Latest / Behind The Knife: The Surgery Podcast / Clinical Challenges in Breast Surgery: The Fundamentals of Cancer Immunotherapy
Transcript
- breast BTK_Episode3 === Speaker: [00:00:00] Welcome back to the Breast Specialty Podcast series on Behind the Knife. I'm Rashmi, your host and a general surgery resident at the University of Michigan. Today we're doing a practical episode for the surgical team on immunotherapy and breast cancer. I'm joined by our favorite breast surgery experts, Dr. Dowskanlar, joining us from Memorial Sloan Kettering Cancer Center, and Dr. Plewski, co-director of the Weiser Family Center for Breast Cancer at the University of Michigan. Thank you both for being back. Speaker 2: Thanks so much. I'm really excited for this podcast today. Speaker 3: Yeah, great to be here. And I will just comment that we're so lucky to have Dr. Dawn Skanner, who is truly an expert in the world of immunotherapy and breast cancer on this call today. Speaker: Yes, I'm so excited to dive right in. I'm gonna briefly go over the objectives for the episode. First, we'll define immunotherapy and immune checkpoint inhibition in breast cancer. Then we'll summarize current clinical indications and some evidence for pembrolizumab, an immunotherapy agent, in triple-negative breast cancer. And then [00:01:00] finally, we'll equip perioperative clinicians to identify and manage immune-related adverse events or side effects of immunotherapy. Before we define immunotherapy, let's define triple-negative breast cancer, or TNBC, because that's where immunotherapy has the most established role right now in breast oncology. TNBC is breast cancer that lacks expression of estrogen receptor and progesterone receptor, and also does not overexpress HER2, which is the human epidermal growth factor receptor. So it's triple-negative. Why does triple-negative breast cancer matter in the context of immunotherapy? Speaker 2: So if we look at triple-negative breast cancer compared to other types of breast cancer, especially hormone receptor-positive breast cancer, we see a different behavior. We know that it tends to have a higher risk of metastatic recurrence, and these recurrences tend to be early, often within the first five years after treatment. And outcomes are often driven by whether we [00:02:00] can then achieve systemic control. So when we're thinking about outcomes, it's really important for us to look at event-free survival and overall survival. Speaker 3: And I'll add when we compare triple-negative breast cancer to other subtypes, importantly, we haven't had a target the way that we do with hormone receptor-positive and HER2 positive breast cancer. And historically, cytotoxic chemotherapy alone was used despite these worse outcomes, and immunotherapy wasn't a routine part of breast cancer treatment the way that it has been for a longer period of time in cancers like melanoma or other tumors with high mutational burden. But triple-negative breast cancer is often more immunogenic than other breast cancer subtypes. And so that means it may have features like tumor-infiltrating lymphocytes or immune activation. And so this is the reason that triple-negative breast cancer was the subtype where immunotherapy was really studied and fortunately has shown promising, meaningful clinical [00:03:00] benefit Speaker: For listeners who want a deeper dive on why TNBC is a rational immunotherapy target, we're including reference in our show notes, which is actually a review in Seminars in Cancer Biology by Dr. Downes-Scanner and Dr. Medendorp. And so let's transition to defining immunotherapy in breast cancer. First, a little basic immunology. Our immune system has checks and balances, so it can perform immune surveillance, recognize and eliminate abnormal cells, while also maintaining immune tolerance, meaning recognition of self versus non-self. This is where the term immune checkpoint comes from. T cells in particular can recognize and destroy abnormal cells, including cancer cells, but the body also has built-in safety switches called checkpoints that prevent the immune system from overreacting and attacking normal tissues. Cancer can exploit these safety switches by sending a "don't attack me" signal that makes immune cells stand down. Dr. Downes-Scanner, could you briefly [00:04:00] explain the two-signal hypothesis and why it's important for immunotherapy? Speaker 2: Yes. I think this is really fundamental to understanding the mechanism and will also help people understand the potential side effects of the treatment, which we're gonna be talking about a little bit later. So basically, our immune system doesn't want T cells, which in this case we're talking about cytotoxic T cells or T cells that can kill other cells. We don't want