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Journal of Clinical Oncology (JCO) Podcast

Podcast Journal of Clinical Oncology (JCO) Podcast
American Society of Clinical Oncology (ASCO)
The JCO Podcast hosted by Dr. Shannon Westin features discussions of new and noteworthy results published in ASCO’s Journal of Clinical Oncology.

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  • JCO Article Insights: Long-Term Outcome of Neoadjuvant Chemotherapy for Rectal Cancer
    In this JCO Article Insights episode, Peter Li summarizes “Neoadjuvant Modified Infusional Fluorouracil, Leucovorin, and Oxaliplatin With or Without Radiation Versus Fluorouracil Plus Radiation for Locally Advanced Rectal Cancer: Updated Results of the FOWARC Study After a Median Follow-Up of 10 Years,” by Dr. Jianwei Zhang et al. published on December 13, 2024. TRANSCRIPT Peter Li: Hello and welcome to the JCO Article Insights. I'm your host Peter Li and today we will be discussing the Journal of Clinical Oncology article, “Neoadjuvant Modified Infusional Fluorouracil, Leucovorin, and Oxaliplatin With or Without Radiation Versus Fluorouracil Plus Radiation for Locally Advanced Rectal Cancer: Updated Results of the FOWARC Study After a Median Follow-Up of 10 Years,” by Dr. Jianwei Zhang et al.  For a reminder to the audience, the FOWARC study is a Chinese-based study that looked into the treatment of locally advanced rectal cancers with neoadjuvant chemotherapy based regimens with or without radiation. This study was first published back in 2019 where the three-year data showed no difference in three-year disease-free survival over survival between the three study arms. As a reminder of what those arms were, there were one historical control and two interventional arms. The control arm used 5-FU with radiation therapy with five cycles of 5-fluorouracil with radiation during cycles two to four followed by surgery and then seven cycles adjuvantly. Their first interventional arm was the same as the control arm with the addition of oxaliplatin on day 1of each cycle. And lastly, the third arm was FOLFOX only for four to six cycles followed by surgery and then six to eight cycles adjuvantly completing about a total of 12 weeks of chemotherapy.  They recruited about 495 patients with 165 patients randomized to each arm. They were relatively well balanced by age, clinical staging and distance from the anal verge. Median age was about mid-50s with a slight male predominance and patients were primarily stage 3 with 20% to 30% being stage 2. About 30% had clinical T4 disease and about 25% had clinical N2 disease. Median follow up time was 122.5 months or 10 years and their follow up endpoints were disease-free survival, overall survival and local recurrence, and they also performed subgroup analyses based on post surgical pathological staging. Survival was analyzed using Kaplan-Meier method with a significant threshold of p being less than 0.05. About 451 patients actually underwent surgery, which is about 91% of patients. The main reason for not going through surgery was due to refusal but one was due to toxicity and two were due to disease progression in the control arm. Follow up loss rate was about 10% in each group. Now looking at their primary endpoints in their initial study, local recurrence was about 8.8% in the control arm versus 7.9% in the FOLFOX radiation group versus 9.2% in the FOLFOX only group. Distant metastasis was about 30% in each arm and the sites of metastases were primarily in the lung and liver.   Now, following up with 10 years, there were only three new events in the chemoradiation group with local recurrence happening at 10.8% in the control arm versus 8% in the FOLFOX RT group versus 9.6% in the chemo only group. These findings were not statistically significant. In their subgroup analysis by pathological staging, they found that pathological CR or complete response had a lower rate of local recurrence compared to those with increasing pathological staging coming in at 3% versus 4.3% versus 11.6% versus 15.8% in pCR versus Stage 1, 2, 3 respectively. And they found no difference in each stage with each interventional arm. Looking at long term survival their 10-year disease free survival showed 52.5% in the 5-FU radiation group versus 62.6% in the FOLFOX RT group versus 60.5% in the chemotherapy only group with no statistically significant difference between three groups. By pathological staging, they found improved 10-year disease survival in those who achieved pathological complete response versus those who did not with 84.3% in the pCR group versus 78.7% versus 56.8% versus 27.7% in the stage 1 versus 2 versus 3 group. And again they found no statistical significance difference between each arm.   Now looking at the 10-year overall survival rates between the three arms, in the control arm the 10-year overall survival was 65.9% versus 72.3% in the FOLFOX RT group versus 73.4% in the chemo only group. By pathological stage, again, they showed a statistically significant difference in those who achieved pCR versus those who had pathological stage 1 to 3 disease with overall survival being 92.4% in those who achieved pCR versus 84.9% versus 68.6% versus 48.8% in stage 1, 2, 3 respectively. Now in the discussion, authors mentioned that with a median follow up of 10 years, FOLFOX alone had similar disease-free survival, local recurrence and distant metastasis and overall survival compared to those who received neoadjuvant chemoradiation, justifying the omission of radiation without compromising results or outcomes for each patient. There were no differences in subgroup analysis for disease free survival local recurrence or overall survival based on pathological staging. There were only three new events compared to the last follow up, with local recurrence happening only in the chemo radiation groups. Local recurrence rates at 10 years was about 10%. Compared to other clinical trials such as CAO, ARO or AIO-94, the rate of local recurrence was similar to those historical trials.  The authors also compared their findings to the PROSPECT study which looks at the use of total neoadjuvant chemo radiation versus chemotherapy alone, which boasted only about a 2% local recurrence rate. But as a reminder, high risk locally advanced rectal cancers were excluded, mainly those with T4 or N2 disease, which may explain the difference in terms of local recurrence in the PROSPECT versus this study. Another finding is that pathological complete responses are also an important prognostic marker with lower 10-year local recurrence rate, disease-free survival and overall survival with worse outcomes with increased pathological staging. Distant metastasis rates were still at 30%, with the most common site being lung then liver then lymph nodes consistent with other historical studies. Chemotherapy seemed to be better at reducing liver mets than lung metastasis per their findings. In their post hoc analysis of their own study, chemo radiation was also associated with higher incidence of low anterior resection syndrome and persistent ostomy compared to chemotherapy alone, meaning that they had better quality of life with the chemotherapy only approach.  In conclusion, a chemotherapy only approach can be safe and a feasible treatment for locally advanced rectal cancer without compromising outcomes. Omission of radiation may reduce the risk of overtreatment and improve quality of life for some of these patients. However, this does not necessarily exclude the role of radiation as it may still play a role in a response escalation approach for those who do not respond to chemotherapy alone.   This wraps up today's episode. Thank you for listening to JCO Article Insights. Please come back for more interviews and article summaries and be sure to leave us a rating and review so others can find our show. For more podcasts and episodes from ASCO, please visit asco.org/podcasts.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.  
