Breast Cancer Treatment: How is Biology's Integration into the Clinic Transforming Healthcare? Hope Rugo

Breast Cancer Treatment: How is Biology's Integration into the Clinic Transforming Healthcare? Hope Rugo

By Hope Rugo, MD, FASCO, Professor, Medicine at Professor, Department of Medicine (Hematology/Oncology); Director, Breast Oncology and Clinical Trials Education; and Medical Director of Cancer Infusion Services, UCSF

Good afternoon. Welcome to UCSF Department of Medicine Grand Rounds. I'm Bob Walker, 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." The speaker is Hope Rugo, who is a Professor of Medicine and Director of Breast Oncology and Clinical Trials Education at UCSF Health.

Dr. Hope has had a long and distinguished career as a medical oncologist, specializing in breast cancer research and treatment. She began her career after graduating from medical school at the University of Pennsylvania in 1983, which sounded familiar, and then I remembered that's when I graduated from the University of Pennsylvania. Hope was a classmate of mine. She did a residency in Internal Medicine, a Hematology-Oncology fellowship at UCSF, an Immunology postdoc at Stanford, and then joined our faculty in 1990. She has been here ever since, starting off in the world of bone marrow transplant and malignant hematology, and transitioning to treat breast cancer because she saw tremendous need and opportunity. She has filled that role admirably.

As I mentioned, she is the Director of Breast Oncology and Clinical Trials Education. She's a principal investigator of a number of clinical trials, many of which have been published in very prominent places, focusing on novel targeted treatments to improve the outcomes of patients with breast cancer. Her research involves immunotherapy combinations of targeted agents, as well as the management of toxicity. In addition to her remarkable research career, Hope is a very active and go-to clinician for many of our patients. She has received numerous honors for her work, including just last week being awarded one of our Master Clinician Awards, which is the highest honor our department gives to its clinicians.

Dr. Hope, welcome aboard, and I'm looking forward to hearing your comments. Thanks so much, Bob, for that very kind introduction. It's really such an honor to be presenting Grand Rounds today on this exciting topic that means a lot to me. I'll just share my slides now on the recent advances in the treatment of breast cancer and the incorporation of a better understanding of biology, both from the laboratory and in the clinic, to optimize the treatment of our patients and improve their quality of life. 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 to treat breast cancer without first giving the general audience some background, which seems really critical. So, we'll start by talking about a little bit of background and then we'll delve into the key advances in the treatment of breast cancer over the last couple of years that we've been very excited about and have had the opportunity to actively participate in.


Why is Breast Cancer so Common Among Women?

Breast cancer is the most common cancer in women and the leading cause of cancer death worldwide. In the United States, it represents 30 percent of all new cancers in women, and one in eight women will be diagnosed with breast cancer sometime during their lifetime. This is a disease that largely affects older women, with the median age at diagnosis being 63. However, what we consider "older" continues to get older. We do see a significant number of young patients, particularly at a referral center like UCSF. Ten percent of patients are under the age of 45, and almost 30 percent of patients are under the age of 55.

In the United States, almost 300,000 new cases of invasive breast cancer will be diagnosed in women. However, breast cancer is not the most common cause of cancer death in the country. I believe it's essential to highlight the inequities in access to treatment worldwide. Approximately 43,000 women will die from the disease. In our research, we have identified significant racial and ethnic differences that are crucial for better treating our patients and understanding risk factors while optimizing early-stage diagnosis. This area remains an active field of research.

Black women have the highest death rate from breast cancer, with a higher incidence of the disease occurring under the age of 40. On the slide, you can observe the differences in mortality rates comparing black women to non-Hispanic white women, given per 100,000 person-years. Among young black women, we observe a higher rate of the most challenging-to-treat subset of breast cancer, which also carries the highest mortality. For instance, after a diagnosis of metastatic triple-negative breast cancer, the median survival is only around 18 to 20 months, compared to over five years for hormone receptor-positive disease. Additionally, black women experience an 81 percent higher rate of this breast cancer subset compared to non-Hispanic white women.

The rate of breast cancer in the United States has increased by approximately 0.4 percent per year over the last decade. However, mortality has decreased at a higher rate of 1.3 percent per year. This improvement demonstrates advancements in understanding the biology of the disease and utilizing more effective treatments.

The five-year relative survival rate, including all patients diagnosed with breast cancer, is about 91 percent. We estimate that over 80 percent of women diagnosed with breast cancer today will survive the disease. When examining the incidence of breast cancer from The Seer database, we see that it is higher in white women than in black women. However, the mortality rate is higher among black women. This difference is an area of great interest under study and is believed to be associated with variations in biological subtypes, microbiome, genetic factors, and environmental risk factors.


Breast Cancer Treatment Options

Now, let's discuss general treatment for breast cancer, which is based on biologic subtypes. Approximately 60 to 70 percent of breast cancers are hormone receptor-positive, commonly referred to as hormone receptor-positive/HER2-negative. HER2 is interesting as it is associated with the overexpression of a gene called HER2/neu, resulting in overexpression of the HER2 receptor. This subtype represents around 15 to 20 percent of breast cancers and is the most curable subset at present. It is the only subtype where some women with metastatic incurable disease can achieve long-term survival and essentially be cured.

Triple-negative diseases are defined as diseases that lack known receptors, such as non-A non-B hepatitis. They represent about 15 percent of breast cancer cases. The disease subsets vary by age. We tend to see more highly proliferative diseases like triple-negative and HER2-positive disease in younger women, while older women are more likely to have indolent hormone receptor-positive disease.