those cells firing or exerting their full force on ourself or when it's not really necessary because it can cause a lot of collateral damage. So to prevent this from happening, there are two signals or two yes signals required before a T cell can attack. So the first signal is what we call antigen recognition. So does the receptor on the T cell recognize the antigen or pattern of amino acids on the target? And number two, is it safe and appropriate to attack? Now, that's the second signal. That's a [00:05:00] co-stimulatory signal. So without both recognizing the antigen as something that is a target or not self and the co-stimulation, the T cell will not be activated. And cancer can really take advantage of these safety checks by sending messages to hold the T cell back, even if the cancer is right there and recognized by the T cell as foreign. And immunotherapy works by blocking these sort of stop signals, which then releases the brakes on the immune system and allows it to stay engaged against the tumor. And historically, this approach dramatically changed the outcomes in certain cancers, most notably melanoma. And actually, the Nobel Prize was awarded to the researchers who discovered these immune checkpoints Speaker: For learners, the toxicity profile of immunotherapy is very different from classical chemotherapeutic agents. Based off of how immune checkpoint inhibitors work, the side effects will make more sense. Dr. Paluski, why is that? Speaker 3: Yeah, so [00:06:00] just for context, oftentimes generically we think about side effects of chemotherapy as being those related to targeting rapidly dividing cells. When we're thinking about side effects from checkpoint inhibitors, these are really immune-mediated, hence the name immune-related adverse events. But think of this as a spectrum of really any autoimmune-like symptom that can affect really any organ system. It's super important for providers who are treating patients on these drugs to understand that autoimmune-like symptoms are a worrisome and common side effect of these drugs because of the alteration of the checkpoints that we just heard about. Speaker 2: Yeah, that's a great point. So... And we'll get into this a little bit later when we talk about the actual regimen that we use for our patients. But they're exposed to now two types of side effects, the side effects from chemotherapy, which, as Dr. Paluski mentioned, is targeting rapidly dividing cells, but also these immune-related adverse events. And it's important to know that immune-related [00:07:00] adverse events can show up during treatment, but unlike chemotherapy, the side effects can show up months later. And this really matters because as surgeons, we may be the first person to identify an immune-related adverse event, as the patients we're seeing may not be actively under the care of their oncologist. The timeline in these immune-related adverse events is variable, in part because the checkpoint inhibitors can remain bound to the targets and sustain immune activation well beyond the infusion date. And this variability is why teams taking care of patients on immunotherapy need a high index of suspicion and good education about what to look out for. Speaker: And we will cover a case scenario where we'll dive into this a little bit more in a second. But first, let's walk through the indications chronologically and highlight some major landmark studies so we can discuss what are the current indications for immunotherapy in breast cancer. So Dr. Downes- Skinner, where did [00:08:00] immunotherapy first enter the breast cancer practice space? Speaker 2: So like most new drugs, the first studies of immunotherapy were in metastatic triple-negative breast cancer, and the study that showed a positive result was called Keynote-three five five. In this study, patients with metastatic triple-negative breast cancer received pembrolizumab, which is an immune checkpoint inhibitor, plus chemotherapy if their cancer was PD-L1 positive. PD-L1 is one of these checkpoint molecules or protein that some tumors and some immune cells express And it is one of these do not attack signals which helps cancers evade immune destruction. Pembrolizumab is an anti-PD-1 drug, so it blocks the PD-1 receptor, the off switch on T cells, so that T cells can stay active and kill cancer cells. So it's a little bit like a double negative. [00:09:00] It's blocking the preventative signal or releasing the brakes on the T cell. So in KEYNOTE-three five five, pembrolizumab plus chemotherapy improved overall survival compared with chemotherapy alone in patients who had a higher level of PD-L1 expression. And once this study was published and during its execution, plans were made to look at this in earlier stage disease when