A Career Driven by Passion for Providing IO Options for Breast Cancer Patients

What are you learning about when and how to implement immunotherapy in breast cancer? 

We started out with studying immunotherapy in the metastatic setting and understood that the treatment didn't work as well as cancer progressed, because of immune response down-regulation and then development of mechanisms of resistance. Therefore, we started looking into moving treatments as early as possible into the treatment paradigm for high-risk, highly proliferative disease. We’ve been working on the I-SPY2 neoadjuvant regimen – a series of neoadjuvant treatments – to study checkpoint inhibitors in combination with novel agents early in the course of treatment.

We’re also trying to improve the immune response for immunologically cold tumors. We’re actively exploring combining immunotherapy with novel agents that could help to enhance the immune response. The most recent combinations include small molecule targeted agents and antibody-drug conjugates. 

"I was very frustrated by the care options for patients with breast cancer, and the inability to change treatment outcomes or toxicity."

What are your focuses at UCSF right now? 

My interests are novel therapeutics and toxicity identification and management. In novel therapeutics, we’re trying to understand how to best explore these agents. We want to move them into the clinic as quickly as possible and at the same time abandon any drugs where we don’t see a future so that we don’t spend a lot of time treating large numbers of patients with negative results. 

I am very interested in understanding risk factors for both early and late immune toxicity. This would allow us to optimally treat patients who have immune toxicity.  Clearly early identification of immune adverse events is critical, and understanding the impact these events have on disease outcome.

What can you share on understanding and reducing immune toxicity?

I’ll share three different things.  

One: In our metastatic breast cancer trial studying a pembrolizumab-chemotherapy combination, we found that the treatment may be more effective in patients who have some degree of immune toxicity, as an indicator of the host immune response. We presented some data on this at ESMO breast cancer in 2023, and it did appear, in a retrospective subset analysis, that patients who had immune toxicities seemed to have improved progression-free and overall survival. This data would clearly need to be confirmed but is intriguing.

Two: we are interested in understanding which patients are at risk for developing late immune toxicity, in order to recognize who is at risk and how best to identify and treat these events. That's particularly important in the early-stage setting, for patients who have completed their immunotherapy but later turn up with serious or life-threatening toxicities.  

Three: optimal treatment combinations through the lens of toxicity. For example, I presented data from a study (KEYLYNK-009) where patients with metastatic triple-negative breast cancer were treated with an induction regimen consisting of pembrolizumab in combination with chemotherapy, and if they had responding or stable disease, they were randomized to either a maintenance strategy with pembrolizumab and a PARP inhibitor, olaparib, or a continuation of chemotherapy and pembrolizumab. 

"We want to move novel agents into the clinic as quickly as possible and at the same time abandon any drugs where we don’t see a future so that we don’t spend a lot of time treating large numbers of patients with negative results."

What have you learned about chemotherapy combinations versus non-chemotherapy combinations? 

We showed that there was no difference in progression-free or overall survival if you were randomized to the pembrolizumab-olaparib combination versus continuing chemotherapy with pembrolizumab. Patients had a similar progression-free survival and could safely stop chemotherapy and continue a much more tolerable regimen with significantly less toxicity and still have the same duration of disease control. We were not able to evaluate the role of olaparib in this study, although patients with germline BRCA mutations appeared to have better outcome with the pembrolizumab/olaparib combination compared to pembrolizumab/chemotherapy.  Additional work is ongoing to better understand this potential benefit.

We've also been able to show that although there's more overall immune toxicity when  immunotherapy is combined with chemotherapy, after you stop the chemotherapy, you actually have less immune-related events.  And immunotherapy does not increase chemotherapy toxicities.

What novel combinations are you exploring? 

We're very excited about antibody-drug conjugates (ADCs) as a new way to deliver chemotherapy. Our earliest understanding of ADCs was using trastuzumab; it not only delivers the toxin to the cancer cell, but might also impact antibody-dependent cellular cytotoxicity. We've seen now that the impact of ADCs extends beyond HER-2-targeted antibodies and that other antibodies can also have this effect – we have seen improved survival with several classes of ADCs, clearly changing the way the tumor responds to other treatments subsequently as well. There is great interest in combining ADCs with immunotherapy, as the ADCs may enhance the immune response, and therefore potentially can improve the efficacy of immunotherapy in combination.

We know that resistance to antibody-drug conjugates is due to multiple mechanisms. Recent work has shown that resistance may be contributed to by downregulation of the receptor that the antibody targets and mutations that impact efficacy of the payload. Therefore, it may be important to provide treatment early in the course of disease, before these mechanisms of resistance have a chance to develop.

"There is great interest in combining ADCs with immunotherapy, as the ADCs may enhance the immune response, and therefore potentially can improve the efficacy of immunotherapy in combination."

How are you utilizing research in the neoadjuvant space to optimize patient treatment of immunotherapy? 

We want to understand the optimal duration of immunotherapy, and one way to avoid giving more immunotherapy than necessary is to look at the response in the neoadjuvant setting and stop treatment earlier once imaging/biopsy show there is no residual cancer. We will be seeing more neoadjuvant data and more data on trying to individualize treatment to the individual patient's response and then to optimize treatment in the patients who have a poor response to therapy.  We do not know if a checkpoint inhibitor needs to be continued after a pathologic complete response in breast and node in patients with early stage high risk triple negative breast cancer; this question is now being explored in a national trial.

