Pushing the Boundaries of Personalized Cancer Care

When imagining a champion of change, one can easily point to Laura J. van ’t Veer, PhD, the 2020 Giants of Cancer Care^® award winner in Cancer Diagnostics, as a prime example.

Born and raised in Amsterdam, The Netherlands, van ’t Veer, an only child, had always been drawn to science. She was inspired early on by her biology teacher, who taught his students about the development of animal and human embryos and the identification of genes.

“He taught us about DNA and genes in high school, which was not commonly done in those years,” said van ’t Veer, leader of the Breast Oncology Program and director of Applied Genomics at the UCSF Helen Diller Family Comprehensive Cancer Center.

Although the educational structure in The Netherlands required students to pick a particular track of study at age 18, van ’t Veer said she never felt pressured to pursue biology.

“I also entertained other ideas to study history, but I was fascinated by DNA and development, and I decided I wanted to study biology for that,” she said.

van ’t Veer enrolled in an undergraduate program in biology and molecular biology at the University of Amsterdam after graduating from high school in 1976. In graduate school, she shifted her focus to experimental oncology, during which time the first mutated gene in bladder cancer was discovered. As part of her master’s program, van ’t Veer completed several rotations at The Netherlands Cancer Institute.

“That’s where my interest in cancer research started,” she said.

van ’t Veer began her rotations with an interest in genetics, embryology, and physiology. She did not expect her investigations would lead her to a career in cancer research. She started off studying zebrafish and system-to-nerve innovation, which turned into cancer research, and she “sort of stayed” in the field.

By the mid-1980s, van ’t Veer enrolled in a doctoral program at the University of Leiden, becoming the first PhD student in medicine and oncogene activation and tumorigenesis. Her thesis centered around 1 particular patient with ovarian cancer, whom van ’t Veer remembers vividly.

At the time, genomic research in ovarian cancer was still relatively new, the breadth of which van ’t Veer was only just beginning to understand. As part of the program requirements, van ’t Veer and her patient with ovarian cancer appeared together at a Grand Rounds of Medicine at the university to present van ’t Veer’s findings on oncogene activation and tumorigenesis. The auditorium was filled with doctors in white coats, making both women nervous; neither had ever drawn the attention of so many academics at once.

Unfortunately, a year later the women died of her ovarian cancer despite treatment. Although van ’t Veer kept in touch with the woman’s husband for some time, she knew consolation was not enough. She decided that she needed to do more for patients.

Prior to working at The Netherlands Cancer Institute, van ’t Veer came to the United States for a postdoctoral fellowship at Harvard Medical School Cancer Center and Massachusetts General Hospital in Boston from 1989 to 1991. van ’t Veer said she had always wanted to come to the United States to broaden her worldview. Although the faster pace at which Americans moved was not something she had anticipated, van ’t Veer embraced the opportunity to surround herself with open-minded individuals with shared interests.

“I remember the first time I went to a molecular biology [conference], where there were approximately 500 people. I’d never seen 500 people all working together on molecular biology in cancer. That stimulated my thinking and my experience in many aspects,” she said.

Time at the Netherland Cancer Institute

In 1993, van ’t Veer joined the faculty at The Netherlands Cancer Institute as a molecular biologist, where she built and led the departments of Molecular Pathology and Genetic Counseling, a new extension of the institute. She later became the head of Diagnostic Oncology, overseeing clinical work and associated research. Although molecular diagnostics had begun to surface in lymphoma and leukemia, its application in solid tumors was not yet evident.

By this time, she had developed an interest in studying estrogen receptor functioning, which—coupled with ongoing epidemiology, functional, cell biology, and clinical studies in breast cancer being conducted at the institute—cemented her interest in the field, despite the menial jobs that came along with it.

In order to conduct an experiment, van ’t Veer said she had to clean pipette tips, put them back in the box, and sterilize them. “That might be the thing I didn’t like, but you had to do it, otherwise you couldn’t do an experiment,” she said.