cure is the goal, not just prolongation of life. Speaker: Let's shift to the early stage trial that then changed practice. Dr. Paluski, could you walk us through KEYNOTE-five two two? Speaker 3: Absolutely. So KEYNOTE-five two two was really a game changer, and when we think about treatment for non-metastatic triple-negative breast cancer. So this trial randomized patients with stage two to three triple-negative breast cancer. So this was either node-positive disease or patients who had tumors greater [00:10:00] than two centimeters. And patients in the study were randomized to a four-drug polychemotherapy backbone with or without the addition of the checkpoint inhibitor pembrolizumab. So same checkpoint inhibitor that we heard about in the metastatic stage now being added in the neoadjuvant chemotherapy space. So following neoadjuvant chemotherapy with or without pembrolizumab, patients went on to receive surgery. And then in the adjuvant setting, pembrolizumab continued every three weeks for additional nine cycles for the patients who were receiving immunotherapy on trial. The key endpoints of this study were pathologic complete response as well as event-free survival And there are a number of secondary endpoints, including overall survival, safety tolerability, um, and subgroup analyses looking at PD-L1 status. Speaker: One [00:11:00] thing that I wanted to talk about very quickly is this term pathological complete response, or path CR. It generally means no residual invasive cancer in the breast and sampled lymph nodes at the time of surgery. Why is this important for us to understand, Dr. Paluski? Speaker 3: Right. So pathologic complete response is our surrogate looking at efficacy for these treatment regimens. And importantly, what we have found in particular with triple-negative and HER2-positive breast cancer is that a pathologic complete response often translates into improved survival for patients. And so this is really our goal in terms of systemic therapy in the neoadjuvant setting, is improving the complete response to tumor eradication. And what we see in the Keynote-five two two trial is that the addition of pembrolizumab to neoadjuvant chemotherapy increased the pathologic complete response by nearly fourteen percent. And in [00:12:00] addition, that translated to an improved event-free survival with hazard ratio of zero point six three. So a really significant benefit in terms of outcomes that we're seeing. And then longer-term analysis showed an improvement in overall survival benefit with this regimen. And so this has really become standard of care for most patients with stage two to three triple-negative breast cancer. And importantly, in the subgroup analysis, we see the benefit across subtypes regardless of PD-L1 expression. So unlike in the metastatic setting, where that is a driver for indication for immunotherapy, this was beneficial regardless. And so testing for PD-L1 is not required to determine candidacy for this treatment approach. Speaker: For the time being, we're not covering the IMpassion trials one thirty and one thirty-one, which evaluated an alternative agent. I can never say this, immunotherapy agent, [00:13:00] atezolizumab, uh, which is an anti-PD-L1 agent in advanced TNBC. IMpassion one thirty-one, which evaluated the use of atezolizumab with paclitaxel, did not meet its primary endpoint, and the median progression-free survival was the same in both arms. So Dr. Dawn Skinner, what is the only FDA-approved immune checkpoint inhibitor for breast cancer currently? Speaker 2: Thanks for pointing that out. So there's a few different randomized trials of different backbones and different immune checkpoint blockades, including atezolizumab. And none of them met their primary endpoint of, of event-free survival difference, except for the Keynote-five two two study, which is why pembrolizumab is the only FDA-approved immune checkpoint inhibitor for breast cancer currently. And actually, the Keynote-five two two regimen is the only FDA-approved neoadjuvant regimen in any cancer using immunotherapy. Just so everyone knows, [00:14:00] pembrolizumab goes by the brand name Keytruda. Speaker: Great. And so let's transition to talking about what are the contraindications to receiving this therapy, especially because these contraindications matter significantly in the preoperative setting. So what about absolute contraindications? Speaker 3: So absolute contraindications to checkpoint inhibitors or use of pembrolizumab right now would be patients who have active severe autoimmune disease, those who are on systemic immunosuppression or prior history of life-threatening adverse events, something like myocarditis or pulmonary toxicity, severe neurologic toxicity, where a re-challenge