A Continuous Race of Biomarker Research and Molecular Strategies

The path toward becoming a pioneer in breast cancer biomarker research began in the mountains for Fabrice André, MD, PhD. After growing up in southern France, André left his family at 11 years old to live in the French Alps. For the next several years, he honed his skills in downhill ski racing while practicing other adrenaline-fueled outdoor sports. He took his talents even further, visiting various countries to further test his abilities in ski racing and mountain biking.

André performed at what he called a “decent level.” His skills earned him the 10th-highest rank for downhill ski racing in France. As much as André embraced the lifestyle surrounding this winter sport, he was content not to climb the ranks any higher. In fact, he says he was fortunate to not be “too good” as a competitive skier. “When you are too good in a sport, you sometimes feel [tempted] to leave your studies,” André said.

Even as André sped down the snow, he harbored a deep interest in biological science. In medical school, he sought to better understand biology, physiology, and diseases through the biological mechanism.

Initially, André wanted to pursue research in hematology. During a ski trip in New Zealand, he asked a close friend to select his specialty on his behalf. His friend then went to Institut Gustave Roussy (Gustave Roussy) in Villejuif, France, where he discovered a single available position for fellows. By the time André had returned, he learned that he was enrolled in the oncology track. His friend insisted that he should pursue this opportunity, even if meant forgoing his original plans to study hematology.

Much like an Alpine trail, André's career could have twisted and veered down several paths. Perhaps there’s a path in which he was no longer “fortunate,” one where he abandoned his studies and ended up becoming the No. 1 downhill skier in all of France. Perhaps there’s a path in which he hadn’t entrusted his friend with the responsibility of his enrollment, leading him to specialize in the hematology field like he initially anticipated.

Whether his time in the mountains was linked to fate or coincidence, these events set everything in motion for André to cement himself as a trailblazer in breast cancer molecular oncology and a 2024 Giant of Cancer Care inductee in translational science.

Moving Through The Oncology Track

André pursued his first oncology fellowship at Gustave Roussy before relocating to The University of Texas MD Anderson Cancer Center in Houston to learn more about translational research. During his time in the United States, he spent a year working as a visiting assistant professor while advancing his knowledge of high-throughput genomic analysis, which was around the time those in the oncology field began to make use of gene expression arrays for research.

Colleagues who accompanied André at MD Anderson included Lajos Pusztai, MD, DPhil, a professor of medicine at Yale University and coleader of genetics, genomics, and epigenetics at Yale Cancer Center in New Haven, Connecticut. Pusztai encouraged André to use high-throughput technologies for diagnostic purposes rather than for research alone. This discussion with Pusztai prompted André to more closely consider the genomic targets one could use to inform treatment decision-making.

“Fabrice was a [postdoctoral fellow] in my lab at MD Anderson in the early 2000s and [has] remained a good friend [since]. I am very proud of his accomplishments,” Pusztai stated in a written comment. “I remember him as a young physician welcoming new ideas coupled with a deep commitment to applying the then-emerging new technologies of genomics to cancer. Fabrice had a healthy skepticism for established orthodoxies, which is an essential quality for innovation and progress, and [it] makes for a great conversation partner.”

André received his MD from the Université Grenoble Alpes in 2002 and his PhD in biotechnology from the University of Paris-Saclay in 2005. In 2010, he created his own research lab at Gustave Roussy. Today, André serves as director of research and as a professor in the Department of Medical Oncology at Gustave Roussy. He also works as a professor of medicine at the University of Paris-Saclay.

Across his career, André has led research efforts in the field of biomarkers and personalized therapies, focusing on discovering biomarkers, developing targeted agents, and implementing personalized care. Over time, he has contributed as a main author or coauthor for more than 200 peer-reviewed papers, including those featured in publications such as The New England Journal of Medicine, Lancet, Nature Medicine, Science, Lancet Oncology, and the Journal of Clinical Oncology.

