New Directions in the Treatment of Breast Cancer: Bringing Biology to the Clinic and Back

[00:00] Good afternoon. Welcome to UCSF Department of Medicine Grand Rounds. I'm Bob Wachter, chair of the Department of Medicine at UCSF. I'm really thrilled today to introduce our speaker and topic. The topic is new directions in the treatment of breast cancer, bringing biology to the clinic and back. And the speaker is Hope Rugo.

[00:20] who is Professor of Medicine, Director of Breast Oncology and Clinical Trials Education at UCSF Health. Hope has a long and distinguished career as a medical oncologist. She specialized in breast cancer research and treatment. She actually began her career after, graduating from medical school at the University of Pennsylvania in 1983,

[00:40] sounded familiar and then I remember that's when I graduated from the University of Pennsylvania. Hope was a classmate of mine. She did a residency in internal medicine, hemog fellowship at UCSF, did a immunology postdoc at Stanford and then joined our faculty in 1990 and has been here ever since. Started off in the world of bone marrow transplant and malignant hematology and transition

[01:00] to breast cancer in part because she saw tremendous need and opportunity and she has filled that admirably. She, as I mentioned, is Director of Breast Oncology and Clinical Trials Education. She's a principal investigator of a number of clinical trials, many published in very prominent places, a novel targeted treatment to

[01:20] improve the outcomes of patients with breast cancer. Her research involves immunotherapy, combinations of targeted agents, as well as management of toxicity. In addition to a really remarkable research career, Hope is a very active and go-to clinician for many of our patients and receives lots of.

[01:40] honors for that work, including just last week being awarded one of our Master Clinician awards, which is the highest honor our department gives to its clinicians. So, I hope, welcome aboard and looking forward to hearing your comments. Thanks so much, Bob, for that very kind introduction.

[02:00] And it's really such an honor to be presenting Grand Rounds today on this topic, which is very exciting to me. I'll just share my slides now, the recent advances in the treatment of breast cancer, and the incorporation of a better understanding of biology, both from the laboratory and

[02:20] and in the clinic to optimize the treatment of our patients and to optimize their quality of life as well. So we'll go through this area and then have time for questions afterwards. I was challenged a little bit in thinking about how to talk about advances in breast cancer without first giving the general audience a background, which seems early.

[02:40] critical. So we'll start talking about a little bit of a background and then we'll go into the key advances over the last couple of years in the treatment of breast cancer that we've been very excited about and have had the opportunity to participate actively in as well. So breast cancer is the most common cancer in women and the most common cause of cancer death or

[03:00] worldwide, and in the United States it represents 30% of all new cancers and women, and 1 in 8 women will be diagnosed with breast cancer sometime during their lifetime. This is a disease largely of older women. The median age at diagnosis is 63. Although I have to say, and I'm sure that's true for Bob as well, what we call older continues to

[03:20] get older. However, we do see a large number of young patients, particularly at referral center like UCSF, 10% of patients are under the age of 45, 29%, almost 30% of patients are under the age of 55. In the United States, almost 300,000 new cases of invasive breast cancer will be

[03:40] and women. And breast cancer is not the most common cause of cancer death in the United States. I think highlighting the inequities and access to treatment worldwide, about 43,000 women will die of the disease. We have identified racial and ethnic differences, which are so important for us in our research to.

[04:00] better treating our patients and understanding risk factors and optimizing diagnosis at an earlier stage. And this is an area of active research. Black women have the highest death rate from breast cancer and they have a higher rate of breast cancer under the age of 40. And you can see the differences in mortality listed on the slide comparing black women to non-Black women.

[04:20] non-Hispanic white women per 100,000 person years. In young black women, we see a higher rate of the most difficult to treat subset of breast cancer that has the highest mortality and short-term mortality. For example, after a diagnosis of metastatic triple negative breast cancer, the median survival is just in the 18 to 20 months.

[04:40] range compared to over five years for hormone receptor positive disease. There's an 81% higher rate of this breast cancer subset in black women compared to non-Hispanic white women. The rate of breast cancer in the United States has increased about 0.4% per year over the last decade, but mortality has

[05:00] decreased more at 1.3% per year, I think highlighting the improvements in both understanding biology and treating with more effective agents. The five year relative survival if you include all patients diagnosed with breast cancer is about 91%. And we estimate that more than 80% of women diagnosed with breast cancer

[05:20] today will survive their disease. You can see on the right hand side from the SEER database, the incidence of breast cancer is higher in white women than black women, but the mortality in black women is higher. And this is an area of great interest being studied and is thought to be related to that difference in the biologic sub-state, difference in

[05:40] differences in the microbiome, differences in genetic factors, as well as differences in environmental risk factors. So let's talk a little bit about general treatment for breast cancer and what we consider. Treatment is based on biologic subsets. 60 to 70% of breast cancers will be hormone-resistant.

[06:00] receptor positive. And we talk about this as being hormone receptor positive, HER2 negative. HER2 is interesting. It's related to overexpression of a gene called ERB2, and that leads to overexpression of the HER2 receptor. That represents about 15 to 20% of breast cancers, and it is the most curable subset of breast cancer to

[06:20] disease. It's the only subset of breast cancer where some women with metastatic incurable disease will be long-term survivors essentially cured of their disease. Triple negative disease is defined like non-A, non-B hepatitis was when I was training with the absence of known receptors and represents about 15% of breast cancer. The disease is known for its use in the case of breast cancer.

[06:40] These subsets vary by age. We tend to see more highly proliferative disease like triple negative and HER2-positive disease in younger women and more indolent hormone receptor-positive disease in older women. I've showed you the general treatment approaches for breast cancer across the subsets in early-stage disease where hormone receptor-positive disease is a very important factor.

[07:00] disease in the light green may be more proliferative, luminal B-like, or a lower proliferative indolent disease, luminal A-like. We tend to see the lower proliferative disease in older women and the higher proliferative disease in younger women. And treatment varies between endocrine therapy with or without chemotherapy and the early stage setting with the goal to prevent

[07:20] recurrent disease in distant sites, as well as, of course, local therapy and systemic therapy to prevent local recurrence. Triple negative disease, this absence of receptors, is treated with chemotherapy and now immunotherapy. We tend to really push the treatment for early stage. Triple negative and hertose disease.