would be unsafe. And patients who have a history of solid organ transplant because the risk of rejection can be substantial with immune therapy. And then significant baseline interstitial lung disease or pneumonitis, and this is because the risk of immunotherapy pneumonitis can be fatal, [00:15:00] as well as pregnancy Speaker: What about the relative contraindications for immunotherapy? Speaker 2: For patients who are chronically on steroids or other immunosuppressive agents, efficacy could potentially be blunted, um, but decisions would be individualized. And then patients with really poorly controlled endocrine disease, because this disease can be destabilized, um, because of the different side effects that can be induced by immunotherapy. Speaker: This next section is really for the trainees and the clinicians that are seeing patients that are on these agents. Spending some time on these immune-related adverse events in the context of what trainees and perioperative providers should look for is really the focus of the next segment. The mindset is simple. Really think about the fact that any organ can be affected, and early recognition matters. If something new appears during therapy or even months later, keep this on your differential. [00:16:00] These patients are monitored by their medical oncologist, but they often present first to the ED, and surgery is frequently consulted. So these adverse events can also delay the time to OR, so it's important to have a framework for recognition and triage of these patients. So Dr. Pilewski, could you help us go over the high-yield immune-related adverse events? Speaker 3: Yeah, absolutely. And I think it's important to just remember that this is really a whole body possibility. I mean, you can scan the entire body and think about potential immune-related complications. Skin or dermatologic reactions, rash and pruritus. GI system with colitis, enteritis, which can present as abdominal pain, diarrhea, blood or mucus in the stool. Liver toxicity with hepatitis often picked up with just lab abnormalities and elevation of ALT and AST. Importantly, [00:17:00] looking for endocrine toxicities, which unfortunately can often be permanent in patients who, um, sustain these side effects. But thyroiditis, significant hypothyroidism, adrenal insufficiency, which we monitor with ACTH or cortisol levels, and rarely type I diabetes. We briefly mentioned pulmonary symptoms with autoimmune pneumonitis, which can present with cough, dyspnea, hypoxia. And while less common but can be unfortunately deadly, in addition to pneumonitis, myocarditis and severe neurologic symptoms Speaker: I wanna take some time to focus on the endocrine dysfunction, specifically the thyroid dysfunction and adrenal insufficiency because the perioperative risk is huge. Dr. Dawn Skinner, could you talk a little bit about these two and sort of what we should be doing in the perioperative setting in terms of testing? Speaker 2: [00:18:00] Yeah, that's a great point. So thyroid dysfunction we'll start with. One thing to note is that often these patients first develop hyperthyroidism from the stimulation of thyroid with antibody, but it ultimately sort of burns out the thyroid and results in hypothyroidism. So you can see sort of that time course happening throughout treatment. But the reason we really care about this in the perioperative period is patients can have thyrotoxicosis, uh, or thyroid storm around the time of surgery. So this would be high fever, tachycardia, hypertension, agitation, confusion, sweating. Um, and this could potentially be, you know, induced by The anesthesia. And so this is part of routine screening prior to taking any patient to the operating room. We typically want to screen for this sometime between the end of neoadjuvant therapy and the operating room. Typically, with enough time that you can intervene [00:19:00] and fix this problem for the patient before taking them to the operating room. So at our institution, we do it about two weeks pre-op, but there's some variability in that. And how would we deal with this? So beta blockade, methimazole or PTU, which are thionamides, and sometimes high-dose corticosteroids are needed to control the thyroid dysfunction. And I'll also just add that it's not insignificant. In, in real-world studies, over ten percent of patients end up having some thyroid dysfunction related to immunotherapy. So pretty common. And then the second issue is adrenal insufficiency, which I think all of us remember can result in adrenal crisis. So when people are adrenally insufficient, when they're stressed, for example, by severe illness or anesthetic, they can have an adrenal crisis, which presents as hypotension. Shock leading up to this could be presenting