JCO Precision Oncology Conversations American Society of Clinical Oncology (ASCO)

In this JCO PO Article Insights episode, Miki Horiguchi provides a summary on the article, “TARGET: A Randomized, Noninferiority Trial of a Pretest, Patient-Driven Genetic Education Webtool Versus Genetic Counseling for Prostate Cancer Germline Testing and explains what a non-inferiority trial is. 
TRANSCRIPT
Miki Horiguchi: Hello and welcome to JCO Precision Oncology Article Insights. I'm your host Miki Horiguchi, an ASCO Journal’s Editorial Fellow. Today, I'll be providing a summary of the article titled "TARGET: A Randomized Non-Inferiority Trial of a Pre-Test, Patient-Driven Genetic Education Webtool Versus Genetic Counseling for Prostate Cancer Germline Testing" by Dr. Stacy Loeb and colleagues.
To help you understand the TARGET study design, I'll first explain what a non-inferiority trial is.
One of the most common clinical trial designs we see in clinical papers is the superiority trial. A superiority trial is designed to demonstrate that a new treatment is superior to a control, such as a placebo or a standard treatment, in terms of a primary outcome that is relevant to the study's purpose. In a superiority trial, a statistical test is performed for the null hypothesis that there is no treatment difference between the two arms. If a significant p-value, which is conventionally less than 0.05 is observed, we consider that the probability that the null hypothesis being true is very low, and thus conclude that there is a treatment difference between the two arms. On the other hand, if the p-value is larger than 0.05, we cannot conclude that there is a treatment difference because the probability that the null hypothesis being true is not low enough. Here, it's very important for us to keep in mind that a non-significant p-value does not mean no difference between the two arms.
Therefore, if the study objective is to show that a new treatment has a similar treatment effect to a control treatment, the standard statistical testing approach used in a superiority trial is not appropriate. To meet this specific study objective, utilizing a non-inferiority test is more appropriate. The formulation of a hypothesis in a non-inferiority test is distinct from that in a superiority test. In essence, the null hypothesis is that the new treatment is inferior by more than the predefined margin, whereas the alternative hypothesis argues against this, suggesting that the new treatment is not inferior within this margin. A significant p-value from the non-inferiority test indicates support for the alternative hypothesis, implying that the new treatment is at least as effective as the control treatment considering the predefined margin of non-inferiority. 
There are a couple of points to consider prior to designing a non-inferiority trial. The first is about the justification for using a non-inferiority study. The new treatment must offer a clear advantage other than the treatment effect, such as fewer side effects and lower cost, so that it can be a viable alternative to the control treatment as long as it maintains a certain level of treatment effect that is not inferior to the controls.  
The second point is about the non-inferiority margin. The non-inferiority margin defines the threshold below which the new treatment is deemed non-inferior to the control. The selection of an appropriate margin is pivotal as it profoundly influences the power and sample size of the study, as well as the interpretation of the statistical test results. To ensure the study's objectives are met, the non-inferiority margin must be established during the study design phase. This decision should be informed by clinical expert opinions, findings from previous studies, or regulatory guidelines. 
Now let me move on to the introduction of the TARGET study. The TARGET study was a multicenter, non-inferiority randomized trial to compare the effects of two types of interventions for pre-test genetic education in patients with prostate cancer. The

JCO PO author Dr. Christian Rolfo shares insights into his JCO PO article, “Liquid Biopsy of Lung Cancer Before Pathological Diagnosis Is Associated With Shorter Time to Treatment.” Host Dr. Rafeh Naqash and Dr. Rolfo discuss how early liquid biopsy in aNSCLC in parallel with path dx is associated with shorter time to treatment.
TRANSCRIPT 
Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCOPO articles. I'm your host, Dr. Rafeh Naqash, Social Media Editor for JCO Precision Oncology and Assistant Professor at the Stephenson Cancer Center, University of Oklahoma.  