[07:40] positive disease and more proliferative hormone receptor positive disease to focus on treatment before surgery so that we can use response to modify treatment. And we'll talk about that a little bit more. Hertute positive disease is treated with chemotherapy with Hertute targeted agents. Antibodies, the most common antibodies used are Trastosumab, the cornerstone of therapy, with the

[08:00] addition of proteasumab in higher stage disease and endocrine therapy when hormone receptors are present. There's a biologic difference in the patterns of recurrence, and you can see in the lower right hand corner of this slide that patients who have triple negative disease tend to have a front loaded risk of recurrence with almost all recurrences occurring in the first three to five years.

[08:20] Whereas hormone receptor positive disease has a very long natural history, with recurrences occurring out to 20 years. 50% of the recurrences seen occur after five years, and the latest recurrence I've seen is at 32 years. So this is a disease with a very long natural history. What about an advanced disease? What is our standard of treatment?

[08:40] treatment prior to the most recent advances that I'll talk about today. Therapy in the metastatic setting in general is characterized by increasing toxicity. There's cumulative toxicity over time and can be related to prior toxicity as well as shorter durations of response with each sequential treatment. Mormon receptor-positive disease

[09:00] treated with our international guidelines helping us with sequential endocrine therapy followed by sequential chemotherapy, triple negative disease until quite recently we only had sequential single agent or combination chemotherapy and this didn't last long. HER2 positive disease has been treated now for quite a long time, a

[09:20] in the metastatic setting for more than 20, about 25 years with HER2-targeted antibodies combined with chemotherapy, which has markedly improved the survival and outcome in this subset. But now in the last 10 years, our sequential therapy has included first generation antibody drug conjugate. I'll talk about that more later.

[09:40] and oral tyrosine kinase inhibitors, but we've made enormous progress in the treatment of all three subsets of disease and have been able to move our treatments from the metastatic setting into the early stage setting fairly rapidly. Our advances in treatment and supportive care have included adding agents targeted to tumor biology to stand for the disease.

[10:00] standard therapy, and this is really a cornerstone of most of the advances in our treatment. We also have been able to use that process of adding agents targeted to tumor biology to improve our endocrine therapy, targeting known mechanisms of resistance. We now have exciting agents that have provided us the opportunity to help.

[10:20] opportunity to deliver chemotherapy more efficiently and more effectively, and we're working on improving toxicity understanding prevention and management. I've been very involved in the study of novel agents, but became really interested in understanding the toxicity, which is so important to be able to treat our patients, both in early

[10:40] and late-stage disease and have focused on really trying to work on an early analysis of trials that will change treatment practice in terms of understanding the timeframe of toxicity and how to optimally prevent and manage these. And I'll show you one example because some of these studies have resulted in a change in preventative

[11:00] and management strategies that expand not only that agent, but multiple agents coming in the future. Shared decision making access to care is obviously a critical area where we're working with our national and international organizations to improve education about clinical trials and critically to expand access and tailor treatment to our poorly served population.

[11:20] patients in the United States and worldwide. So what examples will we talk about today? We'll talk about moving effective therapy from the advanced to early stage setting, reducing the risk of recurrence, and improving survival for our patients. We'll focus this on subset-specific therapy, triple negative disease with immunotherapy,

[11:40] and receptor positive disease talking about adding a really very interesting oral agents, enzyme inhibitors, cycloindipinase, kinase 4, 6 inhibitors to endocrine therapy, and a newer approach of targeting specific mutations with targeted agents. Novel chemotherapy delivery across subsets is a, I think, one of the

[12:00] most exciting areas of research that spans not only breast cancer, but many solid and liquid tumors. These are antibody drug conjugates that appear to be effective even in tumors that don't express the target well. So it's really been an incredible advance and I think antibody drug conjugates have

[12:20] the potential to replace naked chemotherapy in the not too distant future and are already incorporating into our treatment paradigms. Neo-agimit therapy is really a big area for advancement in delivering drugs to the patient that are effective and effective for their specific treatment as early as possible. We can tailor things.

[12:40] therapy to response. And this essentially allows us to tailor treatment in the neoadjuvant setting before surgery for the best response. That means that tumors that respond rapidly, those patients could get less treatment. Patients whose tumors respond more slowly might get different treatments or more extensive therapy. And then based on the amount

[13:00] cancer left at the time of surgery, you can modify the treatment that you're giving after surgery and we've already shown this to work in several settings to improve outcome. For example, we're able to now give certain kinds of chemotherapy inhibitors that are called PARP inhibitors for patients who have germline BRCA1 or BRCA1.

[13:20] or two mutations that have already improved survival in patients whose cancers did not melt away with neoadjuvant therapy. And this really is our key next step in allowing individualization of therapy and improving outcome. So let's talk about these specific examples now. We'll start with immuno-cancelled patients.

[13:40] therapy for triple negative breast cancer. So this beautiful cartoon was developed by former fellows in our program who've all gone on to impressive faculty positions and our Laura Hubbard, shown in the lower right hand corner, is one of our early faculty members that helped to develop this cartoon.

[14:00] And it shows you the complex interaction between the host immune system and the tumor cell, and trying to understand those interactions led to the development of a number of different immunotherapy agents that have been incorporated into the treatment of multiple solid tumors.

[14:20] and pembrolizumab with that little box is a PD1 inhibitor that's now approved for the treatment of late and early stage triple negative breast cancer. So one of the questions for breast cancer was whether or not immunotherapy would ever work. You have to have, the host immune system has to recognize the tumor as something foreign. And with these slow

[14:40] In the case of cell-growing hormone receptor-positive cancers, they look like normal cells. In fact, some of them look just like lymphocytes and can be hard to identify without special stains. So really, for some time, we thought that immunotherapy would not really work well for breast cancer. But then there was a better understanding of the difference in biology.

[15:00] between these different subsets and interest in looking at triple negative breast cancer as a target for immunotherapy. Triple negative breast cancer was a great place to start. It has a higher mutation rate versus other subsets of breast cancer and is heralded by infiltration of tills or tumor infiltrating lymphocytes that are T cells

[15:20] Infiltrate the tumor and have been associated with a much better outcome. Very interesting that if your host, you know, your own immunity is attacking the cancer, the cancer does better. And I'll show you that that's really played out in trials. In addition, there's more expression of PD-L1, both in the tumor microenvironment and in the tumor itself. So this made it an option.