I have shown you the general treatment approaches for hormone-positive breast cancer across the subsets in early-stage disease. Hormone receptor-positive disease, represented by the light green color, may be either more proliferative (luminal B-like) or less proliferative (indolent disease, luminal A-like). We tend to observe lower proliferative disease in older women and higher proliferative disease in younger women. Treatment options vary between endocrine therapy with or without chemotherapy in the early-stage setting. The goal is to prevent recurrent disease at distant sites, as well as local therapy and systemic therapy to prevent local recurrence.

Triple-negative disease, characterized by the absence of receptors, is treated with chemotherapy and now immunotherapy. We tend to prioritize treatment for early-stage triple-negative and HER2-positive disease, as well as more proliferative hormone receptor-positive disease, before surgery. This allows us to assess the response and modify treatment accordingly. We'll discuss this in more detail later.

HER2-positive disease is treated with chemotherapy and HER2-targeted agents, with antibodies being the most commonly used. They serve as the cornerstone of therapy, and pertuzumab is added for higher-stage disease. Endocrine therapy is also used when hormone receptors are present.

There's a biological difference in the patterns of recurrence. In the lower right-hand corner of this slide, you can see that patients with triple-negative disease have a higher risk of early recurrence, with almost all recurrences occurring within the first three to five years. On the other hand, hormone receptor-positive disease has a much longer natural history, with recurrences occurring up to 20 years after diagnosis. Approximately 50 percent of recurrences are observed 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 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 it can be related to prior toxicity, as well as shorter durations of response with each sequential treatment. Hormone receptor-positive disease is 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 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, 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 standard therapy, and this is really a cornerstone of most of the advances in our treatment. We have also been able to use the 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 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 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 time frame 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 preventive and management strategies that expand not only that agent but multiple agents coming in the future. Shared decision-making and access to care are obviously critical areas 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 populations 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 the early-stage setting, reducing the risk of recurrence and improving survival for our patients. We'll focus on subset-specific therapy, such as triple-negative disease with immunotherapy, and hormone receptor-positive disease. We'll discuss the addition of very interesting oral agents, enzyme inhibitors (cyclin-dependent kinase 4/6 inhibitors), to endocrine therapy. We'll also explore a newer approach of targeting specific mutations with targeted agents and novel chemotherapy delivery across subsets. One of the most exciting areas of research that spans not only to treat breast cancer but also many solid and liquid tumors is antibody-drug conjugates. These conjugates appear to be effective, even in tumors that don't express the target well. This advance has been incredible, and antibody-drug conjugates have the potential to replace naked chemotherapy in the not-too-distant future. They are already being incorporated into our treatment paradigms.

Neoadjuvant therapy is a significant area for advancement in delivering effective drugs to patients as early as possible, tailored to their specific treatment needs. We can customize therapy based on the response, allowing us to optimize treatment in the neoadjuvant setting before surgery. This approach yields the best response. It means that patients whose tumors respond rapidly may require less treatment, while patients with slower-responding tumors might need different or more extensive therapy. Based on the amount of cancer remaining at the time of surgery, we can modify the treatment given after surgery. We have already demonstrated the efficacy of this approach in several settings, improving outcomes. For example, we can now administer PARP inhibitors, a certain type of chemotherapy inhibitors, to patients with germline BRCA1 or BRCA2 mutations. These inhibitors have already improved survival in patients whose cancers did not completely disappear with neoadjuvant therapy. Individualizing therapy and improving outcomes is our key next step.

Let's talk about these specific examples now. I will start with immunotherapy for triple-negative breast cancer. This beautiful cartoon was developed by former fellows in our program, all of whom have gone on to impressive faculty positions. Laura Hubbard, shown in the lower right-hand corner, is one of our early faculty members who helped develop this cartoon. It illustrates the complex interaction between the host immune system and the tumor cell. Understanding these interactions has led to the development of several different immunotherapy agents that have been incorporated into the treatment of multiple solid tumors. One of these agents is pembrolizumab, a PD-1 inhibitor that is now approved for the treatment of late and early-stage triple-negative breast cancer.

One of the questions to treat breast cancer was whether immunotherapy would ever work. The host immune system has to recognize the tumor as something foreign, and with these slow-growing hormone receptor-positive cancers, they can resemble normal breast cancer cells. In fact, some of them look just like lymphocytes and can be hard to identify with special stains. For some time, we thought that immunotherapy wouldn't work well for breast cancer. However, there was a better understanding of the differences in biology between these different subsets, and interest grew in looking at triple-negative breast cancer as a target for immunotherapy. Triple-negative breast cancer was a great place to start because it has a higher mutation rate compared to other subsets of breast cancer and is characterized by the infiltration of TILs (tumor-infiltrating lymphocytes), which are T cells that infiltrate the tumor and have been associated with much better outcomes. It's fascinating to see that when the host immune system attacks the cancer, the cancer responds better. This has been observed in trials.

In addition, there is more expression of PD-L1 both in the tumor microenvironment and in the tumor itself, making it an optimal target for investigating immunotherapy in breast cancer. We conducted some studies looking at immunotherapy as single agents and observed low but durable responses. Subsequently, we initiated randomized trials combining the checkpoint inhibitor with chemotherapy, based on the known induction of immunomodulatory changes in the tumor microenvironment by chemotherapy. These changes include the upregulation of immunogenic cell surface markers, increased infiltration of lymphocytes, and upregulation of PD-L1. I'm presenting one phase three trial because pembrolizumab is currently the only checkpoint inhibitor approved for the treatment of breast cancer in the United States.