Today we are thrilled to be joined by Dr. Christian Rolfo, Associate Director of Clinical Research at the Center of Thoracic Oncology at the Tisch Cancer Institute at Mount Sinai Health System. He is also the lead author of the JCO Precision Oncology article entitled "Liquid Biopsy of Lung Cancer Before Pathological Diagnosis is Associated with Shorter Time to Treatment." 
Our guest's disclosures will be linked in the transcript. 
Christian, it's great to have you here. Welcome to our podcast and we are excited to learn about some of the interesting results from your study. 
Dr. Christian Rolfo: Thank you very much, Rafeh. It's a pleasure to be here and discuss about liquid biopsy.
Dr. Rafeh Naqash: You have a very important role in different liquid biopsy consortiums. This is an initiative that you have been leading and spearheading for quite a while, and it's nice to see that it is becoming something of a phenomenon now on a global scale where liquid biopsies are being implemented more and more in earlier stages, especially. For the sake of our audience, which revolves around academic oncologists, community oncologists, trainees, and patient advocates or patients themselves, could you tell us a little bit about the background of what liquid biopsies are? And currently, how do we utilize them in the management of lung cancer or cancers in general?
Dr. Christian Rolfo: Liquid biopsy has been gaining importance over the years. We started to talk about liquid biopsy in 2009 when we started to see some correlations with EGFR mutations. In practicality, what we are doing is the most common or most applicable indication is to go for liquid biopsies from the blood, peripheral blood. So we are doing a blood draw and from there, what we are capturing is the DNA or fragments of DNA that are still in circulation. But the liquid biopsy definition is a little bit more broad and we can apply the concept of a minimally invasive approach to different fluids of the body, including pleural effusion, urine, and including CSF that is another indication, there, we are going to be a little bit more invasive than peripheral blood, but it is also an emerging tool that we will have to find specific indicators. In cancer, we started the history of liquid biopsy in advanced disease with the identification of biomarkers, and then from there, we are moving to other scenarios, including, nowadays, monitoring minimal residual disease and early detection. And that is applicable also for other tumors.
Dr. Rafeh Naqash: Thank you, Christian, for that summary. Now, as you've rightly pointed out, we have come to implement liquid biopsies more and more, both in the academic setting and the community setting. And this has definitely led to faster turnaround time in some ways compared to tissue. In this study that you have authored with the help of many other collaborators and Foundation Medicine Flatiron Health data, the goal here, from what I understand, was to look at liquid biopsies that were done before, resulted before the pathological diagnosis. Could you tell us a little bit more about the premise of this study, why you thought about this question and how did you try to implement that idea to get to some of the interesting results that you

In this JCO PO Article Insights episode, Fergus Keane provides a summary on "Microsatellite Instability Is Insufficiently Used as a Biomarker for Lynch Syndrome Testing in Clinical Practice", by Papadopoulou, et al published January 25, 2024
TRANSCRIPT
The guest on this podcast episode has no disclosures to declare.
Fergus Keane: Hello and welcome to JCO Precision Oncology Article Insights. I'm your host, Fergus Keane, an ASCO Editorial Fellow. Today, I will be providing a summary of the article entitled "Microsatellite Instability Is Insufficiently Used as a Biomarker for Lynch Syndrome Testing in Clinical Practice" by Dr. Eirini Papadopoulou.
The mismatch repair pathway has gained interest in recent years due to advances in precision oncology, the widespread use of immune checkpoint blockade, and next-generation sequencing-based assays to identify microsatellite instability. The mismatch repair pathway has a key role in DNA repair and maintaining genomic stability. Tumor cells, which are MMR deficient are prone to mismatch errors in the microsatellite regions during DNA replication. Microsatellite instable, referred to as MSI-High tumors are observed across a variety of tumor types, most commonly colorectal and endometrial cancers. 
Germline Lynch syndrome is caused by inactivating variants in one of five primary MMR genes, namely MSH2, MLH1, MSH6, PMS2, and EPCAM, and is associated with an autosomal dominant pattern of inheritance. Mismatch repair deficiency is observed in most tumors in individuals with Lynch syndrome and can also occur sporadically. In mismatch repair deficient colorectal cancer, sporadic cases are identified by BRAF V600E mutations or MLH1 gene promoter hypermethylation. The absence of both of these findings should raise suspicion for germline Lynch syndrome.