[15:40] optimal target for immunotherapy investigation in breast cancer. So then we did some studies looking at immunotherapy as single agents and saw low but durable responses. And then started with the randomized trials combining the checkpoint inhibitor with chemotherapy based on the known induction

[16:00] of immunomodulatory changes in the tumor microenvironment by chemotherapy with included upregulation of immunogenic cell surface markers, increase to infiltration of lymphocytes, and upregulation of PD-L1. So I'm showing you just one phase 3 trial because Pembrolizumab is the only check for it.

[16:20] inhibitor now approved the treatment of breast cancer in the United States. So this trial, we designed to look at a menu of different chemotherapy options, since patients might be eligible for different chemotherapies, but really two classes, and patients who had newly diagnosed metastatic triple negative breast cancer, no prior chemotherapy,

[16:40] in the advanced setting were randomized to receive chemotherapy with either pembrolizumab or a placebo, and they continued on this treatment until disease progression, but pembrolizumab itself stops at two years. We looked at all patients, but also looked at a subset of patients whose tumors and the tumor microenvironment expressed PDL1.

[17:00] For Pembrolizumab, this is assessed using something called the combined positive score that looks at the PD-L1 expression not just in the tumor, but in these lymphocytes in the tumor microenvironment, which turn out to be incredibly important. A CPS score of 10 or more, which was seen in 38% of patients, was associated with a significant number of patients.

[17:20] significant improvement in progression-free survival and importantly in overall survival with the seven-month median improvement. But you can see that there's a little bit of a flattening of that green curve where some patients really can stay on the checkpoint inhibitor or on no therapy for a long time without disease progression. And I have a couple of patients whose disease appears to be cured.

[17:40] by the use of checkpoint inhibitors. Fortunately, this only is 38% of patients. So there's a lot of interest in trying to expand the population of patients who might benefit from checkpoint inhibitors. And this is a cartoon of a trial that we're running through our Translational Breast Cancer Research Consortium that's supported by the

[18:00] Breast Cancer Research Foundation, which randomizes patients with pre-treated, largely triple negative, breast cancer to receive an induction of various different agents followed by combinations with an immune checkpoint inhibitor called a velomab with serial biopsies and blood collection. And we're collaborating with other investigators, Andre Gocca, UTSC.

[18:20] and a colleague at the Vanderbilt as well for the correlative studies that will help us understand which patients might benefit from this approach. Now, of course, the interest was, you know, we have this small number of patients who benefit from checkpoint inhibitors in the metastatic setting. Can we cure some women who have early stage triplets?

[18:40] negative breast cancer. We know that having no invasive disease at the time of surgery correlates with very good event-free and distant recurrence free survival and breast cancer. And you can see here data from our multi-center randomized phase 2 I-SPY-2 trial that's run by Laura Esmerman.

[19:00] out of our UCSF breast cancer center, that is investigating multiple novel agents in the treatment of patients who have high risk early stage breast cancer, all three major subtypes. And what we've been able to show, as have many other investigators, but I thought I'd show the data we contributed to most,

[19:20] is that patients who have a pathologic complete response have an excellent outcome. You can see in the dark blue line versus the red line in patients with residual disease at the time of surgery, and that this is true in these lower two curves, regardless of subset. If you have a PCR and you have high risk breast cancer, you have a very good outcome. Patients who do not have a PCR need something.

[19:40] something more, which is another aspect of our study. So that's, ISPI study was the first trial to really look at a neoadjuvant checkpoint inhibitor. We gave just four doses of pembrolizumab as neoadjuvant therapy along with the standard chemotherapy backbone, and we were able to show a marked improvement in PCR that was more dramatic.

[20:00] in the triple negative population shown in the upper right hand side compared to the hormone receptor positive group. Now these patients with hormone receptor positive disease in I-SPY have a high risk disease that's characterized by a test called Mammaprint, a gene expression test developed by Laura Van Teveer, also a leader.

[20:20] in our breast cancer program at UCSF. So this is a specific subset and those patients benefited as well, but to a lesser degree, something we're understanding more. So this trial actually led to a randomized phase three sponsored trial by the Merck who make a Pembrolizumab, understanding the benefit of Pembrolizumab.

[20:40] as neoadjuvant therapy combined with chemotherapy for triple negative breast cancer. Patients who had tumors greater than two centimeters or node-positive disease, almost 1,200 of them were randomized to receive pembrolizumab or placebo with chemotherapy. And then the pembrol was continued for a year or placebo. So six months after the age.

[21:00] end of chemotherapy. In the first 602 patients published in the New England Journal of Medicine, shown in the upper right hand side, PCR was markedly enhanced in patients who received pembrolizumab. And what we found was that unlike metastatic disease, PD-01 didn't matter. The benefit of immunotherapy in these patients with presumably health

[21:20] healthier immune response to the cancer was independent of PD-01 status, but PD-01 predicted response to chemotherapy shown in the bar graphs in the lower part of this slide, where green is the Pembrolizumab-treated group. Patients who had PD-01 positive disease, regardless of Pembrol or not, had a better response, but in all cases,

[21:40] groups the addition of Pembro helped outcome. We of course don't know if you have no cancer at the time of surgery. If you need to complete a year of Pembro, that's being studied and we also are looking at ways to try and improve outcome in those patients who do not have a PCR. Of course, PCR is just one output. We understand that it correlates with outcome, but it

[22:00] It was important for us to see this particular event-free and distant recurrence-free benefit. And in fact, the FDA declined to improve Pembroke until we showed that event-free survival and distant recurrence-free survival were improved in patients who received Pembrolism by almost 8% at a follow-up of about 30 months.

[22:20] And interestingly, if you looked at the patients who had a pathologic complete response, thankfully they had a very good outcome. But in the patients who didn't have a PCR, patients who received Pembrolizumab had a significantly better outcome shown in that right-hand graph, which is really fascinating. We're trying to understand what the difference is in the microenvironment caused by

[22:40] hyperpembrolizumab that results in better outcome even in patients who don't have a PCR. Of course, we still want to improve this outcome with additional therapies. We were very interested in understanding which patients with hormone receptor positive her2 negative disease might benefit from immunotherapy and not limit this only to triple negative disease.