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  • High Omega-3, Low Omega-6 Diet with Fish Oil and Prostate Cancer
    Host Dr. Shannon Westin and guests Dr. Bill Aronson discuss the article "High Omega-3, Low Omega-6 Diet With Fish Oil for Men With Prostate Cancer on Active Surveillance: The CAPFISH-3 Randomized Clinical Trial" and how Omega-6 are predominant in the American diet while the study significantly lowered the intake of Omega- 6 fats. TRANSCRIPT  Dr. Shannon Westin: Hello everyone and welcome to another episode of JCO After Hours, the podcast where we get in depth on manuscripts published in the Journal of Clinical Oncology. I'm your host, Dr. Shannon Westin, GYN Oncologist by trade and one of the grateful Social Media Editors of the JCO. And I am very excited to welcome a special guest today, Dr. William Aronson. He is professor of Urology in the UCLA Department of Urology, the Chief of Urology at Olive View UCLA Medical Center, and Chief of Urologic Oncology at the Veterans Administration West Los Angeles. Welcome, Dr. Aronson. Dr. William Aronson: Thank you, Shannon, and delighted to be here. Dr. Shannon Westin: We are so excited to have you discussing your manuscript, “High Omega-3, Low Omega-6 Diet With Fish Oil for Men With Prostate Cancer on Active Surveillance: The CAPFISH-3 Randomized Clinical Trial,” which was published in the Journal of Clinical Oncology on December 13, 2024. So let's get right to it. First of all, you know we have a very mixed audience, so can you just level set for us and speak about the population you studied in this important trial - that low risk, favorable, intermediate risk prostate cancer. How common is that? How is it defined? That would really help. Dr. William Aronson: I would say about 50% of the patients that we diagnose with prostate cancer either have low risk disease or what we call favorable intermediate risk disease. So when the pathologists look at the cancer under the microscope, they assign what's called a Gleason grade. Grade 3 is the slower growing type of prostate cancer, grade 5 is the fastest growing type, and grade 4 is somewhere in between. So a low risk group would be only the grade 3, the slower growing type. And the favorable intermediate risk group would actually be the grade 3+4, which means they mostly see the low risk type in there, but they also see the slightly faster growing type, grade 4. So this is what we typically see. We see these patients on a very regular basis when they're newly diagnosed with prostate cancer. Dr. Shannon Westin: Okay, got it. And then can you walk us through just what the management options are typically for this patient population? Dr. William Aronson: So typically for what we call the low risk group, the patients with a low PSA and only that grade 3 type, slower growing type of prostate cancer, the standard recommendations are active surveillance. So typically, we'll periodically monitor these patients with PSA blood testing and periodically do prostate biopsies depending upon the patient's other medical problems. Dr. Shannon Westin: So I think it would also be really helpful just to understand what your typical management options are for this patient population. Dr. William Aronson: So for patients with low risk prostate cancer, they only have the Gleason Grade 3+3 with a low PSA. The standard practice is observation. And so these men will periodically see them and measure their PSA values. And periodically, they'll undergo prostate biopsy to make sure they're not getting progression of their disease. For men with favorable intermediate risk prostate cancer, that's a little different. In some practices, the patient and the urologist will decide to do active surveillance. In other scenarios, these patients will definitely elect treatment, either with radical prostatectomy or radiation therapy or other treatments that are available. Dr. Shannon Westin: So your manuscript notes that there was a high level of interest in dietary supplements and approaches among patients with prostate cancer that do elect for active surveillance. Prior to the results of CAPFISH-3, did we have any data to support those types of recommendations? Dr. William Aronson: We actually don't have any long term prospective randomized trials that support that recommendation. There have been a number of very interesting epidemiologic studies, for example, suggesting maybe a plant-based diet might be helpful. Or a number of other studies suggesting maybe more tomato-based products like tomato sauces or tomato paste may be helpful. But no prospective longer term randomized trials that were positive. Dr. Shannon Westin: Okay, that makes sense. So what led you all to explore the high omega-3, low omega-6 fatty acid diet in this trial? Dr. William Aronson: After our initial omega-6 studies, we subsequently did some studies where we raised the omega-3 from fish oil and lowered the 6, looking at a more favorable ratio of the omega-3 to omega-6. And once again, we found that in our animal models, there was a significant delay in progression of prostate cancer. That then led us to perform a clinical trial. It was a short term trial in men prior to undergoing radical prostatectomy. And in these men, they were randomly assigned to one of two groups, either a western high fat diet or a low fat diet with fish oil. And we found after just four to six weeks, a significant change in the Ki67 level in their radical prostatectomy tissue. And Ki67 is actually a strong indicator of prostate cancer progression, spread, or even death from prostate cancer. Dr. Shannon Westin: Well, and I think that leads us really nicely into the design of the current study. So why don't you walk us through how CAPFISH-3 was designed. And you've already spoken a little bit about your primary endpoint. Dr. William Aronson: Based on the results of what we saw in the lab and what we saw in our short term clinical trial, we decided to perform a one year trial, a longer term trial in men on active surveillance. And these men were randomly assigned to either a diet with slight reduction in dietary fat, specifically reduction in the omega-6 intake as well as increase in foods with omega-3 and fish oil capsules. The other group, we asked the men to just not take fish oil capsules, but they could eat whatever else they wanted during the course of the study. Men in the diet where we lowered the omega-6 and raised the omega-3, they were seen by a dietitian once a month to really ensure that they were compliant with that intervention, which they were. The other intriguing part of our study, which I think is super important, is the precision that was used when these men underwent prostate biopsy. So, at baseline and at one year, when these men underwent prostate biopsy, they had the same site within the prostate biopsied. That's important because it's not so easy to find the same site within the prostate because of heterogeneity throughout the prostate. And so we were able to obtain that high level of precision as they were in an active surveillance program