So, this trial was designed to examine a menu of different chemotherapy options because patients might be eligible for different chemotherapies. However, there are really two classes for patients with newly diagnosed metastatic triple negative breast cancer and no prior chemotherapy in the advanced setting. They were randomized to receive chemotherapy with either pembrolizumab or placebo, and they continued this treatment until disease progression. However, pembrolizumab itself stops at two years. We looked at all patients, but we also focused on a subset of patients whose tumors and tumor microenvironment expressed PD-L1 for pembrolizumab. This was assessed using something called the Combined Positive Score (CPS) that looks at PD-L1 expression not only in the tumor but also in the lymphocytes in the tumor microenvironment. This turned out to be incredibly important, as a CPS score of 10 or more, which was seen in 38 percent of patients, was associated with a significant improvement in progression-free survival and, importantly, overall survival with a seven-month median improvement. However, you can see that there is a slight flattening of the green curve, where some patients can stay on the checkpoint inhibitor or receive no therapy for a long time without disease progression. I have a couple of patients whose disease appears to be cured by the use of checkpoint inhibitors. Fortunately, this only applies to 38 percent of patients, so there is a lot of interest in trying to expand the population of patients who might benefit from checkpoint inhibitors.

This is a cartoon of a trial that we are running through our Translational Breast Cancer Research Consortium, which is supported by the Breast Cancer Research Foundation. The trial randomizes patients with pretreated, largely triple negative breast cancer to receive an induction of various different agents, followed by combinations with an immune checkpoint inhibitor called avelumab, with serial biopsies and blood collection. We are collaborating with other investigators, including Andre Goga at UCSF and a colleague at Vanderbilt, for the correlative studies that will help us understand which patients might benefit from this approach.

Now, of course, the interest lies in whether we can cure some women who have early-stage triple negative breast cancer with checkpoint inhibitors. We know that having no invasive disease at the time of surgery correlates with very good event-free and distant recurrence-free survival in breast cancer. Here, you can see data from our multicenter randomized phase two ICE-2 trial, which is being run by Laura Esserman from our UCSF Breast Care Cancer Center. The trial investigates multiple novel agents in the treatment of patients with high-risk early-stage breast cancer of all three major subtypes. What we have been able to show, as have many other investigators, But I thought I'd show that the data we contributed to the most is that patients who have a pathologic complete response (PCR) have an excellent outcome. You can see this in the dark blue line versus the red line in patients with residual disease at the time of surgery. This holds true in the lower two curves, regardless of subset. If you have a PCR and high-risk breast cancer, you have a very good outcome. Patients who do not have a PCR need something more, which is another aspect of our study.

The iSpy study was the first trial to really look at a neoadjuvant checkpoint inhibitor. We administered just four doses of pembrolizumab as neoadjuvant therapy along with the standard chemotherapy backbone. We were able to demonstrate a significant improvement in PCR, which was more dramatic in the triple-negative population shown in the upper right-hand side compared to the hormone receptor-positive group.


What is Mammaprint?

Now, these patients with hormone receptor-positive disease in iSpy have high-risk disease characterized by a test called Mammaprint, a gene expression test developed by Laura van't Veer, who is also a leader in our breast cancer program at UCSF.

So, this is a specific subset, and those patients benefited as well, but to a lesser degree. It's something we're understanding more now. This trial actually led to a randomized Phase III sponsored trial by the company called Mark, who makes pembrolizumab. We were trying to understand the benefit of pembrolizumab as neoadjuvant therapy combined with chemotherapy for triple-negative breast cancer patients who had tumors greater than two centimeters or node-positive disease. Almost 1200 of them were randomized to receive pembrolizumab or placebo with chemotherapy, and then the pembrolizumab was continued for a year or placebo. Six months after the end of chemotherapy, in the first 602 patients published in the New England Journal of Medicine, it was shown that PCR was markedly enhanced in patients who received pembrolizumab. What we found was that, unlike metastatic disease, PD-L1 didn't matter. The benefit of immunotherapy in these patients, with presumably healthier immune responses to the cancer, was independent of PD-L1 status. However, PD-L1 predicted response to chemotherapy, as shown in the bar graphs in the lower part of this slide. The green bar represents the pembrolizumab-treated group. Patients who had PD-L1 positive disease, regardless of pembrolizumab, had a better response. But in all groups, the addition of pembrolizumab helped the outcome. Of course, we don't know if you have no cancer at the time of surgery if you need to complete a year of pembrolizumab. That's being studied. We are also looking at ways to try and improve outcomes in those patients who do not have a PCR. Of course, PCR is just one output. We understand that it correlates with outcomes, but it was important for us to see this particular event-free and distant recurrence-free survival benefit. In fact, the FDA declined to approve pembrolizumab until we showed that event-free survival and distant recurrence-free survival were improved in patients who received pembrolizumab by almost 8% at a follow-up of about 30 months. 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, as shown in the right-hand graph, which is really fascinating. We're trying to understand what the difference is in the microenvironment caused by pembrolizumab that results in a 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. Our colleagues working on the iSpy program in the laboratory, Denise Wolfe and Christina Yao, developed a response predictive subtype. So, these gene signatures can help us understand the benefit from immunotherapy and also DNA damaging agents. This has now been incorporated into our iSpy2 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. 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 receptor-positive high-risk disease, 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. 

When we're adding new agents, we always want to understand toxicity, an area near and dear to my heart. I'm the toxicity co-chair for the National Ice By Trial, along with a colleague from the University of Chicago. We know that by combining chemotherapy with immunotherapy, we achieve a better effect, but we also experience more of this peculiar toxicity known as immune-related adverse events. This is a new toxicity that we've learned a lot about in terms of recognition, even though we previously didn't know how to identify it. We've gained this knowledge from our colleagues who have been using immunotherapy for a long time in melanoma, lung cancer, and other similar cases.