Physicians at The Netherlands Cancer Institute had been screening families for cancer for years, but there was still no way to determine who would inherit an increased risk for the disease. The breakthrough came in the mid-1990s with the discovery of the BRCA gene, prompting van ’t Veer to establish the Hereditary Cancer Clinic in 1994. Now family members of patients with cancer who had inherited the gene could receive proper screening and, if necessary, prophylactic surgeries.

“It opened a whole new opportunity to diagnose patients with a family history of cancer,” van ’t Veer said. “The Netherlands Cancer Institute is a very strong combined clinical and research institute, half clinic and half research as an independent academic institution. They moved quickly into embracing molecular diagnostics, both from a research point of view but also to make it available to patients when it became available.”

To ensure the information was accessible, to investigators van ’t Veer, along with 2 epidemiologists, created the Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON). Now 25 years old, HEBON houses information on more than 40,000 individuals, allowing for longitudinal study of the impact of screening and prophylactic interventions.

Identifying those who were predisposed to cancer was merely the first step. The second was predicting the risk of recurrence in women diagnosed with breast cancer. By 2000, Stephen H. Friend, MD, PhD, cofounder of Rosetta Inpharmatics, had developed microarray technology, allowing investigators to measure the expression levels of large numbers of genes simultaneously.

van ’t Veer and her longtime scientific partner René Bernards, PhD, then connected with Rosetta Inpharmatics. They took Rosetta’s technology to develop the first prognostic and predictive 70-gene signature assay known as MammaPrint.

“MammaPrint got way beyond everything else I did. We never anticipated that it could be used to guide the use of chemotherapy,” she said. “In 2004, René Bernards and I, with support from The Netherlands Cancer Institute, founded the spin-off company Agendia to ensure this new information would become broadly available to breast cancer patients.”

The commercial assay, which is incorporated into treatment guidelines from American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology, combines genomic and clinical risk factors to better analyze a patient’s risk of recurrence. Along with her coprincipal investigators Martine Piccart, MD, PhD, the 2020 Giants of Cancer Care® award winner in Breast Cancer; Emiel Rutgers, MD, PhD; Fatima Cardoso, MD; and the European Organisation of Research and Treatment of Cancer, van ’t Veer evaluated the assay’s validity in MINDACT, the first large-scale clinical trial to incorporate the use of genomics into risk assessment.

At 5 year outcome data demonstrated that 46% of patients with clinically high-risk disease can safely forgo chemotherapy, empowering patients to make more informed treatment decisions. The assay, which is used by tens of thousands of women worldwide, saves approximately 2500 of every 10,000 patients with early breast cancer from undergoing unnecessary chemotherapy.

The 9-year results from the MINDACT trial were presented at the 2020 ASCO Virtual Scientific Program. The updated data further solidified the assay as a valuable tool for risk assessment.

Although van ’t Veer was a preeminent voice at The Netherlands Cancer Institute, she was 1 of just 5 female group leaders among a total of 50. Van ’t Veer says she never had to deal with overt gender inequality, but, she understood how subtle prejudices could be. In order to raise the profiles of women at The Netherlands Cancer Institute, she and the 4 other women met regularly to exchange ideas and opinions, allowing them to bring their voices to the forefront of discussion.

“I don’t necessarily think what men were doing was wrong, but there are different voices to be heard,” van ’t Veer said. “We looked into promoting young female investigators into senior-tracked positions. The group was needed to give women a better position at the institution.”

Unlocking the Secrets of Tumor Biology

y the early 2000s, van ’t Veer had become a fixture at The Netherlands Cancer Institute. But she couldn’t pass up the opportunity to work with Laura J. Esserman, MD, MBA, director of the UCSF Carol Franc Buck Breast Care Center and the 2018 Giant of Cancer Care^® award winner for Cancer Diagnostics, on the I-SPY 2 trial. Investigators in the adaptive neoadjuvant trial sought to identify biomarkers of response to treatment.