[23:00] Our colleagues working on the I-SPY program in the laboratory, Denise Wolf and Christina Yao, developed a response predictive subtype. So this gene signatures that can help us understand the benefit from immunotherapy and also DNA damaging agents. And this has now been incorporated.

[23:20] into our I-spyte trial. We use this as well as other gene expression dividers where you look at basal versus luminal, something we won't go into today. And what we found was really interesting presented by Laura Hubbard at our national international meetings last year that in the patients who had this immune positive subtype and hormone

[23:40] receptor-positive high-risk disease, that PCR from the addition of pembrolizumab was remarkably high. Now this obviously needs to be confirmed in larger studies, but it's a fascinating first step into understanding the benefit of immunotherapy across different subsets. So when we're adding new agents, we always want to add new agents.

[24:00] to understand toxicity and area near and dear to my heart. I'm the toxicity, the safety co-chair for the national I-SPY trial with a colleague from the University of Chicago. We know that by combining chemotherapy with immunotherapy, we get a better effect, but we also get more of this kind of weird toxicity, immune-related adverse events.

[24:20] This is a new toxicity. We've learned a lot about how to recognize immune toxicities that we didn't even know how to see. And we've learned it from our colleagues who used immunotherapy for a long time in melanoma, lung cancer, et cetera. Now, once you give the immunotherapy agent alone shown in the lower right-hand part of the curve, the risk of immune-related adverse disease.

[24:40] events goes down significantly. Most of these events are low numbers, and I've highlighted some of them, but the thyroid effects and some of the endocrine effects are seen more frequently and also are very important because they appear to be permanent. We can't just give patients steroids and make them go away like we can with some others like colitis and hepatitis.

[25:00] We've worked very closely with Zoe Quant here in the division of endocrine at UCSF on trying to accurately identify and manage endocrine immune toxicities and she's also working on a collaborative project across the United States identifying risk factors for these immune toxicities.

[25:20] than others. And I show you an intriguing picture in the upper right hand corner where two of my patients who had childhood vitiligo that had resolved had a massive flare of the vitiligo after treatment. Some of these toxicities occur months after the last exposure to immunotherapy. And they also got something called polyosis where the skin and their scalp had patchy hypopilm-

[25:40] mutation, and the hair that grows in in those little patches of hypopigmented skin has no color. It's white. And this happened in a patchy way in their eyebrows and eyelashes as well, all hair in the body, which of course then they dyed. But this is long-lasting. So I just saw one of these patients two years later and she still has the polyosis and you can see this really intriguing difference.

[26:00] and pattern in two different patients. So we're learning every day about immune-related adverse events, a big area of study. And of course, I focus on this as well as toxicity from novel agents in I-SPY-2. So what about endocrine therapy? So we know hormone receptor-positive disease is the most common subset of breast cancer. So this is a big factor.

[26:20] area to target and endocrine therapy works really well in the advanced stage setting, but the cancers learn to be resistant to the endocrine therapy over time, single agents and then sequential agents so that we only have chemotherapy. The discovery of these cyclin-dependent kinase 4, 6 inhibitors was very important. Our colleagues, Ed,

[26:40] UCLA studied CDK4.6 inhibitors, a specific one, palmosiclid, in their whole panel of cell lines and showed that in the hormone receptor-positive tumors in the light blue below that there was remarkable efficacy in suppressing these tumor cell line to grow. What cyclin-dependent kinase 4.5 is.

[27:00] number 6 does, these enzymes help the cell cycle. So they help the cell go into G1S phase transition and cell cycle entry. And we know that the endocrine-resistant cell line seems to be dependent on this cell cycling approach. And if you have activation of cyclin D1, you have tumors that

[27:20] are more resistant. So CDK46 inhibitors then were studied, and in fact, three CDK46 inhibitors are now approved for the treatment of metastatic hormone receptor positive breast cancer. These remarkable agents led to numerous trials, both as first-line treatment as well as later-line treatment in the metastatic setting.

[27:40] And I'm showing you the five randomized phase three trials that have been reported and led to drug approval in the treatment of hormone receptor-positive, untreated metastatic breast cancer. These trials combined the CDK4.6 inhibitor with various endocrine therapies. There are these three CDK4.6 inhibitor.

[28:00] are pulposiclid, ribosiclid, and abemosiclid. And they are different between the three, but all of them in these trials resulted in a marked improvement in progression-free survival with almost identical hazard ratios across the trials, including postmenopausal and premenopausal women and different endocrine therapies.

[28:20] Interestingly, there's been some difference in overall survival with ribosiclid showing overall survival benefits in all three studies that have evaluated the agent. Abemosiclid shows a remarkable numeric improvement that's not yet statistically significant but has a final readout. And palmosiclid, interestingly, the first kid on the block in this area, showed survival

[28:40] benefit only in patients who had more endocrine-sensitive disease overall. So the reasons for these differences are not well understood, but there is, of course, interest in using the agents that have the best survival data currently, and this is relatively new information. Now when we see data like this that's

[29:00] so exciting where we see improvements in survival. I mean, we participated in all of these trials with the CDK4.6 inhibitors and we opened the first phase three trial in first-line treatment for metastatic hormone receptor positive disease with palmosiclid. I enrolled one of the second

[29:20] patients in the trial and about five patients in the first few months because we had patients waiting to go on. And of those patients, four of them are still on palmosiclid and their first line endocrine therapy with electrosol. One of these patients is now almost 10 years out. Her little child is now in high school. This is a huge

[29:40] impact that we can make in patients by encouraging participation in trials and by really understanding the agents that are most likely to move forward. Very, very exciting advance to participate in. But when we saw this kind of effect, we really wanted to, of course, understand who would benefit. That's it.

[30:00] something too complex to go into today, but to move these agents into the early stage setting. This shows you the most successful trial, Monarch E. In this trial, the big consideration was, okay, you have a disease that has a 20 year natural history. We can't wait 20 years to see the endpoint. So we selected patients for this.