Now, when you administer the immunotherapy agent alone, as shown in the lower right-hand part of the curve, the risk of immune-related adverse events significantly decreases. Most of these events occur at low numbers, and I've highlighted some of them. However, thyroid effects and some endocrine effects are seen more frequently and are particularly important because they seem to be permanent. Unlike some other adverse events like colitis and hepatitis, we can't simply administer steroids to make them go away. We have closely collaborated with Zoe Quant in the Division of Endocrinology at UCSF to accurately identify and manage endocrine immune toxicities. She is also involved in a nationwide collaborative project aimed at identifying risk factors for these immune toxicities.

Of course, some of these toxicities are more serious than others. In the upper right-hand corner, I present an intriguing picture of two of my patients who had previously resolved childhood vitiligo. After treatment, they experienced a massive flare-up of vitiligo. Some of these toxicities can occur months after the last exposure to immunotherapy. They also developed a condition called poliosis, where the skin on their scalp exhibited patchy hypopigmentation and the hair that grew in those patches had no color, appearing white. This also occurred in their eyebrows, eyelashes, and all the hair on their body. Unfortunately, this condition was long-lasting, and both patients still have poliosis even two years later. The picture demonstrates a distinct and intriguing pattern in these two different patients.

We continue to learn every day about immune-related adverse events, as it is a significant area of study. Naturally, I focus on this aspect, as well as the toxicity from novel agents in the National Ice By Trial. Now, let's discuss endocrine therapy. We are aware that hormone receptor-positive disease is the most common subset of breast cancer, making it a major area of focus. Endocrine therapy has proven to be highly effective in the advanced stage setting.


But the cancers learn to be resistant to endocrine therapy over time, starting with single agents and then sequential agents. As a result, we only have chemotherapy as an option. The discovery of cyclin-dependent kinase 4/6 inhibitors was very important. Our colleagues at UCLA studied a specific inhibitor called pelvisyclib in their panel of cell lines and demonstrated remarkable efficacy in suppressing the growth of hormone receptor-positive tumors (shown in light blue below). Cyclin-dependent kinase 4/6 enzymes assist in the cell cycle by promoting the transition into the G1/S phase, and we know that endocrine-resistant cell lines depend on this cell cycling process. Tumors with activated cyclin D1 are more resistant, which led to the study of CDK4/6 inhibitors. In fact, three CDK4/6 inhibitors are now approved for treating metastatic hormone receptor-positive breast cancer. These remarkable agents have been extensively studied in numerous trials, both as first-line and later-line treatments in the metastatic setting. The image displays the five randomized phase three trials that have been reported, leading 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. The three CDK4/6 inhibitors are palbociclib, ribociclib, and abemaciclib, each with slight differences. However, all of them resulted in a significant improvement in progression-free survival, with almost identical hazard ratios across the trials, including postmenopausal and premenopausal women receiving different endocrine therapies. Interestingly, there have been some differences in overall survival. Ribociclib has demonstrated overall survival benefits in all three studies evaluating the agent, while abemaciclib shows a remarkable numerical improvement that has not yet reached statistical significance but has completed its final readout. Notably, palbociclib, as the first CDK4/6 inhibitor in this area, showed a survival benefit only in patients with more endocrine-sensitive disease overall. The reasons for these differences are not well understood, but there is a growing interest in utilizing the agents with the best survival data currently available. This information is relatively new. When we observe such exciting data with improvements in survival, it is encouraging. We participated in all of these trials with CDK4/6 inhibitors, and we were the first to open a phase three trial for first-line treatment of metastatic hormone receptor-positive disease with palbociclib. I enrolled as the second patient in the trial, and within the first few months, around five patients were enrolled because we had patients waiting to participate. Of those patients, four are still on palbociclib as their first-line endocrine therapy with letrozole.


Patient Story

One of these patients is now almost 10 years out. Her little child is now in high school. This is a huge impact that we can make on patients by encouraging participation in trials and by really understanding the agents that are most likely to move forward. It's a very, very exciting advance to participate in. However, when we saw this kind of effect, we really wanted to, of course, understand who would benefit. That's 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 trial who had a higher risk of recurrence in the first five years. Those high-risk patients were patients who had more positive lymph nodes at the time of diagnosis or higher proliferative disease, looked to more aggressive, bigger tumor size. 5,600 women with these high-risk features were randomized to receive their standard five or more years of endocrine therapy with abemaciclib or without abemaciclib, one of the CDK-46 inhibitors. We also looked at proliferation with a marker called Ki-67.

What we've shown in this trial is really remarkable, and abemaciclib is now approved in women with high-risk early-stage breast cancer. Abemaciclib was given for two 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 and distant recurrence-free survival has increased over time, and that the difference two years after finishing abemaciclib is greater now, a carryover effect, than it was during abemaciclib, with an absolute improvement of 6.4 percent in invasive disease-free survival and almost six percent in the risk of distant recurrence. So, very exciting data. The issue with abemaciclib is that it causes diarrhea, so we have to manage the diarrhea. I'm very interested in this toxicity area. We looked at the time course, the rate of discontinuation, and we've published guidelines on the 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 tamoxifen. Therefore, we could recommend that you take a different endocrine therapy in these patients to reduce that risk.

