Journal of Clinical Oncology (JCO) Podcast

• Botensilimab Plus Balstilimab in Advanced Sarcomas

  Dr. Shannon Westin and her guest, Dr. Breelyn Wilky, discuss the JCO article, "“Botensilimab (Fc-enhanced anti-cytotoxic lymphocyte-association protein-4 antibody) Plus Balstilimab (anti-PD-1 antibody) in Patients With Relapsed/Refractory Metastatic Sarcomas." TRANSCRIPT  Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we get in depth on research that has been published in the Journal of Clinical Oncology. I am your host, Gynecologic Oncologist and Social Media Consultant Editor of the JCO, Shannon Westin. I serve here from the University of Texas MD Anderson Cancer Center. And I am so excited to welcome Dr. Breelyn Wilky. She's an Associate Professor and the Director of Sarcoma Medical Oncology in the Department of Medicine Division of Medical Oncology, and the Cheryl Bennett & McNeilly family endowed chair in Sarcoma Research, the Deputy Associate Director of Clinical research at the University of Colorado Cancer Center. Welcome. Dr. Breelyn Wilky: Thank you so much. I'm delighted to be here. Shannon Westin: And with all those titles, I'm super impressed that she was able to complete the manuscript that we're going to discuss today, which is “Botensilimab (Fc-enhanced anti-cytotoxic lymphocyte-association protein-4 antibody) Plus Balstilimab (anti-PD-1 antibody) in Patients With Relapsed/Refractory Metastatic Sarcomas.” And this was published in the JCO on January 27, 2025. And please note, our participants do not have any conflicts of interest. So this is exciting. Let's first level set. Can you review with us just the current state of sarcoma incidents, survival outcomes, that kind of thing so we all know where we're starting? Dr. Breelyn Wilky: Yes. So, you know, sarcomas are really, I like to call them the black box cancer type. And the big thing is that there's really more than a hundred different kinds of sarcomas, which collectively altogether make up only 1% of adult cancers. And so we talk about these as being bone and soft tissue tumors, but really, the heterogeneity is just incredible. You're talking maybe 10,000 to 12,000 new cases of soft tissue sarcoma per year, which is pretty rare in the grand scheme of things. And the trouble with these is that while you can cure sarcomas if you find them early and they're localized, when they metastasize and spread and are not resectable, we're looking at median overall survivals of really only 12 to 18 months, even, you know, with our best therapies that we have. So, really there's just a dire need for new treatments for this really tough group of diseases. Shannon Westin: Yeah, I agree. I'm a gynecologic oncologist, and we have our little subset of sarcomas that I know there's a little bit out of every one. So I'm really excited to pull this manuscript as one of our podcasts offerings because I think we're all seeing these patients in the clinic and certainly our listeners that have sarcoma or have family members with sarcoma, this is so good to have a real focus on a rare group of tumors that have been a little bit lumped together. Now, with that being said, I know this is such a heterogeneous population, but can you briefly overview a little bit around the standard of care for treatment of recurrent sarcomas? Dr. Breelyn Wilky: We have actually been using the same drugs really since about the 1970s, and up until very recently, nothing had really challenged doxorubicin, the old ‘red devil’, like we used to call it. And this has been the mainstay of treatment for metastatic sarcomas and really used across the board. In the GYN literature, for uterine leiomyosarcoma, we did see some promising activity with the combination of doxorubicin and trabectedin coming out of the French group. But, except for that study, no combination therapy or new drug has been proven better in terms of overall survival compared to doxorubicin monotherapy, really over 40, 50 years. So it's definitely a tough situation. Now, we do have other drugs that we use, so most patients will wind up getting doxorubicin-based therapy. There's a couple of other regimens that we'll reach to, like gemcitabine docetaxel. And once you get into the specific subtypes, we have some approvals in liposarcomas and leiomyosarcomas for some other drugs. But really the median progression for survival for most of these regimens is somewhere four to six months. And response rates typically are somewhere like 10%, 15% for most of these. So it's really just a very tough field and a tough group of patients to try to make an impact for. Shannon Westin: So let's talk a little bit more kind of getting focused on what you've studied here. What's been the role of immunotherapy thus far in the treatment of sarcomas maybe prior to this particular study? Dr. Breelyn Wilky: Clearly, we all know that immune therapy has just changed cancer care forever over the last few years for so many different types of cancers and diseases like melanoma and renal cell and lung cancer have just been transformed by checkpoint inhibitors specifically directed against PD-1 or CTLA-4 or both. And so, of course, you know, sarcoma docs we're super excited to try to see if these might potentially have activity in our tumors as well. I never had seen myself in my career getting into immunotherapy until I was able to run an investigator-initiated study during my role in Miami, where we combined pembrolizumab, so PD-1 inhibitor, with axitinib which was a pan-VEGF