[30:20] trial who had a higher risk of recurrence in the first five years. So those high risk patients were patients who had more positive lymph nodes at the time of diagnosis or higher proliferative disease looked more aggressive, bigger tumor size. 5,600 women with these high risk features were randomized to receive their standard

[30:40] five or more years of endocrine therapy with a bemosiclid or without a bemosiclid, one of the CDK4.6 inhibitors. And we also looked at proliferation with a marker called Key 67. What we've shown in this trial is really remarkable. And a bemosiclid is now approved in women with high risk, early stage breast cancer. A bemosiclid was given for two years.

[31:00] years. In the most recent update, which has almost four years of median follow-up, what we saw was that the improvement in outcome in both invasive, distant recurrence-free survival has increased over time and that the difference two years after finishing at Bemosiclub is greater now a carryover effect than it was during the

[31:20] bimiciclid with an absolute improvement of 6.4% in invasive disease-free survival and almost 6% in the risk of distant recurrence. So very exciting data. The issue with bimiciclid is that it causes diarrhea. So we have to manage the diarrhea. So I'm very interested in this toxicity area. We looked at the time course.

[31:40] the rate of discontinuation, and we published now guidelines on management of diarrhea with dose reduction and antipropulsive agents to try and help patients be able to continue treatment without it impacting their quality of life too much. We also saw an increase in venous thromboembolism that was increased in women taking tomoxifen. So therefore, we could recommend

[32:00] that you take a different endocrine therapy in these patients to reduce that risk. There is another phase III trial called the Nataly trial that used three years of ribosyclic that already has a press release showing positive outcome and we'll see that data at our international meeting in early June. I mentioned targeting other

[32:20] pathways that drive resistance to hormone therapy. And the most commonly mutated gene in breast cancer is PI3-kinase alpha-sopic 3CA called. About 40% of breast cancers that are hormone receptor positive have this mutation. And we've been interested in targeting it for a long time. We actually participate in that.

[32:40] anticipated in the very first studies of the mTOR inhibitor everolimus now approved for the treatment of patients who have metastatic mermen receptor-positive disease that have progressed on other endocrine treatments. And then the next agent that was approved was alpelosive, an alpha-specific PI3 kinase inhibitor that targets specifically

[33:00] PI3 kinase. This alterations in this entire pathway have been associated with resistance to endocrine therapy and shorter duration of response to endocrine therapies. The newest agent is a really fascinating drug that targets AKT and you can see that's just downstream of PI3 kinase, capivacerta.

[33:20] And we just presented positive data from this drug that I'll show you in just a moment. So this is the data with Alpelosib, the phase three trial, that was the only drug that we've had and will be until capivisertib is approved. We saw an improvement in progression-free survival, a numeric but not significant improvement

[33:40] and overall survival as second line treatment for patients with hormone receptor-positive disease. But this actually trial was really important because not only did we have a new targeted agent, but it also was the first trial on breast cancer to show that you could understand the mutation status of the tumor by looking in blood. So we could look at

[34:00] circulating tumor DNA and look for mutations in PIC-3CA and use this to identify patients who are more likely to benefit from a pelosive. So that's a really important advance because that means you don't have to keep going and sticking big needles into the liver or a biopsing lung which is quite difficult in order to understand the mutational profile.

[34:20] of the tumor and it's being increasingly used to determine eligibility for treatments in metastatic disease. Now you can see here that the benefit here was only in patients who had mutations in PIC-3CA, important as we talk about capiviserta, but before that, why do we need more agents? This was good.

[34:40] We, patients didn't have CDK4.6 inhibitors, but we led another trial in patients who all had CDK4.6 inhibitors and showed that alpilosib maintains its efficacy and sequence. So we looked at the reasons why alpilosib was so difficult to administer and the most, alpilosib is the case.

[35:00] is really difficult because of class effects. By inhibiting that pathway, we see really significant hyperglycemia in patients who have no risk factors for diabetes. They have a normal hemoglobin A1C, and they come in after two weeks of treatment with a glucose of 450, as a patient did earlier this week for me. They also get rash, which can be dose limiting.

[35:20] and diarrhea late. So we were able to show that the risk of both rash and hyperglycemia is very early so that you need to monitor patients and follow them very quickly. And then subsequent studies have looked at prophylaxis with a glucophage, which may be actually quite effective, but it's still quite difficult to manage these patients. So we were really interested in this.

[35:40] this AKT inhibitor, Capivisartib, to see whether or not this would not only be effective across PI3 kinase mutations, but also might offer us treatment with less toxicity. And indeed, Capivisartib improved progression-free survival, both in patients who had alterations in the PI3 kinase pathway.

[36:00] and in the small number of patients enrolled who did not have any alterations. So this is really exciting data. There's a hint, an early hint of a survival benefit, not yet significant. And we're hopeful that this drug, which has a better toxicity profile, much less hyperglycemia and rash, will be approved later this year by the USFDA.

[36:20] Let's talk about what's really taking our world by storm antibody drug conjugates, an incredibly exciting area. What are they? Well, these are antibodies that are usually designed to a selected for an antigen with high copy expression on the target tumor cell. Although now it turns out that many of these new generation ADCs

[36:40] work even in tumors who have low expression of whatever the target was. Then you have a linker. The linker has to be plasma-stable because you don't want the toxin that's being carried by the antibody drug conjugate to be released in the circulation. And then the cytotoxic drug has to be very potent at very low at conduction.

[37:00] concentrations because you're only giving a little. So you don't want to kick a drug that you need to give a lot of drug in order to have efficacy. The other critical aspect of the antibody is it needs to be internalized into the cancer cell when it binds to the receptor and you can see that in the lower right-hand corner here, the antibody drug conjugate brings its payload into the cell.

[37:20] The linker is digested by the lysosome and then releases the payload essentially into the cancer cell to kill the cell. Now, obviously, when you kill the cell, you release the payload so you could kill neighboring cells, but also the newer antibody drug conjugates, not all, but largely have cytotoxic drugs that are membrane-permeable.

[37:40] not so hydrophobic and they can leak out of the tumor cell and kill neighboring cells through this effect called the bystander effect, which may be very important for some ADCs. And that's shown in this cartoon here where you have this death of the cancer cell and leakage of the payload and then can target other cells. But you also have a cancer cell that's not so bad.

[38:00] also have some linkage even in cancer cells that don't die. So really important and here's the membrane, in-premial drug and the bystander effect here. So what is going on in breast cancer in terms of clinical data? So we have two new antibody drug conjugates that are approved and a third one with imminent data.