There is another Phase III trial called the Natalie trial that used three years of ribociclib that already has a press release showing positive outcomes, and we'll see that data at our international meeting in early June. I mentioned targeting other pathways that drive resistance to hormone therapy, and the most commonly mutated gene in breast cancer is PI3 kinase alpha. PI3Kα is mutated in about 40 percent of breast cancers that are hormone receptor positive. We've been interested in targeting it for a long time. We actually participated in the very first studies of the mTOR inhibitor everolimus, now approved for the treatment of patients who have metastatic hormone receptor-positive disease that have progressed on other endocrine treatments. The next agent that was approved was alpelisib, an alpha-specific PI3 kinase inhibitor that targets PI specifically. 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 fascinating drug that targets Akt. It's downstream of PI3 kinase, specifically Capivasertib. We have just presented positive data from this drug, which I'll show you shortly.

Now, let's discuss the data from the Phase III trial with Alpelisib. It's the only drug we currently have until Capivasertib is approved. We observed an improvement in progression-free survival and a numeric, albeit not significant, improvement in overall survival as a second-line treatment for patients with hormone receptor-positive disease. This trial was significant because, apart from introducing a new targeted agent, it was the first breast cancer trial to demonstrate that the mutational status of the tumor can be understood by analyzing circulating tumor DNA. By examining mutations in PIK3CA, we can identify patients who are more likely to benefit from Alpelisib. This is a crucial advancement as it eliminates the need for invasive procedures like liver biopsies or lung biopsies to determine the tumor's mutational profile. This approach is increasingly being used to determine eligibility for treatments in metastatic disease.

It's worth noting that the observed benefit was only seen in patients with mutations in PIK3CA, which brings us to the discussion about Capivasertib. But before that, why do we need more agents? While Alpelisib was effective for patients without CDK4/6 inhibitors, we conducted another trial involving patients who were already receiving CDK4/6 inhibitors. The trial showed that Alpelisib maintained its efficacy even in sequence with CDK4/6 inhibitors.

We investigated the reasons why Alpelisib administration was challenging. The most notable difficulty is its class effects. By inhibiting the pathway, significant hyperglycemia is observed in patients without any risk factors for diabetes. These patients have a normal hemoglobin A1c level, but after two weeks of treatment, their glucose levels can reach 450. Additionally, patients experience dose-limiting rash and late-onset diarrhea. We were able to demonstrate that the risk of both rash and hyperglycemia is present early, necessitating close monitoring and prompt follow-up. Subsequent studies have explored prophylaxis with glucophage, which has shown promising results. However, managing these patients remains challenging.

Due to the difficulties associated with Alpelisib, we were particularly interested in exploring the Akt inhibitor, Capivasertib. We wanted to determine if it would not only be effective across PI3 kinase mutations but also offer a treatment option with less toxicity. Excitingly, Capivasertib improved progression-free survival in patients with alterations in the PI3 kinase pathway, as well as in a small number of patients without any alterations. Although there is an early hint of a survival benefit, it has not yet reached significance. We remain hopeful that this drug, with its improved toxicity profile, including reduced hyperglycemia and rash, will be approved by the USFDA later this year.

Now, let's delve into another area that is revolutionizing our field—antibody-drug conjugates (ADCs). ADCs are incredibly promising and have gained significant attention. These antibodies are designed to target tumor cells with high expression of specific antigens. Interestingly, some of the newer generation ADCs have demonstrated effectiveness even in tumors with low antigen expression. The linker used in ADCs must be stable in plasma to prevent the premature release of the cytotoxic drug carried by the conjugate. The cytotoxic drug itself must be highly potent at low concentrations since only a small amount is administered. Another critical feature of ADCs is their ability to be internalized into breast tissue  upon binding to receptors.

And you can see that in the lower right-hand corner here, the antibody-drug conjugate brings its payload into the cell. 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 breast cancer cells. But also, the newer antibody-drug conjugates, not all but largely, have cytotoxic drugs that are membrane permeable. So, they're not as hydrophobic and they can leak out of the tumor cell and kill neighboring breast cancer cells through this effect called the bystander effect, which may be very important for some ADCs. That's shown in this cartoon here, where you have the death of the cancer cell and leakage of the payload, and then it can target other breast cancer cells. But you also have some linkage even in breast cancer cells that don't die, so it's really important. Here's the membrane in primary old drug, and the bystander effect here. So, what is going on in breast cancer in terms of clinical data? We have two new antibody-drug conjugates that are approved, and a third one with imminent data. These drugs are only approved in the metastatic setting, but there are many trials going on in the early-stage setting and high-risk disease to try and further improve outcomes in patients with these incredibly effective drugs. Trastuzumab deruxtecan and T-DXd are HER2 ADCs remarkably effective in HER2-positive disease, but they work in tumors that have low expression of HER2. We've now coined a new term in the last year, HER2-low, which refers to tumors that are not really HER2-positive and never responded to HER2-targeted therapy.

But they respond to this ADC remarkably well, as I'll show you in a moment. Sassatism is a Trope II ADC. Turns out, Trope2 is expressed on most solid tumors, not just breast cancer, regardless of subtype. That drug is now approved in triple-negative breast cancer, as well as pre-treated hormone receptor-positive metastatic disease. Another Trope2 ADC, data podomab, is in Phase Three trials in both hormone receptor-positive and triple-negative disease, with early data suggesting remarkable efficacy. It's fascinating that these antibody drug conjugates (ADCs), as you can see here, have different antibodies. Some have the same toxin, directs to can, while some have other toxins. The toxins all target topoisomerase, but these three drugs have completely different toxicity profiles. We don't 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 trustizumab, drugs to can, a HER2 biosimilar with a very high drug-to-antibody ratio and a topoisomerase inhibitor payload. The first trial I'll 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. You can see how these curves are separated, and you can't even count the number of zeros. Hazard ratio 0.33, and it also showed a remarkable improvement in overall survival. 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 cdxd tdxd. It has a unique toxicity—nausea is the most common—but it also causes inflammation of the lung, 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 one percent, but definitely patients have died in all studies and outside of the clinical trial setting. This is an area of active work.