inhibitor. And lo and behold, like I had patients that I was seeing responses when other treatments, all those chemotherapies I was just talking about had failed. And one of my first patients I treated was about a 60-year-old lady with something called cutaneous angiosarcoma. So this is a blood vessel sarcoma all over her face. And we had treated her with 10 different therapies, all the chemotherapy regimens, targeted therapies, clinical trials, and nothing was working. But I put her on a phase 1 trial with a baby dose of CTLA-4 and this woman had a complete response. And so for me, once I saw it work in even just those couple of patients, like that was nothing that we'd ever seen with our chemotherapy regimens. And so that sort of shifted my career towards really focusing on this, and this is about the time where some of the studies started to come out for sarcomas. And the take home with sarcoma is about 20% of sarcomas have this sort of immune hot physiology. So what that basically means is if you look at gene expression of immune related gene signatures, or you look for infiltrating T-cells, sort of the SWAT team of our immune system, like you can find those in the tumors. And it's sort of evidence that the immune system had some clue for that 20% of patients that this was a foreign tumor and that it should be attacking it and maybe just needed a little help. But globally, about 80% of sarcomas are these immune cold tumors, which means the immune system has no clue that these things are even a threat. And there's almost no immune activation, very, very few antigens. In other cancer types, high neoantigens or tumor antigens help the immune system work better. And so that basically goes with what we've seen with trials of PD-1 or CTLA-4 blockade. About 20% of sarcomas, with some exceptions, can respond. But really 80% across the board, you're stuck, you just can't get them to be recognized. And so that's where I think this data is so interesting is there's some signals of activity in these immune cold tumors which, at least historically with the trials we've done so far, we really haven't seen that with sort of the traditional checkpoints. Shannon Westin: So I think now this is a great time to maybe talk about the study design in general, the eligibility and just give us kind of a run through of that. Dr. Breelyn Wilky: So this trial was a phase 1 trial of a drug called botensilimab, which is a next generation CTLA-4 directed immune modulator. So what makes botensilimab different is that the CTLA-4 end is very similar to other CTLA-4 inhibitors that are out there, but it's been engineered on the back end of the molecule that binds to Fc gamma receptors to basically bind tighter with higher affinity. And what this translates to in laboratory models and increasingly now in patients is it does a better job of priming, of educating our T cells, our, again, these highly intelligent antigen specific cells, but also natural killer cells. It does a better job of sort of educating those. It helps to activate macrophages and other supporting actors in the immune response. And so the idea here is that there's evidence that botensilimab may do a better job at creating new responses in immune cold tumors. The study combined either botensilimab as monotherapy or in combination with a PD-1 inhibitor called balstilimab. And this was all comers, really a variety of tumor types. And to date I think we're close to about 500 patients with a variety of solid tumors that have been accrued to this study, this C-800-01 phase 1 trial. This paper reports on the sarcoma patients that were enrolled as part of this study. And so, again, given what I've told you about sarcomas being really immune cold, we were just so excited to have the opportunity to enroll on a next generation immune therapy for these tumors that really we were running into roadblocks trying to use immunotherapy previously. Shannon Westin: It's a very compelling idea and I'm so excited for you to tell people what you found. I think first things first, it was an early phase trial. So why don't we talk a little bit about the safety of the regimen. Was there anything that you didn't expect? Dr. Breelyn Wilky: Right. So similar to other checkpoint inhibitors, you know, the idea is that these drugs can cause immune mediated toxicities, right? So essentially you're revving up the immune system and it can sometimes get a bit confused and start attacking our normal cells, our normal organs, leading to essentially any number of toxicities of basically head to toe, something can get inflamed and you can develop a toxicity from that. So the key take homes with this particular drug with, botensilimab with balstilimab, we saw colitis was sort of the primary immune mediated toxicity and it was about a third of patients, give or take. It happens and it can be aggressive and needs to be managed aggressively. And you know, one of the things that we learned very quickly taking part in this study is how important it is that as soon as patients start to get diarrhea, immunosuppression gets on board. So steroids, early use of TNF alpha blockade, so infliximab for example, if we jumped on it quickly and we recognized it and we got the patients treated, it would resolve fairly quickly and even some patients could remain on treatment. So I think that was sort of the first take home is “Okay if you get colitis, you treat it fast, you treat it early and you can still have patients not only recover, which