[38:20] So these drugs are only approved in the metastatic setting, but there are many trials going on in the early stage setting in high risk disease to try and further improve outcome in patients with these incredibly effective drugs. Trastizumab drugs to can is a HER2 ADC, remarkably effective in HER2 positive disease, but it works in tumors that have

[38:40] low expression of HER2, we've now coined a new term in the last year, HER2 low. Which are tumors that are not really HER2 positive. They never responded to HER2 targeted therapy, but they respond to this ADC remarkably well, as I'll show you in a moment. Sacetosum Abgovatikan is a TROPE2 ADC. Turns out TROPE2 is expressed

[39:00] on most solid tumors, not just breast cancer, regardless of subtype. And that drug is now approved in triple negative breast cancer as well as pre-treated hormone receptor positive metastatic disease. And then another trope to ADC data, podomap directicand, is in phase 3 trials in both hormone receptor positive and triple negative disease.

[39:20] with early data suggesting remarkable efficacy. Fascinating that these antibody drug-conscious, as you can see here, they have different antibodies. Some have the same toxin, directicand. Some have other toxins. The toxins all target topoisomerase. But these three drugs have completely different toxicity profiles. We don't really

[39:40] really understand whether it's the antibody, the toxin, or both. And right now it appears to be both because the toxicity profiles are so different. So here's Trisazemab drugstocan, HER2 biosimilar with a very high drug to antibody ratio and a topoisomerase inhibitor payload. So the first trial is

[40:00] show you is second-line therapy for patients who have HER2-positive metastatic breast cancer. This trial, Destiny-Bresto-3, showed an incredible improvement. I mean, we had never seen anything like this in breast cancer before. The progression-free survival went from 6.8 to almost 29 months with this drug. And you can see how these curves are separated, and you can't even

[40:20] count the number of zeroes, hazard ratio 0.33, and then also showed a remarkable improvement in overall survival. And it's only this group of breast cancer where the overall survival medians haven't been reached in either group, but it's significantly better with TDXD. TDXD has a unique toxicity. The most common toxicity is nausea. We can generally manage that.

[40:40] But it causes inflammation of the lung called interstitial lung disease and pneumonitis. We're working very hard on understanding how to manage this best because there can be mortality from pneumonitis with TDXD. So it's a low rate, less than 1%. But definitely patients have died in all studies and outside of the clinical trial setting. So this is a very important topic.

[41:00] This is an area of active work. This antibody drug conjugate, big, huge molecule, crosses the blood-brain barrier and can be effective in resistant brain metastases. So that's another very exciting area of research. We have oral tyrosine kinase inhibitor, tucatinib, which also is very effective in targeting brain metastases in patients.

[41:20] with HER2-positive disease only. So the HER2-low is this fascinating area. It's tumors that are not HER2-positive. It's more common to have low expression in hormone receptor-positive than triple negative disease. And we haven't as yet found that it has any other biologic relevance. So it doesn't predict outcome. It's not prognostic.

[41:40] But it did predict benefit from TDXD where a study called Destiny Breast O4 showed a remarkable improvement in progression-free and overall survival leading to maybe the only standing ovation for breast cancer and a plenary session in our international meeting ever. The post-pandemic approach. I mean, we really can improve outcome for our patients.

[42:00] In HER2-positive disease, we did the phase 1B trial, and I have a patient who's just coming off therapy now who's five years on that treatment and only a year on the prior standard therapy. So these are remarkable agents. So improved progression-free in overall survival and the interstitial lung disease with 0.8% mortality.

[42:20] was similar to what was presented before. And now we're looking at whether or not you can retreat patients who got better from their pneumonitis and we'll be presenting that data at another few meetings coming up and have published safety guidelines now in ESMO open and one guideline is in press.

[42:40] So they did an exploratory analysis in triple negative disease as well. And in this tiny number of patients, there were only 58 patients, they showed a marked improvement in progression-free and overall survival. This data led the FDA to approve trastesum abdruxtam and her too low disease, regardless of hormone receptor status, a really important advance in the treatment of her.

[43:00] patients in the metastatic setting. Sacetizumab-Govatikan is a Trope 2 ADC shown an improvement in progression-free and overall survival in triple negative disease and it was our first treatment other than immunotherapy that could improve outcome. It causes more neutropenia and diarrhea and doesn't cause pneumonitis. Really interesting. We're not sure why.

[43:20] The toxin is dillotopo isomerase 1 inhibitor, but a different one than dorextacan, of course. And we extended the study of sassatuzumab to patients who had hormone receptor-positive chemotherapy-resistant disease and also recently showed and published an improvement in progression-free and overall survival in this population.

[43:40] So our next steps with these really exciting drugs are to study them in early stage disease and as first line treatment for metastatic breast cancer. We're looking at in triple negative disease with and without immunotherapy. And then in an important area, patients who didn't get a PCR from neoadjuvant therapy, these drugs are available at the end of the day.

[44:00] drugs are all being studied as a mechanism for rescue. This newer ADC, datopodumab dorextacan, is a fascinating drug and we've incorporated it into ISPY as neoadjuvant therapy that will be a phase III trial that will be sponsored by AstraZeneca to study this really based on our success, which is still being

[44:20] evaluated in the I-SPY-2 trial with datapodum abdurextacan, the idea that you could replace chemotherapy with antibody drug conjugates is very exciting. And then we're studying these use of sequential ADCs and Laura Hubbard will be running a multicenter trial, looking at that as well.

[44:40] So presenting toxicity, how can we sort of capitalize on our involvement in trials to improve the management of our patients? So I mentioned that we had used one study and then been able to apply the treatment to many. So I participated in the trials with Ever Alignments on the steering committee. Stomatitis was a big toxicity.

[45:00] the bad for patients, they hate having mouth sores. So mouth sores have cracked everything about your quality of life. So one of my colleagues and I were thinking about this and noticed that the mouth sores talk to our oral medicine colleagues. They looked more like at this ulcers than like the chemo you caused by huge doses of chemo given for example, in bone marrow transplant.

[45:20] they're different pathologically as well. Our oral medicine colleagues have always used steroids, topical steroids, to treat at the sulfurs. So we used a dexamethasone mouthwash and saw we weren't getting any more mouth sores. We approached Novartis and were able to do a single arm trial, not randomized, in about 100 patients, and showed that they had a mouth wash.