with very vague symptoms that many of our [00:20:00] patients who are undergoing chemotherapy have, like fatigue, vomiting, confusion. We can also see hyponatremia and hypoglycemia as well. Obviously, if you suspect this, you should check cortisol and ACTH and treat with stress to steroids. However, it's also important that like thyroid function, adrenal function is tested in the perioperative period so that we can identify patients who may be at risk for adrenal crisis so that it can be managed appropriately during anesthesia. Speaker: This is very important for us trainees, in particular, as we start to see more and more of these patients in both the ED and also in clinics as we go through training. One of the things that I found very interesting about preparing for this podcast episode is some misconceptions around immunotherapy, which Dr. Downskanner has provided me with some great resources to bust. So one of the misconceptions I want to talk about is sort of the effect on surgical outcomes because of treatment with immunotherapy.[00:21:00] So does chemoimmunotherapy compared with chemotherapy alone worsen surgical outcomes? Dr. Downskanner, you've published on this. Can you summarize for us? Speaker 2: Yeah. I would also point out the authors of the KEYNOTE-522 study also published their surgical outcomes, which showed in the actual KEYNOTE-522 study no increase in surgical complications or time to surgery in the study arm, so in the patients who got immunotherapy. In our own real-world data we published in 2024, no clinically meaningful differences in time to surgery, time to adjuvant radiation, or postoperative complications among patients who did and did not receive immunotherapy. When patients did develop a grade 3 or higher immune-related adverse event, there was an associated delay to adjuvant radiation, but not with postoperative complications or delay to surgery. So in general, it's pretty safe in terms of taking patients to surgery compared to chemotherapy alone. Speaker: Another [00:22:00] surgery-adjacent issue, which Dr. Palucki previously noted is common, is immune-mediated colitis. So patients can present dehydrated, miserable, sometimes with abdominal pain. You still need to rule out infections like C. diff and consider chemo-related diarrhea. So I wanted to talk about the algorithm for how to manage, recognize a patient with immune-mediated colitis. Dr. Palucki, what's the current treatment approach for this kind of patient? Speaker 3: Well, thanks for the question, Rashmi. I will highlight that severe immune-mediated colitis fortunately is not a common side effect that we see in clinic, but a very important one to recognize so that we treat patients appropriately and don't miss the window of opportunity to hold their immunotherapy and provide appropriate systemic therapy. So just to walk through this, for someone who has moderate to [00:23:00] severe suspected immune-mediated colitis, we obviously need to rule out other etiologies. But for patients who are on these drugs who don't have clear signs of infection, number one is that we wanna hold their immunotherapy, right? Hold the agent of interest here and start systemic steroids. Most institutions have a protocol for this, but steroids are really the backbone of treatment for most of these side effects. This is a time to involve GI and medical oncology. And then if the symptoms of colitis are refractory, um, biologics can be used with an anti-TNF agent such as infliximab. And the goal here is to really treat medically and avoid surgery unless absolutely necessary. So if we think about this endoscopy for biopsy may be required for diagnosis, but the times that surgical intervention may be necessary are really if there's perforation, toxic megacolon, [00:24:00] intractable bleeding intervention to treat an undrained abscess or truly treatment-refractory disease. But the vast majority of these should respond to medical management. Speaker: And as we trainees see this more and more on our app site every year, we've included a high-quality guideline resource from the Society of Immunotherapy for Cancer in our show notes that overview the identification and management of these adverse events. Let's apply these concepts to a case. Our patient is Ms. J, a forty-three-year-old with mild asthma. She presents with a palpable right breast mass. Imaging shows a three-point-eight-centimeter mass and an abnormal axillary node. She undergoes a core biopsy of the breast mass and the axillary node, which shows invasive ductal carcinoma grade three. ER, PR, and HER2 are not detectable, and she's node positive. Staging is negative for distant disease. She is clinically staged as a T2N1M0 [00:25:00] stage 2 triple-negative breast cancer patient. Is