at UCLA with Dr. Leonard Marks. Dr. Shannon Westin: So we spoke a little bit about what's important about the Ki67 index as your primary endpoint. Can you talk a little bit about what the study found with your intervention? Dr. William Aronson: So we found that the Ki67 index increased by 24% in the control group and decreased by 15% in the low omega-6, high omega-3 group with fish oil capsules. So that ended up resulting in a statistically significant change between the groups favoring the low omega-6, high omega-3 group. Dr. Shannon Westin: And then what were the secondary endpoints that CAPFISH-3 explored? Anything of note that you want to review for the listeners? Dr. William Aronson: So a number of positive secondary endpoints from the trial. Firstly, we saw that the triglyceride levels were lower, which is what can typically be seen with omega-3 intake. We also saw reduced levels of a cytokine, a circulating factor in the bloodstream called ‘macrophage colony stimulating factor’. And that's particularly interesting because there's a certain type of macrophage which is well known to be involved in prostate cancer progression in men with more advanced prostate cancer, and we've been able to inhibit that in our animal models and in our tissue culture studies. And it was especially interesting to see that we did have an effect on this particular cytokine in this prospective randomized trial. We did not see changes in a number of other measures, including Gleason grade or PSA. These are measures that we use in clinical practice. To see an effect on those would have required a longer term and larger study to be performed. Dr. Shannon Westin: That makes sense. I think it's always great to try to get as much of these types of translational data as we can. But sometimes you just have to do what is reasonable and you get what you get. It looks to me like this regimen was fairly well tolerated. Did you obtain any patient reported outcomes or feedback on the trial? Dr. William Aronson: So, there were four patients in the fish oil group that did have some side effects, and we withdrew them from the study. They did have some effects on their upset stomach, and a number of men also had some diarrhea as well. And so for those four patients, we did withdraw them from the study. Dr. Shannon Westin: And then I guess the last question I have is really, what's next for this intervention? Are we ready to move this to the clinic or what do you see as next steps? Dr. William Aronson: Well, this next step that we're working on right now is to better understand exactly what happened in these patients. So we have blood, we have tissue, we're doing genetic studies on these patients. So that's really the first step, in our mind, to better understand what happened before moving to the next step. I'm particularly intrigued about trying this intervention in men with more advanced prostate cancer, specifically because of what we see, this particular diet and how it's affecting the patient's immune system and how that may favorably affect their course of their prostate cancer. Dr. Shannon Westin: Well, great. Well, thank you so much for taking the time to chat with us about such an important clinical trial, and I really appreciate all the work you're doing and hope to get to see you soon. Dr. William Aronson: Well, thanks for having me, Shannon. It's really an exciting finding and I think it's something that clinicians and patients are going to be super interested in. Dr. Shannon Westin: We love straightforward interventions that actually make a difference, so you guys are to be congratulated for that. And I just want to thank all of you for listening. Thanks again, and I hope you enjoyed this episode of JCO After Hours. Be sure to check out our other podcast offerings wherever you get your podcasts. Have an awesome day.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Dr. Aronson Disclosures: Stock and Other Ownership Interests Johnson and Johnson Speakers' Bureau Company name: Janssen Oncology, Bayer, Blue Earth Diagnostics, AstraZeneca, Pfizer/Astellas Research Funding: Lantheus Medical Imaging UCLA Health Article Video
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  • JCO Article Insights: TROPION-Lung01 Dato-DXd in NSCLC
    In this JCO Article Insights episode, Ece Cali summarizes findings from the JCO article, "Datopotamab Deruxtecan Versus Docetaxel for Previously Treated Advanced or Metastatic Non–Small Cell Lung Cancer: The Randomized, Open-Label Phase III TROPION-Lung01 Study." TRANSCRIPT Ece Cali: Hello and welcome to the JCO Article Insights. I'm your host Ece Cali and today we will be discussing the Journal of Clinical Oncology article the “Datopotamab Deruxtecan Versus Docetaxel for Previously Treated Advanced or Metastatic Non–Small Cell Lung Cancer: The Randomized, Open-Label Phase III TROPION-Lung01 Study.”  Despite significant advances in non-small cell lung cancer treatment over the past decades, second line treatment options for non-small cell lung cancer without actionable genomic alterations have remained largely unchanged since 2000. Many clinical trials failed to demonstrate improved overall survival compared to docetaxel based regimens. TROPION-Lung01 is a global open label randomized phase 3 trial comparing the efficacy and safety of Dato-DXd to docetaxel in patients with previously treated advanced or metastatic non-small cell lung cancer. Dato-DXd is an antibody drug conjugate targeting TROP2 and delivering deruxtecan, a DNA topoisomerase 1 inhibitor, as its payload. The trial is designed with dual primary endpoints of progression free survival, as assessed by blinded independent central review, and overall survival. The initial PFS results were presented at ESMO in 2023 and this article reports more detailed data and overall survival analysis of the trial.   In the TROPION-Lung01, 299 patients were randomly assigned to receive Dato-DXd and 305 patients to receive docetaxel. Patients were stratified by the presence of actionable genomic alterations, histology, treatment with PD-1/PD-L1 immunotherapy as the last line of therapy, and geographical region. The baseline characteristics of the patient population were overall balanced between the treatment arms. I'd like to highlight a couple of key points here. The median age was 63 years in the Dato-DXd and 64 years in the docetaxel arm. Similar to the many clinical trials in the thoracic oncology field, this is younger than the median age of lung cancer diagnosis in the US, which is around 70. African American and Hispanic patients were underrepresented in this trial with 41% of patients identifying themselves as white and 39% as Asian. The D\docetaxel arm had a slightly higher percentage of male patients, 69% versus 61%. The majority of the trial population, 73%, had adenocarcinoma. Patients with actionable genomic alterations were included in this trial if they received one or more targeted therapy and platinum based chemotherapy prior to the enrollment. 17% of the trial population had an actionable genomic alteration in this trial.  