The aim of this study was to report the prevalence of microsatellite instability in a large cohort of patients in Europe, specifically Greek patients. In addition, the authors aimed to evaluate the proportion of patients with microsatellite instability referred for germline testing and what factors appeared to influence clinician decision to refer for germline testing. 4553 patients with metastatic cancer were included between January 2020 and April 2023. All patients were referred for MSI analysis, and at physician discretion, BRAF V600E and MLH1 gene methylation analyses were available. Approximately half of patients included had colorectal cancer. 5.27% of patients exhibited MSI-High in total, of whom 58% were female and 42% were male. 
The rates of MSI-High cancers varied according to tumor type, but the highest rates observed in patients with endometrial cancer at 15.69%, gastric cancer at 8.54%, colorectal cancer at 7.4%, and urinary tract cancers at 4.55%. Of the MSI-High patients, with colorectal cancer identified, 24.85% had a BRAF V600E. Excluding these patients, 198 were eligible for genetic testing with a hereditary cancer panel. Of these, only 22.7% were actually referred for a hereditary panel. The median age at diagnosis in this group was 59 years, compared with 66 years for those who were not referred for germline analyses. The age at diagnosis and referral for genetic analyses were significantly correlated. 
Beyond colorectal cancer, patients with other cancer types who were also referred for germline testing included nine patients with endometrial cancer, four with gastric cancer, two with ovarian cancer, one with breast cancer, and one with gallbladder cancer, and referral patterns differed by tumor type. Of patients with colorectal and endometrial cancer, 24.4% had a positive germline mismatch repair variant identified. Of note, while the median age of patients with a pathogenic or likely pathogenic germline result was 48.5 years, over 40% of patients with a pathogenic germline result were aged over 50 years, highlighting that age alone should not be the only criterion for consideration of a referral for germlin

JCO PO authors Lauren C. Leiman and Dr. Emma Alme share insights into their JCO PO article, “Recommendations for the Equitable and Widespread Implementation of Liquid Biopsy for Cancer Care”. Host Dr. Rafeh Naqash and guests discusses increasing access to liquid biopsy for cancer, reviewing the barriers and examining the proposed solutions.
TRANSCRIPT
Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I'm your host, Dr. Rafeh Naqash, Social Media Editor for JCO Precision Oncology and Assistant Professor of Medicine at the OU Health Stephenson Cancer Center at the University of Oklahoma.
Today, we are excited to be joined by Lauren Leiman, Executive Director of BloodPAC, and Dr. Emma Alme, Public Policy Director at Guardant Health. They are both authors of the JCO Precision Oncology article titled "Recommendations for the Equitable and Widespread Implementation of Liquid Biopsy for Cancer Care." 
Our guest disclosures will be linked in the transcript. 
For the sake of this conversation, we will refer to each other using our first names. So, Lauren and Emma, welcome to the podcast and thank you for joining us today.
Lauren Leiman: Thank you for having us.
Dr. Emma Alme: Thank you so much. 
Dr. Rafeh Naqash: So, this article is an opinion piece that addresses something that is emerging and current and tries to connect it to something that is futuristic also and hopefully, will address a lot of different needs relevant to patients with cancer. For starters, since our audience is pretty diverse, could you tell us what the BloodPAC is? Since the article is somewhat a combined piece from different stakeholders, could you explain what this BloodPAC Consortium is as an entity and what is its role for this BloodPAC?
