Laura Esserman, MD, director of the Carol Franc Buck Breast Care Center at the University of California, San Francisco (UCSF) and Professor of Surgery and Radiology, did not plan to be a disrupter when she started her career as a breast cancer surgeon. But for more than three decades, she has pushed aggressively to change the treatment paradigm for patients with breast cancer, guided by the principle that medicine can do more to personalize their care.
In the early 1990s, Esserman pioneered UCSF’s integrated, holistic approach to treatment. She then designed the ground-breaking I-SPY (Investigation of Serial studies to Predict Your Therapeutic Response with Imaging and Molecular AnaLysis) adaptive clinical trials. These studies enabled faster adoption of more nuanced treatment approaches based on a better understanding of who is at risk of developing the disease.
Most recently, Esserman has helmed the ambitious WISDOM (Women Informed to Screen Depending on Measures of Risk) trial. As the principal investigator, she is testing a personalized approach to breast cancer screening versus annual mammography. Along the way, she created opportunities to learn from experience, question current thinking, and adopt new technologies and learnings. Her curiosity and relentless pursuit of improvement has shaped clinical research and treatments for other cancers and diseases as well.
Esserman joined the UCSF faculty in 1993 at the end of the era of unilaterally treating women with breast cancer with radical mastectomies followed by systemic chemotherapy. “I wondered, as an advocate for patients, is that the best we can aspire to?” Esserman recalled.
As a surgeon, Esserman was in an especially commanding position to question the status quo and was highly persuasive at an organizational level. The integrated approach she advocated for at UCSF, including placing in one location all specialties involved in breast care—ob-gyns, oncologists, palliative care specialists, rehabilitation experts—facilitated shared insights into treatment that otherwise could not have occurred.
I-SPY’s Innovative Approach to Testing New Norms for Breast Cancer Treatment
In the 1990s and early 2000s, breast cancer was at the forefront of important milestones in scientists’ understanding of the role of genetics in oncology, and many experts were questioning the effectiveness of a one-size-fits-all approach to treatment.
The idea for the I-SPY trials came about to change that thinking and make innovative and more personalized treatments available to patients faster.
Esserman sought to create a protocol that would evolve as knowledge of treatments shifted, building on new types of endpoints and collaborations. The first I-SPY trial (initially conducted at six sites, now there are dozens) launched in 2004, specifically enrolling women with fast-growing tumors at high risk of recurrence. The trial used then-new gene expression technologies to profile tumors in real time and identify women most likely to benefit from early interventions with chemotherapy.
Working with long-time collaborator Nola Hylton, PhD, Esserman integrated serial MRI imaging (brand new at that time) and biomarker collection during neoadjuvant (first before surgery) standard treatments—ultimately showing that all tumors were not the same and did not respond the same. In doing this, they learned that those whose tumors went away by the time of surgery had excellent outcomes, regardless of their tumor type.
Starting in 2010, these patients were referred to the newly launched I-SPY 2, to test the effectiveness of neoadjuvant therapies, which patients receive early in their disease process. The treatments consisted of standard chemotherapy, combined with new drugs, given as part of individualized regimens that could be adjusted quickly, depending on frequent evaluation of a patient’s responses. Responders would be stratified based on standard biomarkers, plus new molecular markers and a set of exploratory markers. For example, if investigators found particular subsets of patients had greater efficacy with a drug, it would be more likely to be given to the next participant with that profile. subtype. Without these new tools, traditional trial designs would have taken decades to execute what I-SPY did in months.
Few people in the oncology world expected the I-SPY trials to succeed, so the heresy of testing multiple drugs from different companies in the same trial didn’t raise questions, Esserman says. Because champions at the National Cancer Institute, FDA and private philanthropy worked collaboratively on the design, the FDA reviewers accepted the format. The same was true for the trial sites.
“The secret sauce was to partner [early] with regulatory authorities, advocates, investigators, and drug developers”, said Esserman, adding as an example, “We held a meeting with all of the IRB [institutional review board] chairs to have them work on the consent [forms for patients]--so that they accepted the trial, even though it was very different.”
Over time, as multiple publications based on I-SPY 2 trials emerged, the medical world grew more comfortable with the platform trial concept. By 2021, investigators had put 23 therapeutic combinations through I-SPY 2 trials, of which 10 succeeded in improving clinical outcomes.
Beyond I-SPY, Reforming DCIS Treatment and Mammography Screening
Esserman’s vision of better care of breast cancer patients includes advocating for some highly controversial approaches to preventing over-treatment, such as active surveillance for ductal carcinoma in situ (DCIS), the earliest form of breast cancer, which is noninvasive. Thanks to more robust screening, both DCIS and invasive breast cancer rates are rising, but DCIS, like other forms of breast cancer, is heterogeneous, and many cases do not progress and, therefore, do not need aggressive treatment, Esserman believes. To confirm her hypothesis, the DCIS RECAST Study (DCIS Recast: Reevaluating Conditions for Active Surveillance Suitability as Treatment) recently began under her leadership to test active surveillance (with serial MRI imaging) and estrogen therapies as preventive alternatives to standard of care, which revolves around surgery and radiation.
Perhaps Esserman’s most high-profile project these days is her effort to rethink the current age-related paradigm for annual mammography screening. The ambitious and controversial WISDOM study, which launched in 2016 with the goal of enrolling 100,000 women, is testing the premise that screening regimens should be based on individual women’s risk profiles, which can be accurately characterized using a combination of diagnostic technologies. This contradicts widely accepted standards relating frequency of mammography to age, based on data from clinical trials that Esserman argues are outdated. Readouts of WISDOM data will start in 2025.
Esserman founded WISDOM’s lead organizer, the Athena Breast Health Network, and received funding for it from the US government and private sources. Current screening protocols cost the healthcare system well over $10 billion-a-year, representing a huge burden for patients and payers without resulting in a big difference in mortality. Part of the problem, she said, is that everyone is screened the same, as if they have the same risk for the same type of cancer.
Esserman said: “We can do a better job of predicting who is at risk of fast- and slow-growing tumors--so we should use risk assessment to guide frequency and type of screening as well as preventive interventions. And we should go one step further. Why not think about women’s health more holistically and rethink how we design hormonal interventions through the course of a woman’s life to make them risk-reducing for breast cancer?”
And she continues to be a leader in applying the I-SPY platform to address medical gaps outside of breast cancer. “I’ve built teams who are focused on things that patients care about, and that is what we went into medicine for,” she explained. “I’m a change agent and that is the role I have chosen to play.”