When it comes to the efficacy results in the full analysis set, the PFS improvement was statistically significant. The median PFS was reported as 4.4 months for the Dato-DXd, and 3.7 months for the docetaxel arm with the hazard ratio of 0.75 and a P value of 0.004. However, after a median follow up of 23 months, the trial did not meet its primary endpoint of overall survival. The median overall survival was 12.9 months for patients treated with Dato-DXd and 11.8 months for patients treated with docetaxel with the hazard ratio of 0.94 and a P value of 0.53. Objective response was a secondary endpoint and the confirmed objective response rate was 26% with Dato-DXd, and 13% with docetaxel.  Now let's take a closer look at some of the subgroup analyses. Exploratory analyses of key subgroups in TROPION-Lung01 demonstrated differences in efficacy based on histology. In the nonsquamous subgroup, Dato-DXd showed a longer progression free survival of 5.5 months compared to 3.6 months with docetaxel with a hazard ratio of 0.84. However, in the squamous subgroup, Dato-DXd performed worse with a progression free survival of 2.8 months compared to 3.9 months with docetaxel corresponding to a hazard ratio of 1.32. A similar trend was observed in the overall survival analyses, though confidence intervals crossed 1 in both histology subsets, in this case, the differences observed were not statistically significant. In the nonsquamous subset, the median overall survival was 14.6 months with Dato-DXd and 12.3 months with docetaxel with a hazard ratio of 0.84. In the squamous subset, both arms had shorter survival compared to the nonsquamous subset. The median overall survival with Dato-DXd was almost two months shorter, so 7.6 months, compared to 9.6 months with docetaxel corresponding to a hazard ratio of 1.32. While these analyses suggest the potential survival benefit for Dato-DXd in nonsquamous subset, this trial was not powered to test this hypothesis hence these analyses remain exploratory. Another subgroup analysis of note was the group with actionable genomic alterations. Patients with actionable genomic alterations achieved a median PFS of 5.7 months with Dato-DXD and 2.6 months with docetaxel corresponding to a hazard ratio of 0.35. Similarly, the median overall survival was longer in patients with actionable genomic alterations by almost six months, with a median overall survival of 15.6 months with Dato-DXd and 9.8 months with docetaxel corresponding to a hazard ratio of 0.65.  Now, let's talk about safety. Grade 3 or higher treatment related adverse events occurred in 26% of patients with Dato-DXd and 42% with docetaxel. The most common adverse event of any grade seen in the Dato-DXd arm were stomatitis seen in 47% of patients, nausea in 34%, and alopecia in 32%. Treatment related interstitial lung disease occurred in 8.8% of patients on Dato-DXd and 4.1% of patients on docetaxel. Of note, grade 5 drug related ILD was more frequent with Dato-DXd. Seven patients on Dato-DXd and one patient on docetaxel died secondary to drug related ILD in this trial.  In summary, TROPION-Lung01 aims to address an unmet need for patients with previously treated non-small cell lung cancer. For this population, the treatment options remain limited with poor survival outcomes. TROPION-Lung01 is a positive trial by design due to clinically modest improvement in PFS. However, the lack of overall survival improvement is disappointing. Exploratory subgroup analyses suggest Dato-DXd may offer survival advantage in specific subsets such as nonsquamous non-small cell lung cancer and patients with actionable genomic alterations. However, these findings require further validation in a prospective trial since TROPION-Lung01 was not designed to address these questions. The data from this trial alone is not sufficient to argue for a change in clinical practice. However, it informs how the future trials using this drug should be tailored. This highlights the importance of studying potential predictive biomarkers earlier in the drug development and incorporating these biomarkers prospectively into the clinical trial designs.  Due to the lack of overall survival benefit in this trial, the biologic license application for accelerated approval of Dato-DXd for patients with previously treated nonsquamous non-small cell lung cancer was voluntarily withdrawn. New BLA was submitted for Dato-DXd for patients with previously treated advanced EGFR positive non-small cell lung cancer. This BLA is based on data from TROPION-Lung05, TROPION-Lung01 and TROPION-PanTumor01. Of note, the results of TROPION-Lung05 trial have been just published in JCO.   This wraps up today's episode. Thank you for listening to JCO Article Insights. Please come back for more interviews and article summaries and be sure to leave us a rating and review so others can find our show. For more podcasts and episodes from ASCO, please visit asco.org/podcasts.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    
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  • Air Pollution and Breast Cancer Incidence
    Host Dr. Davide Soldato and his guests Dr. Ann Wu and Dr. Alexa White discuss the article "Air Pollution and Breast Cancer Incidence in the Multiethnic Cohort Study" and the editorial "Growing Evidence for the Role of Air Pollution in Breast Cancer Development"  TRANSCRIPT The guests on this podcast episode have no disclosures to declare.  Dr. Davide Soldato: Hello and welcome to JCO After Hours, the podcast where we sit down with authors from some of the latest articles published in the Journal of Clinical Oncology. I am your host, Dr. Davide Soldato, Medical Oncologist at Ospedale San Martino in Genoa, Italy.  Today, we are joined by JCO authors Dr. Anna Wu and Dr. Alexander White. Dr. Wu is a professor of Population and Public Health Sciences at the Keck School of Medicine of UCS, while Dr. White is an investigator in the Epidemiology branch of the Environment and Cancer Epidemiology Group at the National Institute of Health.  Today, we will be discussing the article titled, “Air Pollution and Breast Cancer Incidence in the Multiethnic Cohort Study,” and the accompanying editorial.  So, thank you for speaking with us, Dr. Wu, Dr. White. Dr. Anna Wu: Thank you for having us. Dr. Alexandra White: Yes, thank you so much for the invitation to be here. Dr. Davide Soldato: So before going in depth about the results of the study that was published in the JCO, I was wondering if you could give us like a brief introduction and a little bit of background about what was known about air pollution as a risk factor for breast cancer and what was the evidence before this study was conducted. Dr. Alexandra White: Okay. I can start with that question. So, there's been research for decades looking at the relationship between air pollution and breast cancer. And it's been a really challenging question to address for a number of reasons. One being that it can be really difficult to assess exposure to air pollution and many previous studies have had really limited information on people's residences over time. But in general, what we thought leading up to this study was that evidence was most consistent that exposure to traffic related pollutants such as nitrogen dioxide was more consistently related to a higher risk of breast cancer. The evidence for fine particulate matter or PM2.5 was less consistent. More recently, there have been a few large, well conducted studies that have supported a positive association. This new study in the multiethnic cohort led by Dr. Wu is really important because it really demonstrated that, in this large study of over 50,000 women in California, that they also do see an association with PM2.5.  