Lauren Leiman: Sure, this is Lauren Leiman. The BloodPAC was formed almost seven years ago as an initial commitment to the White House Cancer Moonshot back in 2016. I was the head of external partnerships and had this idea with a colleague of mine, Dr. Jerry Lee: Could you accelerate the development and approval of liquid biopsy assays for cancer patient benefit if you were able to create some standards and frameworks for the field broadly, and also if you could aggregate data to support those standards and frameworks? So, we brought together about 20 different organizations across pharmaceutical companies, diagnostic partners, foundations funding in the space, government agencies, all to think through can we create these frameworks, are we willing to submit data. We were extremely successful in that first round, and by the end of 2016, we were able to have our first data deposit into- we built a BloodPAC Data Commons, which is housed in Chicago and was created by Dr. Bob Grossman up there.
In 2017, when it became clear that the last administration was not going to continue the White House Cancer Moonshot, we became an independent non-profit 501(c)(3). And we have grown substantially since that time from those original 20 different organizations to about 66 different organizations today, across all those areas again, including today, payers, which is very exciting. And we have added on to our mission statement one word that we will discuss today, which is very exciting, which is “accessibility”. After our five-year anniversary and even slightly before then, we decided that we really feel that we have been able to contribute, as a community, to accelerating the development and approval of these tests. But, in actuality if we don't get them into patients' hands, what is the point of all of our hard work? So, we added the word "accessibility." Today, we have these 66 different organizations that collaborate, essentially, to compete. They’re pulling together projects and deliverables in about ten different working group areas to contribute products to th

In this JCO Precision Oncology Article Insights episode, Mitchell Elliot provides a summary on "Prediction of Benefit From Adjuvant Pertuzumab by 80-Gene Signature in the APHINITY (BIG 4-11) Trial," by Krop, et al published on January 18th, 2024.
TRANSCRIPT
Mitchell Elliott: Hello and welcome to JCO Precision Oncology Article Insights. I'm your host, Mitchell Elliott, an ASCO Journal Editorial Fellow. Today, I will be providing a summary of the article titled "Prediction of Benefit from Adjuvant Pertuzumab by 80-Gene Signature in the APHINITY (BIG 4-11) Trial" by Dr. Ian Krop on behalf of the APHINITY Steering Committee and Investigators.
HER2 epidermal growth factor receptor 2 positive, or HER2 positive breast cancer is characterized by overexpression of the HER2 protein. HER2 is an extracellular receptor that binds with itself and other proteins on the cell surface to facilitate rapid growth and division of cancer cells. Historically, HER2 positive breast cancer carried a worse prognosis than other subtypes. Anti-HER2 therapy with the monoclonal antibody trastuzumab in combination with chemotherapy has been shown to significantly improve clinical outcomes. Pertuzumab, another anti-HER2 monoclonal antibody, binds to a different site on the HER2 protein and has been shown to further disrupt HER2 signaling and improve clinical outcomes.
Primary results from the APHINITY trial, this trial, served as the basis for dual HER2 blockade, combining trastuzumab and pertuzumab with chemotherapy in the adjuvant setting. This data helped establish dual HER2 blockade as the standard of care in many jurisdictions around the world. Understanding patients who do not derive benefit from the additional anti-HER2 therapy is paramount for delivering personalized and effective care while minimizing treatment-related side effects. Understanding the underlying biology of patients who do not drive a response may provide insight into areas of future drug development and integration of novel therapies into future clinical trials.
The clinical definition of HER2 positivity encompasses those that are most likely to have HER2-driven tumors, but previous work has demonstrated that this clinical-pathologic definition does not accurately reflect the molecular heterogeneity of this subtype. These authors completed a translational secondary analysis of the phase III APHINITY trial using nested case-control methods with RNA-seq data derived from primary tumors of patients enrolled in this trial. Both the MammaPrint and Blueprint classifiers are commercially available assays run on microarray data using previously published and validated gene sets. MammaPrint classifies tumors as high or low risk, while Blueprint classifies tumors into luminal, basal-like, or HER2 subtypes. Luminal A tumors are MammaPrint low risk luminal classification, while luminal B tumors are classified as MammaPrint high risk with conventional luminal classification.