[45:40] that we could markedly reduce the rate of stomatitis. So this shows you the stomatitis in our trial that led to approval of Balero, the Balero II trial that led to approval of Evrolimis. You can see this early rate, orange year of stomatitis. And then our trial, which we called the SWISH trial. At 92 patients, getting Evrolimis,

[46:00] guidelines and then using this oral mouthwash. What we saw was really amazing. You can see here the SWIS study knows stomatitis at eight weeks and 79% versus 39% on balera 2 and we completely eliminated grade 3 stomatitis and markedly reduced from 20 to 2% grade 2 stomatitis. So based on this

[46:20] It was the oral steroid mouthwash was added to the label for everaligmas and it's used worldwide, completely changed the use of everaligmas. And now we've been able to apply it as a broad preventive strategy to other agents distressing stomatitis, including that datopodumab directicand that ADC and ISPI were now using the Stematitis.

[46:40] steroid mouthwash to prevent its significant mouth sores with remarkable success. So continuing to improve outcome. So we are really bringing biology to the clinic and back. Targeted agents have rapidly moved into the treatment of early stage disease. We're working on extending efficacy and combinations for immunotherapy and also managing an-

[47:00] We've improved endocrine therapy in a dramatic way for hormone receptor positive or HER2 negative disease with more advances in the near future. There are many new endocrine therapies that can target resistance that are being studied, which I didn't have time to discuss. And of course, antibody drug conjugates really are the most exciting way to deliver ketone.

[47:20] chemotherapy effective across subtypes in many trials. Big question comes up at how can we move faster and better? And Laura Esman and Laura Vantivier really developed the ISPY-2 trial and now ISPY-2.2 with our collaborators, Joe Chen is the, our site PI and developed an endocrine optimization protocol on the neoadjuice.

[47:40] setting and Michelle Maliska works on patient reported outcomes. Nola Hilton has done the work in imaging, which is so critical to this study, which is now looking at experimental agents up front as an initial block. If you have a great response, no disease by MRI imaging and biopsy, you can go to surgery.

[48:00] have disease, you go on to block B, which is our best standard therapy, subtype-specific rescue. If you still don't have a response, you go on to our end rescue AC, but we'll be changing that over time and adding in new rescue approaches. What that does is it allows us to individualize therapy with escalation and de-escalation before any

[48:20] but he even goes to surgery, which is so exciting. And we're monitoring safety and patient reported outcomes very carefully. This treatment with novel agents can be expanded not just to high risk disease, but also slow growing hormone receptor positive disease, where Joe Chen is leading our effort to study many novel endocrine therapies and targeted agents.

[48:40] really an important advance led by UCSF that is changing the way we think about treatment for breast cancer. So as I conclude and we open for questions, certainly we are a village for sure. As a university, as a cancer center and our breast cancer center where we have remarkable staff that help us manage our patients.

[49:00] remarkable colleagues, our APPs in the infusion center, our cancer acute care center where we can manage the acute issues that occur with patients and help keep them out of the emergency room and hospital. We wouldn't be anywhere without our courageous patients who trust us and go on clinical trials and continue on treatment and cut patients who came in.

[49:20] during the pandemic on trials, our collaborators worldwide, and as an academic physician, none of us can be successful without the support of our families, and I'm fortunate to have a wonderful family. And then lastly, I went into breast cancer, and Bob mentioned that I went into breast cancer because I saw a big need, and of course there's a big need.

[49:40] But my mother died of breast cancer when I was already a faculty member, and she really gave me the courage and passion to do this work. And to end with a quote from Mark Twain, the secret of making progress is to get started. Thank you. Thank you, Hope. That was a great question. Thank you.

[50:00] remarkable and inspiring and boy things have changed over the last 10 years or so. So if people have questions put them in the in the Q&A and we will get to get to some of them. I guess one of the things that strikes me is I think in you know in the old old days breast cancer was sort of a bread and butter tumor for a

[50:20] community oncologist. Has the complexity reached the point that it really needs a super specialist to keep up with all this stuff? It's just remarkable how much change we've seen in the last 10 or 15 years. Yeah, it's a great question. And I was just talking to one GI colleague at another institution, and she was saying, yeah, I mean,

[50:40] I'm a pancreas doctor. It's like, okay, you know, there's no more just disease oriented oncologists and academic centers, but in the community, we've really seen a trend towards more focus on specific cancers. You know, breast cancer, G, U cancer, GI cancers are the most common cancers we see in the United States. And we're seeing more and more of that.

[51:00] Because treatment is so nuanced and management of toxicity is so critical for success, we really have, I think our world now is based on having people focus on a greater understanding and management of specific diseases and within those diseases now, specific subsets as well.

[51:20] And it seems like, again, so much of what I learned about this disease a long time ago, and I'm just sort of trying to come to terms with the paradigm shift, it seems like the markers dominate the equation of how you're thinking about aggressiveness and prognosis and how to treat as opposed to side.

[51:40] and lymph nodes. Is that right? Or you're thinking about all of it. It's sort of one big package when you see a woman with an initial diagnosis. It is one big package. And some, you know, obviously the markers I think are the key, the really key first step. You need to understand the markers. But what's really fascinating is that we've learned through these immunotherapy studies,

[52:00] that if you have a smaller cancer, you can get rid of it more easily with the same therapy than if you have a bigger cancer. The bigger the cancer, the better the ability of the cancer to suppress your own response to the cancer. So you suppress the immune response more effectively the more cancer burden you have. The cancer does that itself.