This antibody drug conjugate, a 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 an oral tyrosine kinase inhibitor, to catnip, which is also very effective in targeting brain metastases in patients with HER2-positive disease only.

Now, the HER2-low is a 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 yet found that it has any other biological relevance. So, it doesn't predict outcome, it's not prognostic, but it did predict benefit from tdxd, where a study called Destiny bresto4 showed a remarkable improvement in progression-free and overall survival, leading to maybe the only standing ovation for breast cancer in a plenary session in our international meeting ever. The post-pandemic approach means we can really improve outcomes for our patients in HER2-positive disease. We did the Phase 1B trial.

I have a patient who is just coming off therapy now, having been on that treatment for five years and only a year on the prior standard therapy. These agents are remarkable, improving progression-free and overall survival. The incidence of interstitial lung disease, with 0.8 percent mortality, was similar to the previously presented data. We are now investigating the possibility of retreatment for patients who have recovered from pneumonitis, and we will be presenting that data at upcoming meetings. We have also published safety guidelines in ESMO Open, and one guideline is currently in press.

Furthermore, an exploratory analysis was conducted in a small group of patients with triple-negative disease. Despite the limited sample size of only 58 patients, they showed a significant improvement in progression-free and overall survival. This data led to the FDA approving trastuzumab drugs once again for HER2-low disease, regardless of hormone receptor status. This is a significant advancement in the treatment of our patients in the metastatic setting. The trastuzumab ADC showed an improvement in progression-free and overall survival in triple-negative disease. It was the first treatment, other than immunotherapy, that demonstrated improved outcomes. However, it does cause more neutropenia and diarrhea, but does not induce pneumonitis. The reason for the toxin still being a topoisomerase one inhibitor, albeit a different one than directs to, remains unknown.

We also extended the study of sasatuzumab to patients with hormone receptor-positive chemotherapy-resistant disease and recently published data demonstrating an improvement in progression-free and overall survival in this population as well. Our next steps with these exciting drugs involve studying them in early-stage disease and as first-line treatment for metastatic breast cancer. We are also investigating their use in triple-negative disease with and without immunotherapy. Additionally, we are focusing on an important area, studying patients who did not achieve a pathological complete response from neoadjuvant therapy. These drugs are being evaluated as a potential rescue mechanism.

The newer ADC data for protomab directs to can is a fascinating development, and we have incorporated it into the iSpy trial as neoadjuvant therapy. A phase three trial sponsored by AstraZeneca will be conducted to further evaluate its efficacy based on our ongoing success in the iSpy 2 trial with protomab direct.

And the idea that you could replace chemotherapy with antibody-drug conjugates is very exciting. We are studying the use of sequential ADCs, and Laura Hubbard will be running a multicenter trial to investigate this further. Our goal is to prevent toxicity and capitalize on our involvement in trials to improve patient management.

I mentioned that we had used one study and applied the treatment to many patients. I participated in the trials with EverAlignments on the steering committee. Stomatitis was a significant toxicity that negatively impacted patients' quality of life due to the development of mouth sores. My colleagues and I noticed that these mouth sores resembled aphthous ulcers more than the chemo-induced sores caused by high doses of chemotherapy used in procedures such as bone marrow transplant. Additionally, there were distinct pathological differences.

Our oral medicine colleagues have always used topical steroids to treat aphthous ulcers. Based on this knowledge, we used a dexamethasone mouthwash and observed a significant reduction in mouth sores. We approached Novartis and conducted a single-arm trial with approximately 100 patients, demonstrating a marked decrease in the rate of stomatitis. The results of our trial supported the approval of Bolero.

In the Bolero 2 trial, which led to the approval of everolimus, we observed an early onset of stomatitis. However, in our trial, known as the Swiss trial, which included 92 patients receiving everolimus according to guidelines, along with the use of the oral mouthwash, we achieved remarkable results. At eight weeks, there were no instances of stomatitis in the Swiss study, compared to 79 instances in the Bolero 2 trial. Furthermore, we completely eliminated grade three stomatitis and significantly reduced grade two stomatitis from 20 percent to 2 percent.

Based on the findings of our study, the oral steroid mouthwash was added to the label for EverAlignments, and it is now used worldwide. This discovery has revolutionized the use of EverAlignments, and we have successfully applied it as a broad preventive strategy for other agents associated with stomatitis, including data from the Potomab direct-to-can ADC and the I-SPY trial.

We are now using steroid mouthwash to prevent significant mouth sores, and we have achieved remarkable success in doing so. This has led to improved outcomes, bringing biology to the clinic. Targeted agents have rapidly advanced the treatment of early stage disease. We are currently working on extending efficacy through combinations with immunotherapy, as well as managing and identifying toxicity. We have made dramatic improvements in endocrine therapy for hormone receptor-positive, HER2-negative disease, with even more advancements on the horizon. There are numerous new endocrine therapies being studied that can target resistance, although I didn't have time to discuss them in detail. Furthermore, antibody-drug conjugates are an incredibly exciting way to deliver chemotherapy effectively across subtypes, and there are many ongoing trials.