essentially everybody recovered from this colitis and then being able to continue on treatment and still have their anti-tumor responses.” So that's the first point. The second thing that was really interesting is part of the engineering of botensilimab on the back end of the molecule, it's been designed to decrease complement binding and it's thought that that triggers some of these other toxicities that we've seen with prior CTLA-4 inhibitors like pneumonitis or hypophysitis. We actually don't see that with botensilimab. So there's sort of this selective toxicity that may reflect the design of the molecule. But overall the treatment was, we didn't see any new safety signals that were outside of what we would expect in class. And colitis was sort of the dominant thing that we had to be ready for and ready to manage. Shannon Westin: We've been doing it for a while now, so we kind of know what to do and we can act quickly and really try to mitigate and avoid some of the major toxicities. So that's great that that was what was reflected in what you found. And then of course I think: What about the efficacy?” Right. This is what we care about as practitioners, as patients. Does it work and are there any subtypes that seem to benefit the most from this combination? Dr. Breelyn Wilky: Right. So for the sarcoma patients, we treated 64 patients and 52 of those patients were evaluable for efficacy. So a decent size group of patients in sarcomas, where, you know, typically our trials are pretty small, they're very rare, but we had 52 evaluable with at least one post baseline scan. So that was our criteria. And basically we saw across all of the patients, and keep in mind, these are heavily pre-treated patients, as you mentioned, so a median of 3 prior lines of therapy, so most of these patients had had chemotherapies and then about 20% had also had prior immunotherapy as well. So PD-1 treatments or so on. The overall response rate by RECIST was 19.2% for all of the evaluable patients. And then with iRECIST, which is sort of that immune adapted response criteria that allows for early pseudo progression, we actually had another patient who did have that. And so that response rate was 21.2%. Overall, we were really excited to see this in a heavily pre-treated group of patients. But what was really exciting to me was when we looked at the subset of patients that had angiosarcoma, that blood vessel tumor I was talking about earlier with my other patient. So angios come in two flavors. One is this sort of cutaneous type, or meaning involving the skin that has a UV signature, a UV damage signature, very similar to melanoma. So these tumors tend to have a high mutation burden. And oftentimes there is a track record that we've seen responses with immunotherapy in cutaneous angiosarcomas. But the other group that we deal with is called visceral angiosarcomas. And so these are totally different biologically. These are often driven by mutations in MYC or KDR amplification, and they arise in organs, so primary breast angiosarcoma, not associated with radiation, or they can arise in the liver or the spleen or an extremity. So these are very, very different tumors, and the visceral ones almost never historically have responded to checkpoint inhibitors. So we had 18 patients with angio split - 9 with cutaneous, 9 with visceral. And we were just blown away because the response rate for that group was 27.8%. And if you looked at the responses between the hot ones and the cold ones, it was almost equal and a little bit better in the visceral. So we had a 33% response rate in visceral angiosarcoma, which is crazy, historically speaking, and about 20% again in the cutaneous angios. So for a disease where visceral angio gets treated with chemotherapy, might respond initially, but then rapidly progresses - like these people go through multiple lines of therapy - to have a third of patients responding, and then some of those responses were durable. Our median duration of response for the study was 21.7 months, which is just nuts for sarcomas where we just don't see those sorts of long term benefits with the drugs that we have. So I think those are kind of the two main things. There were other subtypes that had clinical benefit and responses as well in d-diff liposarcoma, soft tissue leiomyosarcoma, which are again thought to be fairly cold immune subtypes. So just really exciting to kind of see responses we hadn't expected in a very challenging group of tumors. Shannon Westin: We see all these patients and we have patients that respond so well to immunotherapy with other histotypes. And so it's so exciting to see an option for these really hard to treat tumors that our patients struggle with. So this is so, so very exciting. I wanted to make mention, you know, I was really impressed with the amount of translational work you were able to do in this early phase study. So do you want to review just maybe a few of the key findings that you guys discovered? Dr. Breelyn Wilky: It's always great. I'm a translational researcher at heart and we do a lot of immune correlative work. And I think the reason I got so excited about this field to begin with was trying to learn why it works for some patients and why it doesn't work for other patients. So I'm a huge believer in learning from every patient that we can. So it's such a testament to the company, Agenus, who sponsored this trial to invest their time and resources into correlative studies at this phase. It's huge. So we