[52:20] through mechanisms that aren't very well understood. And that's really fascinating. You also have to of course, base it on age and comorbidities, but we've learned that that's not enough. All of that isn't enough. So this response predictive subtype that I mentioned developed out of investigators here through the I-SPY network

[52:40] really important because there are a number of different gene expression signatures which are helping us to further understand the intricacies of biologic differences within the subsets. That's really important. For example, we use gene expression tests now to help us decide which patients need chemotherapy who have hormone receptor-positive early stage disease, but we clearly

[53:00] really need to go many steps further. And so if you, I mean, sort of gets into a screening issue as well, you find a very small tumor with negative lymph nodes, but with nasty prognostic markers. How do you approach that today? Well, it's a good question. And there's been a lot of recent changes. I said on the,

[53:20] comprehensive cancer center network breast panel on behalf of UCSF. And it's really interesting to see how everybody talks about it and how we've been changing over time. So neoadjuvant therapy, treatment before surgery, started as something that we only did as treatment for patients who had huge cancers. Now we use it as a way to better improve

[53:40] therapy. So then you get to these nasty cancers, we've actually kept decreasing the amount of cancer that we think is the amount you need to get neoadjuvant therapy. So we will often treat patients who have triple negative disease or her too positive breast cancer who have tumors that aren't node positive that are even just over a cent.

[54:00] centimeter because it can help us individualize the therapy, the amount of treatment to the response. For smaller tumors, we still do surgery first because as I mentioned, outcome seems to be better just because your body response to the cancer is better. Right. I don't think you mentioned the term radiation therapy during the talk.

[54:20] probably some radiation oncologists listening. And so is there any overlap or interaction between radiation therapy and the therapies that you're talking about here? There are huge interactions, and the field of radiation therapy is also moving ahead with leaps and bounds. So thank you for asking that question. My colleagues in radiation therapy also,

[54:40] based on the disease type. And we've made incredible advances. So one is to understand which patients need radiation or not. The second is to actually reduce the, a number of days that you get radiation and the way radiation is given to limit the, both the amount of time, amount of time a patient has to

[55:00] put into radiation, but also the amount of radiation. And they've been able to actually improve the scatter of the radiation field to cause less damage to neighboring normal tissues, which is really important. In the metastatic setting, we used to, when patients had what we call oligometastatic disease, so a single or a few sites of metastases, we used to have a lot of radiation.

[55:20] to try and do what people refer to as cherry picking, go in and take out the lesion. That's quite noxious to the patient, morbid. Now we can do selective brachy-radiotherapy and target specific areas with radiation. So we almost never do big field radiation now in the metastatic setting, whether we're treating for palliation or.

[55:40] to remove a tumor that's oligometastatic. And we do that for all sites, brain and outside of the brain. So big advances. Great. Again, if people have questions, please put them in. I'll keep going until I see any. The antibody drug conjugate's fascinating. I couldn't quite tell. Maybe you sort of said this. Is the antibody drug-

[56:00] is just a delivery mechanism to find the tumor cell and get the toxin into the cell which then kills the cell or is the antibody itself doing something to disrupt the cancer? Well, it's a great question and it varies. In HER2-positive disease, for example, Trastizumab itself is a very effective agent, but it's enormously

[56:20] more effective when it's given with chemotherapy. So yes, the trastizumab plays a role in the treatment effect because there's some synergy between the trastizumab effect, where it changes host immunity, and it also has some cytosidal effects as well as the toxin that's delivered.

[56:40] For the other ADCs, we don't know, and trastizumab itself was not effective in HER2 low disease. So it's not doing that there. We don't know that TROP2 antibodies kill cancer. They didn't seem to work by themselves. So there they're a delivery mechanism, but we've seen an intriguing outcome, which is that HER2-targeted

[57:00] treatment has this specific finding in our trials where the duration of disease control is improved, but overall survival is improved even more. So that's attributed to an immune effect on the host tumor microenvironment where we know it's antibody-dependent cellular cytotoxicity from the antibody.

[57:20] But there's probably other effects as well. We're seeing the same thing with these ADCs, where the survival difference is greater even than the improvement in progression for survival. So the antibody is having another role rather than just delivery. And then the other aspect of this is you don't even need to express the target very much for the ADC to work.

[57:40] So that's another intriguing area which is not well understood. Yeah. You mentioned sort of the prognosis is almost bifurcated. Some people, if they're going to recur, recur early. Some people can recur quite late. For the people that you're following, I know plenty, who are five or

[58:00] 10 years out. Are they still receiving treatment and how are you monitoring them? And also what do you tell them? I mean, in other tumors you reach a point and you say you're cured. What do you tell someone who's 10 years out? Well, this is very much differentiated by biology. If you have hormone receptor negative disease, it's not.

[58:20] is her too positive or not. Once you're five years out and you don't have one of these rare, indolent subtypes we see generally in older women, you are cured. So that's our one subset. Mermin receptor-positive disease has a long natural history. And I tell patients that, but I tell them that every year they go without a recurrence, there's less risk.

[58:40] So you're chipping away at it as you go on. Wurman therapy now has been extended out to 10 years in patients with the highest risk of recurrence. But for small tumors, we don't really know which patients benefit. There's a lot of interest now, and it kind of, I think, responds to one of the question in the Q and A, which is CT DNA.

[59:00] So, you know, circulating tumor DNA can be found in patients who have early-stage breast cancer and it's correlated with a higher risk of recurrence, although everybody doesn't recur. So it puts you into a problematic situation where you don't know if changing therapy helps at all. You could be increasing toxicity, anxiety, and reducing quality of life without an

[59:20] any benefit. So we don't monitor CT DNA in the early stage setting, but clinical trials that try and look at this are really important. And we are thinking about, you know, there's metastatic trials like this where you see the development of a resistance mutation, and then you could change treatment to focus on that mutation. But this is still far off.

[59:40] It's a very tough area to study. Can you mention what is CT DNA? Not every pupil, no. So circulating tumor DNA. So this is such a fascinating idea. You know, we didn't figure out. We were looking at circulating tumor cells for a long time. Cell-free or circulating tumor DNA are fragments of the DNA.

[01:00:00] from the tumor that circulate free in the blood. They're not associated with the cell and they've been remarkable. They've allowed us to now take a blood sample. A patient comes to clinic, their tumor is progressing. They have metastatic disease. I use my little RTLS badge and call the medical assistant who brings a box, they go to the lab, they get their blood out.

[01:00:20] draw it, send it off, we can look to see whether there's mutations in the blood, the tumor in the blood that can help us target treatment. So I don't have to stick a big needle into their liver, which is very helpful. Now we do do biopsy still. They're really important to give us additional information, but this has been a huge advance. Great, great. Hope we're out of time.

[01:00:40] It's an amazing work and thank you for all you do and all the patients that you take care of and help us think through this rapidly evolving disease. Really appreciate it. Thanks so much.