In 2010, van ’t Veer returned to the United States as the Biomarker Working Group chair for the I-SPY 2 trial program, heading the trial’s laboratory. In this role, she established the framework that has enabled her and her team to track serial biospecimens and identify biomarkers of response to therapy and outcome. Moreover, with MammaPrint, investigators are able to identify women at a high risk of recurrence and match them to an appropriate treatment arm.

Since then, she and her team have tested more than 17 drugs in approximately 2000 patients.

“Through [I-SPY 2], we have doubled to tripled the response to therapy for women with early breast cancer, where responses translates to a 95% 4-year survival rate,” van ’t Veer said.

The trial, which allows investigators to add and remove new agents to the study without having to halt enrollment or resubmit the protocol for regulatory review, will expedite drug development and help take the guesswork out of treatment decisions. To that end, van ’t Veer is part of a program project grant for I-SPY 2, leading the effort to understand the biology of patients with resistant, progressive, and nonresponsive tumors.

During the initial planning stages for the I-SPY trial program, before van ’t Veer came on board, the FDA requested that investigators use an FDA-approved test to identify patients at high risk of recurrence. MammaPrint was the only such test at the time. The I-SPY program studies new biomarkers on high-definition 44K expression arrays purchased from Agendia to analyze mRNA expression, signaling protein activation, and DNA sequencing.

Esserman and Donald A. Berry, PhD, I-SPY clinical coprincipal investigators, decided that it would be beneficial to try to create an additional risk stratification for patients with high-risk disease, termed High1 and High2. After restratifying these patients, investigators discovered that High2 is more representative of the basal phenotype even if the patient has hormone receptor–positive disease, suggesting that treatment can be tailored not only according to individual risk but also on the basis of response.

On the opposite side of the spectrum is the concept of very low-risk. Despite the work that had been done to differentiate between low- and high-risk cancers, no one had tried to ascertain the true risk of all low-risk cancers.

By this time, Esserman had come to the conclusion that screening had increased the number of indolent cancers that would end up being subjected to overtreatment.

van ’t Veer and Esserman together determined that they could establish a threshold defining very low-risk. In 2017, they published data in JAMA Oncology confirming that patients found to have very low-risk tumor with MammaPrint can experience long-term remission with or without endocrine therapy.

“It’s not that we don’t want to use the standard of care. It’s just that the standard of care is failing a number of women, and we have to do better,” Esserman said. “It’s just incredible to have a colleague with a great intellect and a great heart who is pushing science and her understanding of molecular biology to help us personalize care.”

What's to Come

Having worked to facilitate the introduction of personalized medicine into the treatment landscape, van ’t Veer’s next goal is to integrate personalized risk assessment into the preventive landscape.

Esserman and van ’t Veer are coleading the WISDOM study. The study evaluates the morbidity and cost-effectiveness of annual mammography versus interval risk-based screening. Currently, annual mammography is the standard for women aged 40 years or older.

Investigators plan to recruit 100,000 women aged 40 to 74 years into the 5-year US study.

“We know that not everyone has the same risk. If you establish early on what someone’s risk is, based on known risk factors and genetic factors, then you can diversify the frequency of screening,” van ’t Veer said.

By applying biology to screening, women at very high-risk can access more screening. At the same time, women at very low-risk may be able to forgo screening procedures that can sometimes cause more harm than good.

Although the coronavirus disease 2019 pandemic has forced van ’t Veer to work from home, she strives to make personalized care, be it therapeutic or preventive, a reality for every individual in need of it.

“If you have 10 different choices, you don’t want trial-and-error test treatment. You want to give the right treatment right away. We’re getting there. More treatments and genetic information will help us establish that,” van ’t Veer said. “I want people to have access to the best treatment right away, so that they don’t lose any time in their treatment scheme.”