group.

Yes. Thank you. So this was a time-driven analysis, when all patients have had at least 1 year of follow-up. The median follow-up was 4 years and so really follow-up is ongoing for all participants. As to what things may look like at the 10-year point, I mean, unfortunately, we will see more events as recurrences do continue to occur, we would expect to have tighter confidence intervals around our point estimates. There's no reason to think the actual estimates themselves should change in any significant way. The question is important because with ER-positive breast cancer, we always talk about the need for a long follow-up because this disease has a lot of natural history. However, for the specific question we're addressing, which is whether or not to deliver chemotherapy, the key point is we know from prior meta-analysis that chemotherapy very much exerts its effect over the first 5 years. if we're not seeing any difference at the 5-year time point, then we would not expect to see a difference, it goes with time.

And I think one final note is in the ER-positive group, there's keen interest in not really understanding the use of CDK 4/6 inhibitors in the OPTIMA study, it was a relatively small proportion that received CDK4/6 just that has to do with the timing of when the therapy became available, but we are engaged in multiple studies to look at the interaction of PAM50 specifically Prosigna with CDK4/6 treatment. There was some discussion of a retrospective analysis of the NATALEE trial immediately following the results of the OPTIMA study. But Iain, what are your thoughts on CDK4/6 in this group?

Yes. So I think approximately 8% or 9% of patients in OPTIMA did receive CDK4/6 inhibitors. And that just reflects the point at which these agents became available relative to our recruitment from 2017 due to 2025. I think the question you pose to what extent this data informs patient selection for CDK4/6 inhibitors is very important. I think we don't have any definitive answer on that yet, but is certainly a really important question, area of interest.

Yes. And that's where our flywheel where we will engage in the RUO only grid with investigators to further explore that question.

Our last question is going to come from the line of Jacob Dodd with Morgan Stanley.

This is Jacob on for Colin. A question on intimate. Growth in the cipher for metastatic has already been impressive since the December launch. But how should we think about the engine results as an incremental tailwind to volumes from here? And what milestones in guideline inclusion and broader coverage for the Cipher what do those look like from here in metastatic specifically?

Yes. Thank you. Yes, it's an important study. It helps to resolve this question as we've mentioned earlier about the use -- the appropriate use, the biomarker-driven use of triplet versus doublet therapy I see it as an incremental tailwind to gain further adoption, which will wait on the inclusion in the guidelines to drive adoption even beyond that. So it's an evolving story.

This is story that we did contemplate when we gave the guide most recently in May because, obviously, we have [indiscernible] the side.

Ladies and gentlemen, this will conclude today's question-and-answer session. This will also conclude today's conference call. Thank you for participating, and you may now disconnect. Everyone, have a great day.