Dr. Davide Soldato: Thank you very much for the introduction. So, Dr. Wu, we just want to hear a little bit more about the results. So, what was the association that was observed for PM2.5? And specifically, the study that you ran was focused on a very diverse population, a multiethnic cohort, and so I was wondering if you observed any type of differences when you consider the different populations that were included in your study. And if you could also give us a little bit of what was the composition of the women that were enrolled in this cohort. Dr. Anna Wu: Thank you for the question. So, the multiethnic cohort study is a cohort of over 200,000 individuals who were enrolled when they lived in Hawaii or California. For the air pollution studies that we've been conducting, we have focused on primarily the California participants. And in this instance for the breast cancer study, it was based on roughly 56,000 individuals out of- there were about 100,000 because half of them were men and they were not included. Of the California participants, 75% of them were African Americans or Latinos and they were self-identified as these racial ethnic groups when they enrolled in the study. And this was a particularly important consideration for us because in most of the studies that have been published so far on-air pollution and breast cancer, as well as other cancer sites, most of those studies were conducted among whites in the US or whites in Europe. And even if they included non-white populations, the numbers tend to be small so that they were not able to conduct racial ethnic specific analysis. So, we were particularly interested in examining these other racial ethnic groups because we know from other studies that racial ethnic minority groups tend to live in communities of low socioeconomic status and those communities also tend to have higher levels of various types of environmental pollutants. And so, it was important for us to actually try to tease apart these various interrelated factors.  So, what we found was that per 10 micrograms per cubic meter, we had a 28% increased risk overall in all participants combined that meet across the racial ethnic groups. We actually did not see any differences or significant differences in the hazard ratios by race ethnicity and they were in general quite compatible with each other. But we did see a stronger finding among the white participants in our study. Dr. Davide Soldato: Thank you, a lot, Dr. Wu. So, I think it's very interesting the fact that in the end you observed that air pollution is a significant risk factor across all the ethnicities that were included in the study. But I think that one very strong point of the manuscript and one very strong point of the analysis was that in the end you also corrected for a series of different factors because we know that the incidence of breast cancer can be modified, for example, by familial history or BMI or smoking habits or also alcohol consumption. And a lot of these risk factors were included in your analysis. And so, I was wondering if you could tell us a little bit whether you observed any significant differences when you observed or included also these risk factors in your analysis, or whether the association for air pollution as a risk factor stands even when we consider all of these other elements. Dr. Anna Wu: Yes. So, we considered all the well-established breast cancer risk factors. And in this situation, we were particularly interested in considering smoking, alcohol intake, use of menopausal hormones, history of diabetes, body mass index, family history, as well as physical activity, because many of these risk factors, such as, for example, diabetes and body mass index, they are risk factors for breast cancer, and air pollution, have also been found to increase risk of these factors.  So, in our analysis, we first adjusted for all of these potential confounders in a mutually adjusted manner, so all of them were considered. In addition, we also conducted stratify analysis. So as an example, we stratified the analysis to examine whether the hazard ratio associated with PM2.5 provided comparable risk estimate or hazard ratio estimates for never smokers, former smokers, and current smokers. Although we did not see significant heterogeneity by these various subgroups, we did see a significantly stronger effect of PM2.5 among individuals who did not have a family history of breast cancer.  Interestingly, our finding was also stronger among individuals who were never smokers and light alcohol drinkers, even though the results were not significantly different. So, we surmised that maybe individuals who already had a high risk because of other established risk factors for breast cancer, we were less likely to be able to observe the effect of air pollution. But it's important to note that other studies, such as the ones that Dr. White has conducted, have also looked at various subgroups, and I think part of the limitation that all of us have is that once you subdivide the study population, even if you start out with a large sample size, often the sample size gets cut in half or a third. And so, we still lack the statistical power to be able to observe significant differences. But I think it is important to note that, in fact, the hazard ratio estimates are actually quite comparable, but we did see a hint of stronger effects among never smokers, and people who were light alcohol drinkers. So, I think this is an area that we certainly need to continue to investigate since there are other subgroups, such as menopausal status, such as hormone receptor status of breast cancer, that we need to consider in future studies. There's still a lot of work we need to do to sort this out, to actually figure out who are the women who are the most susceptible to the exposures. Dr. Davide Soldato: Dr. White, I would really love a comment from you on this specific area and specifically on what still needs to be done. And related to this, a question actually, for both of you, because I think that from a methodological point of view, there is a lot of work that goes into deciding how we are going to assess the exposure to air pollution. So which type of data are we going to use? Which type of data are we currently using in the epidemiological studies that have been conducted and in the one that we are discussing right now in JCO? And what are the