For patients who do not have a pathologic complete response after effective neoadjuvant therapy, we’re looking at combining ADCs along with immunotherapy to improve outcomes. One area of big unmet need in the metastatic setting is understanding the small subset of completely treatment-resistant triple negative breast cancers. There is interest in trying to combine immunotherapy with different targeted agents, such as ADCs, and other promising agents that could enhance the immune response in patients whose tumors are more immunologically cold. 

What drew you to focusing on breast cancer?

Early in my career, I was offered a job at UCSF to work in malignant hematology. While I was working in the bone marrow transplant program and starting stem cell harvesting, my mother's one-centimeter breast cancer came back as metastatic disease in bone. 

During that time, I was very frustrated by the care options for patients with breast cancer, and the inability to change treatment outcomes or toxicity. After my mother died, I was writing a chapter for an oncology book on current medical diagnosis and treatment and I was struck by how we didn’t have the right tools to deal with the cancer my mother died of, which is the most common cancer in women worldwide. 

That really drove me to think about what I was doing and what I wanted to accomplish in my career as an oncologist. Thankfully at the time a position opened in breast oncology at UCSF. That was about 25 years ago, and it was the best career decision I could have made.

What is your advice for young people beginning careers in science? 

One important piece of advice is to find and consult mentors, particularly those who will give you unfettered support not tied to their own success and who can give you direction for your work as you go along in your career. There are so many paths to choose from, and identifying where your passions are and having mentors to help you is critical. 

Another piece of advice relates to the power of collaboration. You don't have to lead every project. As you’re developing your career, you can be very successful developing and caring for sub-studies that support other people’s work. Collaborating within consortia or across institutions is very critical as well. Even collaborating across disciplines within I-SPY has been valuable, and led to fascinating analyses that we wouldn’t have even thought about when we started. The corollary to this is not to be fixated on one area of research that might not be able to move forward – or has met with futility.

Of course it is so important to have a life outside of work, truly a key to success and the pursuit of your passions. 

Do you have any final thoughts to share with our audience? 

Optimal combinations and trial design are such an important area. We think about success being all about the agent, but some agents fail because they’re being studied in the wrong way.

We need to work together, especially with our colleagues in industry, to optimally design studies to minimize our chance of failure. 

Prospectively managing safety – not by excluding a large part of the population but by managing toxicities – is a critical piece of moving drugs forward.

Hope Rugo, MD

Professor, Department of Medicine (Hematology/Oncology); Director, Breast Oncology and Clinical Trials Education; and Medical Director of Cancer Infusion Services

University of California San Francisco (UCSF)

Hope Rugo, MD

Professor, Department of Medicine (Hematology/Oncology); Director, Breast Oncology and Clinical Trials Education; and Medical Director of Cancer Infusion Services
University of California San Francisco (UCSF)

Hope Rugo, MD, is a medical oncologist and hematologist specializing in breast cancer research and treatment. A Clinical Professor of Medicine, Dr Rugo joined the Breast Care Center in 1999 after a decade of experience at UCSF in malignant hematology and bone marrow transplantation for a variety of diseases, including breast cancer. She entered the field of breast cancer in order to incorporate novel therapies based on an understanding of the biology of cancer with excellent quality of care into the treatment of women with breast cancer.Dr Rugo is the Director of the Breast Oncology Clinical Trials Program, and is the principal investigator of multiple clinical trials focusing on combining novel targeted therapeutics with standard treatment to improve the treatment of both early and late stage breast cancer. In addition, Dr Rugo is working on studies to evaluate cognitive function in women receiving chemotherapy for breast cancer, as well as novel ways to reduce toxicity from therapy. Dr Rugo has established collaborations with a number of other large academic medical centers for the purpose of expanding the novel therapies that are available for our patients, including herbal agents that appear to have an antitumor effect in the laboratory. She is an active member of the national cooperative group, CALGB, and is a founding member of the Breast Cancer Research Consortium, as well as serving as an investigator in the UCSF Breast SPORE (the Bay Area Specialized Program of Research Excellence in Breast Cancer). Dr Rugo teaches medical students and physicians, and regularly lectures locally, nationally and internationally on subjects relating to the treatment of breast cancer. At UCSF, Dr Rugo runs the Breast Forum, an open bimonthly evening educational session for breast cancer patients, families and friends from throughout the bay area.Dr Rugo graduated from the University of Pennsylvania School of Medicine in 1983. She completed a residency in internal medicine and primary care followed by a fellowship in hematology and oncology at the University of California San Francisco. She was a post-doctoral fellow in immunology participating in laboratory research at Stanford University from 1988-1990. In 1990, Dr Rugo joined the faculty at UCSF in the Division of Hematology and Oncology. Dr Rugo has been recognized for her excellence in both patient care and in teaching of both medical students and training physicians. She has received several awards including the Bank of America Gianini Foundation Award and a UCSF Clinical Cancer Center Investigator Research Program intra-mural award. In 2006, she was honored for her work in Breast Cancer Research by the Friends of the Breast Care Center.