The big question that arises is how we can move faster and better. Laura Essman and Laura Vansfield have developed the I-SPY 2 trial, and now I-SPY 2.2 with our collaborator Joe Chen. Joe Chen is our site PI and has developed an endocrine optimization protocol in the neoadjuvant setting. Michelle Malisco focuses on patient-reported outcomes, while Nola Hilton has done critical work in imaging, which is essential to the study. The study is currently investigating experimental agents upfront as an initial block. If a patient has a great response and shows no disease by MRI imaging and biopsy, they can proceed to surgery. If disease is still present, they move on to Block B, which consists of our best standard therapy and subtype-specific rescue. If there is still no response, they proceed to our end rescue AC. However, this approach will evolve over time as we add new rescue approaches. This individualizes therapy by allowing for escalation or de-escalation before a patient undergoes surgery, which is incredibly exciting. We are closely monitoring safety and patient-reported outcomes.

This treatment with novel agents can be expanded not only to high-risk disease but also to slow-growing hormone receptor-positive disease, where Joe Chen is leading our efforts to study many novel endocrine therapies and targeted agents. This is an important advance led by UCSF.

That is changing the way we think about treatment for breast cancer. As I conclude and open for questions, I am certain that we are a strong community—a village. As a university and a Cancer Center, we have a remarkable staff that helps us manage our patients. Our colleagues in the infusion center and the Cancer Acute Care Center are truly remarkable. They assist in managing acute issues that occur with patients, helping to keep them out of the emergency room and hospital. We wouldn't be anywhere without our courageous patients who trust us and participate in clinical trials, continuing their treatment. We had patients who came in monthly during the pandemic for trials. Our collaborators worldwide play a crucial role. As an academic physician, none of us can be successful without the support of our families. I am fortunate to have a wonderful family. Lastly, I went into breast cancer because I saw a significant need. Of course, there is a big need, but my mother died of breast cancer when I was already a faculty member. She gave me the courage and passion to do this work. To end with a quote from Mark Twain, 'The secret of making progress is to get started.' Thank you. Thank you. I hope that was remarkable and inspiring. Boy, things have changed over the last time. If people have questions, put them in the Q&A, and we will get to some of them. One thing that strikes me is that in the old days, breast cancer was considered a bread and butter tumor for a community oncologist. Has the complexity reached the point where it really needs a super specialist to keep up with all this stuff? It's remarkable how much change we've seen in the last 10 or 15 years. Yeah, it's a great question. I was just talking to a GI colleague at another institution, and she was saying, 'Yeah, I mean, I'm a pancreas doctor.' It's like, 'Okay, you know, there's no more disease-oriented oncologists in academic centers.' But in the community, we've really seen a trend towards more focus on specific cancers—breast cancer, GU cancer, GI cancers. These are the most common cancers we see in the United States. Because treatment is so nuanced and management of toxicity is so critical for success, we really have our world now based on having people focus on a greater understanding and management of specific diseases. And within those diseases, now specific subsets as well. And it seems like, you know, so much of what I learned about this 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 size and lymph nodes. Is that right? Or are you 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. Some obviously the markers I think the key, the really key first step, is to understand the markers. But what's truly fascinating is that we've learned through these immunotherapy studies 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 its ability to suppress your own response to the cancer. So, the more effectively you suppress the immune response, the more cancer burden you have, the cancer does that itself 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 you know, we've learned that that's not enough. All of that isn't sufficient. So, this predictive subtype response that I mentioned, developed by investigators here through the iSpy network, is really important. There are a number of different gene expression signatures that help us further understand the intricacies of biological differences within the subsets. That's particularly important. For example, we now use gene expression tests to help us decide which patients need chemotherapy, especially those with hormone receptor-positive early-stage disease. However, we clearly need to go many steps further. So, if you're wondering about screening issues as well, what do you do when you find a very small tumor with negative lymph nodes but with nasty prognostic markers? How do you approach that today? It's a good question, and there have been many recent changes. I serve on the national Comprehensive Cancer Center Network breast panel on behalf of UCSF, and it's really interesting to see how everyone talks about and how we've been changing over time.

Neoadjuvant therapy, treatment before surgery, started as something we only did for patients with huge cancers. Now, we use it as a way to improve therapy. So, when it comes to these nasty cancers, we keep decreasing the amount of cancer that we consider requiring neoadjuvant therapy. Therefore, we often treat patients with triple-negative disease or HER2-positive breast cancer, even if they have tumors that aren't node positive and are just over a centimeter. It can help us individualize the therapy and the amount of treatment based on the response. For smaller tumors, we still perform surgery first because, as I mentioned, the outcome seems to be better due to the body's better response to the cancer.

Oh, and you know, I didn't mention the term radiation therapy during the talk. There are probably some radiation oncologists listening, and there is an overlap or interaction between radiation therapy and the therapies I discussed. There are significant interactions in the field of radiation therapy, which is also progressing rapidly. So, thank you for asking that question. My colleagues in radiation therapy also specialize based on the disease type, and we've made incredible advances. Firstly, we aim to determine which patients need radiation and which do not. Secondly, we aim to reduce the number of days of radiation treatment. We want to limit both the time patients need to spend on radiation and the amount of radiation they receive. In addition, we've been able to improve the scatter of the radiation field, causing less damage to neighboring normal tissues. This is particularly important in the metastatic setting.

In the past, when patients had what we referred to as oligometastatic disease, with only a single or a few sites of metastases, we used to attempt what people called 'cherry picking.' That means we would go in and remove the lesion that caused significant harm to the patient. However, this approach was morbid. Now, we can perform selective brachy radiotherapy and target specific areas with radiation.