caveats for this data that we are using? Meaning, I think that we use mostly residential addresses, which means that we are looking at the exposure where people actually live, which might not be the place where they spend most of their time. For example, if someone is working, maybe they could be more exposed and have higher exposure when they are at work compared to when they are at home. So, I was wondering if you could give us a little bit of an overview as to what is the methodological standard of care right now in terms of this analysis and what can we do better to refine and understand this specific factor as Dr. Wu was mentioning? Dr. Alexandra White: Yeah, so I'm happy to take a first stab at that question. So, I think it's important to note just how far we've come. I think even a few years ago, air pollution was really not considered a risk factor for breast cancer. And a lot of the work that we've been doing and others have really moved this forward in terms of understanding this as a risk factor. And as I mentioned earlier, there have been a lot of challenges in exposure assessment. And to get to your question, I think that our studies in general are doing better at looking at exposure over more years, residences, more time. We know that cancer takes time to develop, and we can't rely on just a single snapshot of exposure. But as you mentioned, almost all of the studies published have really exclusively focused on residential estimates of exposure. And so, there's a real need to understand the exposures that people are experiencing in other aspects of their life, from their commute to their jobs, to really capture that totality of exposure.  And then I think one of the points that Dr. Wu was alluding to as well as we know that breast cancer is a very heterogeneous disease, so risk factors for breast cancer vary by tumor subtypes, by menopausal status at diagnosis. And a lot of studies have really focused on considering breast cancer as a combined outcome, and that might be missing some really important signals where we might have a stronger effect for certain subtypes due to the fact that there's different biologic pathways that are underlying these subtypes or by menopausal status. And so having large study populations where, as we discussed earlier, would really give us the power to look among these smaller groups of women who might be more susceptible and those with younger women, we know that incidence of cancer is rising in young people, and we need to understand the risk factors for that. And most of our studies are really focused on older individuals, so I think that's one important gap, as well as having the power to really look at different differences by tumor subtypes. Dr. Davide Soldato: I think it's very interesting, and I think one point both of you made in the original article and in the accompanying editorial is also the fact that we tend to look at these risk factors in people who are actually aged, while we maybe should be looking at this in an earlier phase of development and potentially during puberty. Do you think that we should design studies that are more focused on this population even though I think that they will take a lot of time to produce significant results?  Dr. Alexandra White: Yeah. I think that it is really important to consider how exposure during early life is related to breast cancer risk. We know that exposures during pregnancy or even as early as during puberty might be particularly relevant for breast cancer. And I think a lot of our studies have really been up against the challenge of the fact that exposure monitoring for air pollution really didn't start until the 1990s. And so, it's challenging, especially for these older cohorts, to get back at that time period that might be relevant. But I think that's something that definitely newer cohorts are going to be able to address, and I think it's going to be really important, and also will give us some clues to better understand the important windows of exposure, but also that might provide clues for the biologic pathways as well that are relevant. Dr. Davide Soldato: And just a related question, because I'm not aware of this, but are there right now cohorts that are specifically looking at this in the US or in other parts of the world? If you are aware of that, of course.  Dr. Alexandra White: There have been some cohorts that have focused on exposure during these hypothesized windows of susceptibility, but I don't think they've been able to follow those women long enough to develop breast cancer. One of the things that we're working on in the sister study is trying to expand our assessment of air pollution exposure back in time to try to get at these earlier windows of exposure. So, I'm hoping that it's something we'll be able to comment on and at least for some of the women in our cohort who are younger. But I don't know, Dr. Wu, if you're familiar with any other populations that are doing this now?  Dr. Anna Wu: Well, NCI funded several new cohorts in the last couple years that are really focused on trying to get a much more refined exposure assessment. So, I know colleagues at University of Michigan that are peers and also Dr. Wei Zheng at Vanderbilt, they are putting together newer cohorts that are younger and also trying to include a range of exposure, not just air pollution, but really environmental exposures. Those cohorts I think have the potential in the future to try to address some of these questions, but again, it will take at least another number of years before there are a sufficient number of endpoints so that they can actually do these types of studies.  Another possibility is that there are a number of big cohort studies in Asia. The age of diagnosis tends to be earlier in Asia. I know that investigators in China are very interested and concerned with the air pollution effects in China. I think there are potentials that in other countries where the age of breast cancer diagnosis is actually younger than in the US and if they establish in a manner that allows them to assess air pollution that they may have opportunities.  And I think the other way to try to address this question, whether there are studies where you can actually tap into either biomarkers or pathology samples so you won't be actually studying air pollution in a large population, but you're actually narrowing it down to try to see if you see any signals in a way that would give you some additional clues and insights as to the mechanism. So I think we're going to have to piece together various types of study to try to answer the questions because one type of study like these observational air pollution studies, will allow us to address one slice of the questions that we have and then we need to put together other studies so that we can address other aspects that we're interested in to put it together. Dr. Davide Soldato: Thank you very much both of you. That was very interesting.  