learned a couple of things. IL-6 or interleukin 6 is a cytokine that basically has, in other tumor types, been associated with worse outcomes. And what we were interested in this group is we saw the same thing. And again, sarcomas have very, very little correlative biology that's done. We're really in infancy and understanding the microenvironment and how that milieu balances out in our tumors. So we were really excited to see again that lower peripheral interleukin 6 associated with improved overall survival. So again, kind of sorting out a group of patients that might be immunologically favorable when it comes to this type of therapy. The other thing that's important to know about sarcoma is so the other tumor types are lucky and have PD-L1 expression and the tumor is a biomarker, but we never have PD-L1 expression. We can find it in sarcomas and it can be loosely correlated with a chance of benefit with immunotherapy. But I've had patients respond that were PD-L1 negative, and I've had patients that were loaded with PD-L1 that didn't seem to make a difference. And that's not just in this study. So we saw in this trial a trend towards improved overall survival with PD-L1 expression that wasn't significant, but there was like this trend. And it's really interesting because, again, this is largely a CTLA-4 directed therapy. And so what we wondered is if PD-L1 expression is an index of sort of this underlying potential immunogenicity. And actually PD-1 works very late in the whole immune process. That's really at the very end where you've got the T cell that's facing the tumor cell and it's just activating that T cell that's already grown up and already educated and ready to go. Whereas CTLA-4 is really educating in early immune responses and expanding the T cells that have potential to kill. So I'm interested to look into this in more depth in the future to see if this is actually the biomarker for CTLA-4 directed therapy that we've been looking for, because we really don't have a great sense about that. And then the last piece just to note is that in this trial, like most others, very, very few sarcomas had high mutational burden. Everybody was very low, which reflects the population. And it's just really more encouragement than an immune cold tumor with very crappy neoantigens can still respond to immunotherapy if we get them the right agents. Shannon Westin: Yeah, I mean, I'm taking notes because we have such a struggle with this across the gynecologic tumors. I'm like, “Okay, maybe this is finally it.” So hopefully your work will go on to really inspire us across a number of solid tumors that have been traditionally cold. So, so very exciting. And I would just say for my last question, obviously, congratulations on this successful study. What do you think are the next steps for this combination in sarcomas? Dr. Breelyn Wilky: So, again, just to your point, this trial enrolled a bunch of different subtypes, and sarcomas are not the only immune cold tumor that this combo has looked really promising for, microsatellite stable colorectal cancer, ovarian cancer that was platinum refractory, non-small cell lungs. So I think the future is really bright for immune cold tumors kind of across the board. So, yes, lots of hope for not just sarcomas but in terms of our patients, I just have to be so grateful to Agenus for their interest in a rare disease. Sometimes it's hard to get that interest for a very challenging group of patients that are all heterogeneous, they are not all the same and our big clinical trials are a few hundred patients. It's just a very different environment. But they have been so supportive and involved in making sure that sarcomas are represented in their priorities. So there are ongoing discussions about what the optimal way to explore this further in sarcomas is going to be and I cannot wait to have the official plans in place. But my hope is this will not be the last that we see of these drugs for our patients. Shannon Westin: Well, I support that and my vote is on your side. So, thank you so much again, Dr. Wilky. This time just flew by. This was such a great discussion and I mean, I think it's, again, a testament to your exciting data. And thank you to all of our listeners. This has been JCO After Hours’ discussion of “Botensilimab (Fc-enhanced anti-cytotoxic lymphocyte-association protein-4 antibody) Plus Balstilimab (anti-PD-1 antibody) in Patients With Relapsed/Refractory Metastatic Sarcomas,” published in the JCO on January 27, 2025. So be sure to check out the full manuscript. And we hope that you enjoyed this podcast. And if you want to hear more about research published in the JCO, check this out on our ASCO JCO website or 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. Wilky Disclosures  Consulting or Advisory Role: SpringWorks Therapeutics, Deciphera, Epizyme, Adcendo, Polaris, Boehringer Ingelheim, AADi, InhibRx Research Funding: Exelixis Travel, Accommodations, Expenses: Agenus    

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  21:00
• 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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  8:47
• 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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  12:12
• 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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  10:21
• 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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