So, we almost never use Big Field radiation now in the metastatic setting, whether we're treating for palliation or to remove a tumor that's a Liga metastatic. We do that for all sites, brain and outside of the brain. These are big advances, right? If people have questions, please put them in. I'll keep going until I see any. Um, the antibody-drug conjugates are fascinating. I couldn't quite tell, maybe you sort of said this: is the antibody 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, trastuzumab itself is a very effective agent, but it's enormously more effective when it's given with chemotherapy. So yes, trastuzumab plays a role in the treatment effect because there's some synergy between the trastuzumab effect, where it changes host immunity, and it also has some cytotoxic effects, as well as the toxin that's delivered. For the other ADCs, we don't know, and trastuzumab itself was not effective in her2-low disease, so it's not doing that there. We don't know if Trope 2 antibodies kill cancer; they didn't seem to work by themselves. So they're a delivery mechanism, but we've seen an intriguing outcome, which is that her2-targeted treatment has this specific finding in our trials where the duration of Disease Control is improved, but overall survival has 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, but there are 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-free survival. So the antibodies have another role rather than just delivery. And then the other aspect of this is that you don't even need to express the target very much for the ADC to work, so that's another intriguing area which is not well understood. Yeah, you've mentioned the prognosis. It's almost bifurcated. Some people, if they're going to recover, do so early. Some people can recur quite late. For the people you're following, I know plenty who are five or ten years out, are they still receiving treatment? And how are you monitoring them? Also, what do you tell them? I mean, you know, 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, HER2-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. Hormone receptor-positive disease has a long natural history.

I tell patients that every year they go without a recurrence, the risk diminishes. So, while on hormone therapy, the treatment duration has been extended to 10 years for patients with the highest risk of recurrence. However, for small tumors, we are uncertain about which patients would benefit. There is currently a lot of interest in CT DNA, which stands for circulating tumor DNA. It can be found in patients with early-stage breast cancer and is correlated with a higher risk of recurrence. However, not all patients experience a recurrence, which creates a dilemma. Changing therapy may increase toxicity, anxiety, and reduce quality of life without providing any benefit. Currently, we don't monitor CT DNA in the early-stage setting, but clinical trials investigating this are crucial. We are also considering metastatic trials where resistance mutations can be identified, enabling targeted treatment. However, this field of study is challenging. Not everyone may be familiar with CT DNA, so it refers to circulating tumor DNA. It's an intriguing concept that has emerged after focusing on circulating tumor cells for a long time. Cell-free or circulating tumor DNA refers to fragments of tumor DNA that circulate freely in the blood. They are not associated with the cell. These fragments have been significant as they allow us to analyze a patient's blood sample instead of performing invasive procedures like liver biopsies. By examining the mutations in the blood, we can identify targets for treatment. Although biopsies still provide important additional information, this advancement has been remarkable. I can simply use my badge to call the medical assistant, who brings a box to collect the blood sample, which is then sent to the lab. This development has given us great hope. We are short on time, but your work is amazing. Thank you for your dedication to caring for patients and helping us navigate this rapidly evolving disease. We truly appreciate it. Thank you so much.

Hope Rugo, MD, FASCO - About The Author, Credentials, and Affiliations

Dr. Hope Rugo specializes in breast cancer research and therapy as a medical oncologist and hematologist. Dr. Rugo, a Clinical Professor of Medicine, joined the Breast Care Center in 1999 after a decade of experience in malignant hematology and bone marrow transplantation for breast cancer and other disorders at UCSF. She entered the field of breast cancer to integrate novel medicines based on an understanding of the biology of cancer with great quality of care into the treatment of breast cancer in women.

Dr. Rugo is the Director of the Breast Oncology Clinical Trials Program and the main investigator of many clinical trials that aim to improve the treatment of early and late-stage breast cancer by combining innovative targeted therapies with standard treatment. In addition, Dr. Rugo is conducting research to measure cognitive function in women undergoing chemotherapy for breast cancer, as well as novel approaches to prevent therapy-related damage. Dr. Rugo has formed agreements with a number of other prominent academic medical institutes for the objective of broadening our patients' access to innovative medicines, such as herbal compounds with an apparent anticancer impact in the laboratory. She is an active member of CALGB, a founder member of the Breast Cancer Research Consortium, and an investigator in the UCSF Breast SPORE (the Bay Area Specialized Program of Research Excellence in Breast Cancer). Dr. Rugo trains medical students and clinicians and frequently delivers local, national, and international presentations on breast cancer treatment-related topics. At UCSF, Dr. Rugo coordinates the Breast Forum, a biweekly evening educational program for breast cancer patients, their families, and friends from the entire bay area.

In 1983, Dr. Rugo received his medical degree from the University of Pennsylvania School of Medicine in medical oncology. At the University of California, San Francisco, she earned a residency in internal medicine and primary care, followed by a fellowship in hematology and oncology. From 1988 to 1990, she was an immunology postdoctoral fellow conducting laboratory research at Stanford University. Dr. Rugo joined the UCSF Division of Hematology and Oncology faculty in 1990. Dr. Rugo has been acknowledged for her proficiency in patient care, medical student education, and physician training. She has received various prizes, including the Bank of America Gianini Foundation Award and an intramural award from the UCSF Clinical Cancer Center Investigator Research Program. In 2006, the Friends of the Breast Care Center honored her for her contributions to breast cancer research.

Breast Cancer Treatment: How is Biology's Integration into the Clinic Transforming Healthcare? Hope Rugo

Hope Rugo, MD, discusses Breast Cancer Treatment: How is Biology's Integration into the Clinic Transforming Healthcare?