Coming back to the results of the manuscript, we really focused up until now on PM2.5. But it's true that inside of the study you evaluated different pollutants. So, I was wondering whether you saw a similar association for other pollutants that were included in the study or whether the association for higher risk was observed only for PM2.5. Dr. Anna Wu: The results for NO2, NOx, PM10, and carbon monoxide were actually very compatible with the risk estimates that other studies have published as well as from the meta-analysis. So, I would say that our results from the other pollutants are actually very consistent with other results. I think one difference is that our PM2.5 estimates were based on the satellite-based PM2.5 estimates, whereas all the other pollutants were based on monitoring station estimates from EPA sponsored air monitoring stations. So, they are not measured in the same way. And I think different studies over time have used either monitoring station type measures for other pollutants. And I think we were particularly interested in PM2.5 because the measurement of PM2.5 in the monitoring world didn't start until around 2000. So, studies up until that time were less able to actually provide the assessment of PM2.5 as good as we can for air pollution. There's always misclassification. So, I think it's a matter of how much misclassification in the assessment. But, again, we are really limited in really just having exposure over one part of adult life.  Dr. Davide Soldato: Thank you very much. And one potentially related question. We are speaking in general about air pollution, but I think that since we are considering residential addresses, probably we are capturing more either traffic pollution or pollution that comes from probably industries or stuff like that, which is mostly related to residential areas or the place where people live. But I think that in the end we also think about air pollution as something that can come from different forms. And one very interesting point, Dr. White, that you made in your editorial is also that there is a global change also in the way we are faced with air pollution. For example, you made the example of wildfires in your editorial and how this might potentially change exposure to air pollution, maybe for limited times, but with concentrations that are fairly higher compared to what we generally observed. So, I was wondering if you could comment a little bit on that and also, if there is potentially a way to also consider this in future epidemiological studies. Dr. Alexandra White: Yeah, so when we talk about exposure to fine particulate matter, PM2.5, we're assessing exposure to particles that are based on the size of the particle, and we're really not evaluating the types of particles that people are experiencing exposure to. And we know that, in general, that PM2.5 composition really varies geographically due to differing sources of exposure. So, like you were saying, there might be a stronger contribution to industry or from agriculture or from traffic. And so that could really change the PM2.5 exposure profile that individuals experience. And so it could be that this is another really important area that this research needs to consider, which could really help us identify what sources of exposure are most relevant.   Wildfires are a really important growing concern. We know that wildfires are increasing in both intensity and duration and frequency, and we really don't understand the long-term health impacts of wildfires. But we know that wildfire associated PM2.5 might be one of the most dominant contributors to PM2.5 moving forward. And although we've seen historic declines in PM2.5 in the US after the Clean Air Act, those declines have really stalled. PM2.5 itself is projected to increase over the next few decades, so understanding different PM2.5 composition profiles and the sources that drive them can really help us identify the most important targets for any potential interventions. And wildfire PM2.5 in particular may be of concern because it's a combustion byproduct, and so it's thought to have more of the components that might, we hypothesize, are most relevant for breast cancer, such as PAHs or polycyclic aromatic hydrocarbons or metals. And so, these components are thought to act as endocrine disruptors, which may be particularly relevant for breast cancer. So, I think understanding this changing landscape of PM2.5 moving forward is going to be really important in understanding how PM2.5 contributes to cancers beyond just breast, but as well as other female hormone driven cancers and all of the cancers really.  Dr. Davide Soldato: Thank you very much. So, one closing remark, because I think that in general, we have been really in a field of primary prevention for breast cancer where we were focusing on individual behaviors, for example, smoking cessation, reduction in alcohol intake, reduction of BMI, increase of physical activity. But I think that the evidence that is accumulating in the last three years or so is telling us more and more that we also need to shift the perspective on prevention going not only on individuals, but also as including environmental risk. So, I was wondering, how can we include this new evidence in the policies that we implement and how policymakers should act on the data that we have available right now? Dr. Anna Wu: I think it's really important that this new information is communicated to all the stakeholders, including our policymakers, so that they are, first of all, really aware that any changes and not actually adhering to current guidelines can have long lasting consequences, deleterious consequences. And I think it's important to also note that over 90% of the world actually live in areas where PM2.5 exceeds the limit. We have observed increases in breast cancer in many middle- and low-income countries, so I think it's particularly important to emphasize that this is really not just a western country issue, it is really a global issue. Dr. Alexandra White: I agree. And I would just add to that that air pollution is not something that an individual can really change on their own. There are things you can do, you can monitor air quality, you can try to live in a home that's far away from traffic. But really these are large scale problems that really require large scale solutions. And we know that policy changes can be effective here and that this is something that, in my opinion, is not something that we leave to the individual to change. This is something that we as a society should encourage change for the health of everyone. Dr. Davide Soldato: So, thank you very much again, Dr. Wu, Dr. White, for joining us today on the podcast. Dr. Anna Wu: Thank you. Dr. Alexandra White: Thank you so much for having us.  Dr. Davide Soldato: So we appreciate you sharing more on your JCO article and accompanying editorial titled, “Air Pollution and Breast Cancer Incidents in the Multiethnic Cohort Study.”  If you enjoy our show, please leave us a rating and review and be sure to come back for another episode. You can find all ASCO shows at asco.org/podcasts.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.      