In order to facilitate these analyses, RNA-seq data was converted into pseudo microarray-based sequencing using a bridge study from an independent cohort of 75 patients. Conventional Blueprint scores for luminal type, HER2 type, or basal type were calculated for each sample. The subtype with the highest score of the three was the conventional subtype reported for the tumor. The Blueprint subtype was further sub-stratified as a single-activated or dual-activated subtype. Single-activated samples represented the dominant enriched pathway in each tumor, while dual-activated subtypes were assigned if there was no statistical difference between the two dominant pathways.
The primary endpoint was invasive disease-free survival, IDFS, and was stratified by genomic subtype and treatment arm. IDFS was defined as the time from treatment random assignment until the date of first recurrence of ipsilateral invasive breast tumor, recurrence of ipsilateral local-regional invasive disease, distant disease recurrence, contralateral

JCO PO author Dr. Eric Klein shares insights into his JCO PO article, “Performance of a Cell-Free DNA-Based Multi-Cancer Detection Test in Individuals Presenting with Symptoms Suspicious for Cancers” Host Dr. Rafeh Naqash and Dr. Klein discuss how a multi-cancer detection test may facilitate workup and stratification of cancer risk in symptomatic individuals.
TRANSCRIPT
Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I'm your host, Dr. Rafeh Naqash, Social Media Editor for JCO Precision Oncology and Assistant Professor at the OU Health Stephenson Cancer Center at the University of Oklahoma.  
Today, we are excited to be joined by Dr. Eric Klein, Emirates Professor and Chair at the Glickman Urological and Kidney Institute at the Cleveland Clinic Lerner College of Medicine. Dr. Klein is also a distinguished scientist at Grail and author of the JCO Precision Oncology article titled "Performance of a Cell-free DNA-based Multi-cancer Detection Test in Individuals Presenting with Symptoms Suspicious for Cancer."  
Our guest's disclosures will be linked in the transcript. 
For the sake of our conversation today, we'll refer to each other using our first names. It's great to have you here today, Eric, and welcome to our podcast. 
Dr. Eric Klein: Thanks, Rafeh. I'm happy to be here.
Dr. Rafeh Naqash: So today, we're going to try to delve into this very interesting paper. We've had a couple of very interesting podcasts on liquid biopsies, or plan to have a few more. And this is a different aspect of liquid biopsy assessment, and the context here is early cancer detection. Now, the story as it starts, is based on the methylation profile of cancer. Can you tell us, for the sake of our listeners, as we have a very broad audience ranging from trainees to community academic oncologists, what do you understand by methylation profile on a cancer?
Dr. Eric Klein: Sure. Happy to start with that. There are lots of cancer signals in the blood. Cancer cells secrete or otherwise supply the bloodstream with DNA that has methylation signals that are specific to cancer. That's a hallmark of cancer-specific mutations. You can look at chromosome fragments, you can look at proteins and mRNA and exosomes and that sort of thing. In Grail's development study, we focused on using methylation because that, as I mentioned, is a fundamental process. A fundamental property of cancer cells is altered methylation. And in our original development studies, that was the strongest signal, the one that allowed us to have the lowest limit of detection when cancer was present, and the one that allowed us to have the best predictive accuracy for the cancer signal origin. Some people think about that as predicting the tumor origin or the tumor type. And that's the basis of Grail's assay, a pan-cancer methylation profile.
Dr. Rafeh Naqash: Excellent. And now to understand some of the methodology that you used here, before we go into the details because there's a lot of sensitivity and specificity obviously associated with any cancer detection test, and you want a high sensitivity and specificity. And the idea here is that this would help in triaging patients appropriately using this non-invasive tool. Could you tell us the patient population that you were trying to enroll in this study? And I think there is, again, background to other studies that you have done using the Grail test. Could you put that into context of this specific study? 
Dr. Eric Klein: Sure. The population in this particular publication was from substudy 3 of a much bigger study called the Circulating Cell-free Genome Atlas, or CCGA. That was a discovery, refinement, and validation study of this methylation-based signal. And in total, all three substudies together was about 15,000 people, and it was a case-control study. About 10,0