immunotherapy indicated, and what is her subsequent treatment algorithm? Speaker 2: This patient fits squarely in the inclusion criteria for the KEYNOTE-522 study. And so yes, absolutely, she is a patient with high-risk triple negative breast cancer and would benefit from treatment with neoadjuvant chemoimmunotherapy. So this would be neoadjuvant chemotherapy plus pembrolizumab, followed by surgery and then followed by adjuvant pembrolizumab. Speaker: What are some considerations for monitoring during her course of therapy? Speaker 3: So this is just a good reminder of all of the immune-related adverse events that we have reviewed. So in particular, endocrine symptoms like fatigue, hypotension, headaches, weakness, GI symptoms of diarrhea, colitis, respiratory symptoms suggesting possible pneumonitis, and then hepatic lab [00:26:00] abnormalities and for any concern of hepatitis. Speaker: So after cycle three of her therapy, Ms. J comes to the ED with eight to 10 watery stools per day, abdominal cramping, low-grade fever, and dizziness. What are our next steps as a team? Speaker 2: So first we'll wanna hold any pembrolizumab that she's scheduled for and evaluate for infectious sources, including C. diff, and rule out basically other causes of colitis, keeping in mind that very likely this could be immune-related colitis. We would want to consult her medical oncology team and initiate steroids and involve gastroenterology early. It's important, unlike maybe some other types of colitis that general surgeons are called to manage, that you do include the medical oncologist because they are the team with the expertise at managing these immune-related adverse events. And then if the colitis progresses despite holding pembrolizumab and giving steroids, [00:27:00] consideration can be given to something like infliximab, an anti-TNF, or some newer agents like vedolizumab, which is a gut-selective anti-integrin, which can be effective in cases where the patients are still having symptoms despite steroids. Speaker: Dr. Downskanner's point that this is different from the other types of colitis that we see, like ulcerative colitis or Crohn's, is very important here. She, as our patient, improves with steroids and infliximab. Two weeks later, she comes to pre-op clinic to discuss scheduling surgery. She reports severe fatigue, nausea, and lightheadedness. She's also borderline hypotensive, and labs show hyponatremia. So Dr. Paluski, what are we afraid of here? Speaker 3: Unfortunately, this is one of the dreaded, uh, scenarios that we face in clinic. So from my standpoint, this is adrenal insufficiency until proven otherwise for somebody being treated with pembrolizumab. Um, and so [00:28:00] this is evaluated with cortisol and ACTH levels as well as electrolytes. This is something that I'm gonna be in touch with medical oncology and endocrinology so that the patient can, number one, be admitted and treated if necessary, and then also to manage preoperatively, because once stabilized and we go to the operating room, this patient will likely require stress dose steroids, and we need to coordinate with the endocrinology team how to do that safely. Speaker: We are able to coordinate her surgery after patient J stabilizes, and she undergoes surgery one month later. Her final pathology shows a pathological complete response. Speaker 2: A pathologic complete response is an excellent prognostic sign in triple-negative breast cancer. So patients who have a pathologic complete response do better than those who do not. Interestingly, it doesn't matter how they get there. So if we look at patients treated with chemotherapy who have a pathologic complete response versus those who have [00:29:00] chemotherapy and immunotherapy who have pathologic complete response, they, they sort of do equally well. Topic for another podcast. And then also I'd like to say that even if patients don't have a pathologic complete response, with immunotherapy, when they have some response, they still do quite well compared to patients who had chemotherapy. So we often think of pathologic complete response as the end-all be-all, and with immunotherapy, that's not necessarily the case. So this is an excellent prognostic sign for our patient, and we would recommend continuing the adjuvant pembrolizumab alone if she tolerates. But there are some trials looking at de-escalation of the adjuvant portion of the pembrolizumab in patients who have a PCR Speaker: That brings us to our final section on future directions and where the field is going. So looking ahead, we've covered immunotherapy so far in [00:30:00] metastatic TNBC and early-stage TNBC. What about non-TNBC subtypes in other stages of breast cancer? Is immunotherapy being considered for those