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  • JCO Article Insights: Adoption of Capivasertib in Metastatic Hormone Receptor–Positive, HER2-Negative Breast Cancer – Efficacy, Toxicity and Treatment Sequencing
    In this JCO Article Insights episode, Giselle de Souza Carvalho provides a summary on  "Navigating Treatment Pathways in Metastatic Hormone Receptor–Positive, HER2-Negative Breast Cancer: Optimizing Second-Line Endocrine and Targeted Therapies" by Bhardwarj, et al and "US Food and Drug Administration Approval Summary: Capivasertib With Fulvestrant for Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Locally Advanced or Metastatic Breast Cancer With PIK3CA/AKT1/PTEN Alterations" by Dilawari et al published in the Journal of Clinical Oncology.  TRANSCRIPT Giselle Carvalho: Hello and welcome to JCO Article Insights episode for the December issue of the Journal of Clinical Oncology. I'm your host Giselle Carvalho, Medical Oncologist in Brazil focusing on breast cancer and melanoma skin cancers and one of the ASCO Editorial Fellows at JCO this year. Today, I will be discussing two articles. The first one is “Navigating Treatment Pathways in Metastatic Hormone Receptor–Positive, HER2-Negative Breast Cancer: Optimizing Second-Line Endocrine and Targeted Therapies,” and the second one is the “US FDA Approval Summary on Capivasertib with Fulvestrant  for HR-positive HER2-negative Locally Advanced or Metastatic Breast Cancer with PIK3CA/AKT1/PTEN Alteration.”  As we know, 65% to 70% of all breast cancers are HR-positive HER2-negative and this is also the most common subtype of metastatic breast cancer. The current standard of care for frontline therapy of patients with luminal metastatic disease is a CDK4/6 inhibitor in combination with endocrine therapy. However, as new endocrine and targeted therapies gain approval, choosing the best systemic therapy upon disease progression after frontline therapy is a topic of ongoing debate. Nearly 40 to 50% of HR-positive breast cancers have actionable genomic alterations and molecular testing should be a routine recommendation for patients with metastatic HR-positive HER2-negative disease. This can be performed repeating tissue biopsy at the time of progression or from archival tissue. Treatment options after progression on CDK4/6 inhibitors include alpelisib in combination with fulvestrant in patients with PIK3CA mutant tumors as seen in the SOLAR-1 trial, or capivasertib with fulvestrant in patients with a tumor mutation in (PI3K)–AKT–PTEN pathway as seen in the CAPItello-291 study, which will be discussed further.  In approximately 30% of patients, progression on frontline endocrine plus CDK4/6 inhibitor treatment is caused by endocrine resistance, frequently involving activating mutations in ESR1. For those tumors, elacestrant, an oral SERD is an option as demonstrated in the EMERALD trial. For patients with a BRCA mutation, PARP inhibitors represent another option. If no mutations are detected, everolimus, an mTOR inhibitor, can be used based on the BOLERO-2 results. The phase 2 MAINTAIN and PACE trials, along with the phase 3 postMONARCH trial support changing the endocrine therapy backbone with or without switching the CDK4/6 inhibitor. In less resourced areas, fulvestrant monotherapy is still an option to delay cytotoxic chemotherapy, though its efficacy is limited when used as a single agent. Finally, after progression on at least one line of chemotherapy, antibody drug conjugates including sacituzumab govitecan or trastuzumab deruxtecan may be an option.  Now focusing on the PI3K AKT PTEN signaling pathway, activating mutations in PIK3CA and AKT1 and inactivating alterations in PTEN occur in approximately half of luminal breast cancers. In June 2023, the CAPItello-291 trial was published and treatment with fulvestrant plus capivasertib, a PTEN AKT inhibitor, demonstrated a 3.6 month PFS benefit compared to fulvestrant alone, regardless of the presence of AKT pathway alterations. However, for those with tumors without AKT pathway alteration, an exploratory analysis showed that although there was a numerical improvement in PFS, it did not meet statistical significance, indicating that the biomarker positive population primarily drove the positive results noted in the overall population. Therefore, capivasertib plus fulvestrant was approved by the US FDA in November 2023 exclusively for patients with PI3K/AKT1/PTEN tumor alterations after progression on an aromatized inhibitor with or without a CDK4/6 inhibitor. The approved schedule of capivasertib is slightly different from that of other agents used in breast cancer. It is 400 milligrams taken orally twice a day for four days per week every week in a 28-day cycle in combination with fulvestrant. Diarrhea, rash and hyperglycemia were the most commonly reported grade three or four adverse events in the interventional group. I would like to highlight that even though the CAPItello trial excluded patients with glycosylated hemoglobin levels higher than 8% or those diagnosed with diabetes who required insulin, hyperglycemia occurred in 19% of biomarker positive patients treated with capivasertib, with nearly 2% of this population experiencing grade 3 or 4 hyperglycemia and some patients experiencing life threatening outcomes such as diabetic ketoacidosis.  By way of comparison, hyperglycemia of any grade was three times higher with alpelisib therapy in the SOLAR-1 trial, occurring in 64% of the patients and grade three or higher hyperglycemia was seen in 37% of the patients. Diarrhea was the most common treatment related adverse event experienced by 77% of the biomarker positive population. Prompt use of the antidiarrheal drugs when needed, such as loperamide must be encouraged as untreated diarrhea can lead to dehydration and renal injury. Cutaneous rash occurred in 56% of the biomarker positive population in the interventional group and 15% experienced a grade 3 or 4 rash. Nearly half of the patients with cutaneous adverse reactions required treatment and this was the leading reason for dose reduction of capivasertib.  In the biomarker positive population, the improvement in medium PFS were 4.3 months by investigator assessment. Overall survival data from the CAPItello-291 trial is still immature, but quality of life data was recently published in September this year and was assessed by the 30 item QLQ C30 questionnaire and the QLQ BR23, the breast module. According to Oliveira et al, global health status and quality of life were maintained for a longer period with capivasertib fulvestrant than with placebo fulvestrant except for symptoms of diarrhea which were significantly worse in the capivasertib group. The median time of deterioration of global health status and quality of life was twice as long in the capivasertib group being almost 25 months versus 12 months in the placebo fulvestrant group. These data reinforced the use of capivasertib in combination with fulvestrant for the treatment of HR-positive HER2-negative advanced breast cancer patients with PIK3CA/AKT1/PTEN tumor alterations who have progressed after an aromatase inhibitor-based therapy with or without a CDK4/6 inhibitor.  Thank you for listening to JCO Article Insights. This is Giselle Carvalho. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcasts. See you next time.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.  
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