patients? Speaker 2: So right now, there's no approved indications to use immunotherapy in subtypes of breast cancer other than triple-negative breast cancer. But many ongoing trials are being done to look at if we can see a benefit from the addition of immunotherapy in other cancer subtypes. Often, these are done in combination with agents that we think may make, for example, hormone receptor-positive breast cancers more immunogenic and therefore facilitate the efficacy of immunotherapy. But these are all still ongoing trials, so we anxiously await the results, including the final results from the KEYNOTE-seven five six study, which is looking at immunotherapy in high-risk ER-positive breast cancer. Speaker: And where do we think the field is going in terms of identifying who benefits most? I know biomarkers is often [00:31:00] an area of evolving study, but Dr. Palinski, could you comment on what's being studied so far with respect to identifying patients who would benefit? Speaker 3: Absolutely. This is such an important topic because we've seen, you know, just reviewing the KEYNOTE-five two two data, this improves outcomes for patients with triple-negative breast cancer who have otherwise worse outcomes, but at the cost of significant potential side effect and potentially lifelong negative impact. So ideally, we could identify those patients who will derive most benefit and minimize exposure to other patients from these side effects. And so there is work, as you mentioned, to try and have better biomarkers And we've seen that PDL1 is imperfect, in particular in the early stage setting. And so there is work looking to integrate tumor-infiltrating lymphocytes, gene signatures, ctDNA, [00:32:00] spatial profiling, a lot of different analyses to try and better identify, as we said, patients who will benefit to avoid the toxicity profile for those patients who won't. And one other thing that I would comment in addition to identifying which patients to treat with chemo immunotherapy in the setting is also how we think about escalation in systemic therapy for patients who don't achieve a pathologic complete response. This is another ongoing area of interest. We've heard that pembrolizumab continues in the adjuvant setting. We also have data looking at the addition of capecitabine for patients who don't achieve a pathologic complete response, but those studies weren't done together. They were in isolation. So how different agents should be combined for patients who don't have an excellent response is an ongoing area of interest. And I think of similar interest is the role of de-escalation and how pembrolizumab [00:33:00] comes into play. Speaker 2: Our case that we just presented is a perfect example of this. So this patient had a PCR, but she had two immune-related adverse events. So wouldn't it be great if we could stop giving her pembrolizumab? A major ongoing study is the optimized PCR trial, which is evaluating whether patients who have a PCR after neoadjuvant chemoimmunotherapy can avoid the adjuvant immunotherapy. So patients with PCR are randomized to receive placebo or the adjuvant immunotherapy as was indicated in the Keynote-five two two study, and we anxiously await results Speaker: I just also want to take a second to point out there are other approaches in development, which include developing immunotherapy checkpoint inhibitors for other targets like LAG-3, TIGIT, CTLA-4, new novel immunotherapy agent combinations, vaccines, other adoptive cell therapies like tumor-infiltrating lymphocytes and agonists for STING and other radiosensitizers. So [00:34:00] basically, lots of therapies in development, many in preclinical forms, but also some approaching clinical trial stages. In this episode, we defined immunotherapy and breast cancer through the lens of immune checkpoints and the two-signal hypothesis. We then discussed where it clearly changes outcomes and with the results from the Keynote-355 and the Keynote-522 studies. Finally, we focused on what the surgical team needs to know in terms of keeping the patient safe, recognizing immune-related adverse events that can arise during treatment or months later, and especially understanding how this changes perioperative management with a focus on the endocrine and pulmonary toxicities, as well as specifically the thyroid dysfunction and adrenal crisis, which you must watch out for and test for two weeks before surgery, and applying all of these thoughts into a case-based decision-making format where we evaluated and stabilized a patient and her timing of surgery with oncology and [00:35:00] our specialty teams. So thank you so much for listening, and thank you to our experts. We'll come back with our next episode in the next couple of months. Dominate the day