André is also chairman of the French cooperative biomarker group at UNICANCER and previously served as a member of several scientific committees for international meetings, such as the San Antonio Breast Cancer Symposium and the American Association for Cancer Research. He currently serves as president-elect of the European Society for Medical Oncology (ESMO), and will serve as president in the 2025-2026 term.

These appointments lend themselves to a loaded workweek. Mondays are typically reserved for managerial duties at Gustave Roussy, where he discusses resource division with his colleagues.

On Tuesdays, André devotes half of the day to attending a leadership meeting at his institution. For André, a typical workweek is centered around Wednesdays, which is when he works in the clinic. Thursdays involve a focus on building his institution’s program by interviewing students, colleagues, and young faculty about their careers. Fridays are his research days, where he meets with a team of approximately 70 members to work toward advancements in basic sciences, bioinformatics, biotechnologies, and clinical research. On certain days throughout the month, he is also responsible for traveling and running ESMO-related events and activities.

Each day aligns with a unique responsibility and routine as part of his work. However, there is 1 day of the week that stands above the rest for André. “My favorite day of the week is Saturday, when I bring my daughter to her dance class,” he said. “When we come back, we have a nice lunch with my son and my wife, and we discuss things about life.”

Advancing Biomarker Research

Interestingly, people were ready to “give up” on PI3K as a target, according to André. The resistance mechanism of the PIK3CA mutation in patients with breast cancer toward standard endocrine therapy prompted the necessity of developing alternative treatments that could work around this activated protein. However, the initial wave of PI3K inhibitors appeared to be a “failure,” André said. At this point, the field was redirecting its focus toward other drug classes, such as CDK4 inhibitors.

“The first-generation pan-PI3K and dual-PI3K / mTOR inhibitors have encountered problems in clinical trials, with limited efficacies as a monotherapeutic agent [and] a relatively high rate of [adverse] effects,” wrote the authors of a review published in Acta Pharmacologica Sinica in 2015.1 They added that the objective responses achieved with these first- generation agents had been “modest” when administered as monotherapy.

Novartis came out with alpelisib (Piqray), an orally bioavailable, small-molecule, α-specific PI3K inhibitor designed to specifically target P110α with approximately 50 times as much power as other isoforms.2 According to André, there was initially little willingness to move forward with this candidate following the outcomes reported with the company’s previous pan-class I PI3K inhibitor, CLR457. Findings from a first-in-human, open-label phase 1 study (NCT02189174) showed that treatment with CLR457 conferred “poor tolerability and limited activity” in patients with advanced solid tumors.3

However, following some discussion, André and colleagues bolted through a door that was slowly closing in on PI3K. Efforts would eventually culminate in the phase 3 SOLAR-1 trial (NCT02437318), in which André and coinvestigators assessed alpelisib in combination with fulvestrant (Faslodex) for patients with PIK3CA-mutated, hormone receptor–positive, HER2-negative advanced breast cancer.

André emphasized collaboration among his team as a key component of success for SOLAR-1. “We could see very quickly in the trial that there was some hyperglycemia, and we had to adjust our strategy regarding this. Very quickly, we called some other investigators [and told them], ‘You have to be careful,’” André said. “We made some adjustments to finally have the trial [end up] positive.”

In a cohort of 341 patients with confirmed PIK3CA mutations, treatment with alpelisib/fulvestrant yielded a median progression-free survival of 11.0 months (95% CI, 7.5-14.5) vs 5.7 months (95% CI, 3.7-7.4) with placebo/fulvestrant (HR, 0.65; 95% CI, 0.50-0.85; P < .001).2 Additionally, combining alpelisib with fulvestrant elicited an objective response rate improvement compared with placebo/ fulvestrant among those with PIK3CA-mutated disease (26.6% vs 12.8%).

Some enduring impacts testify to SOLAR-1’s legacy. In May 2019, the FDA approved alpelisib plus fulves- trant for postmenopausal patients with hormone receptor–positive, HER2-negative, PIK3CA-mutated advanced or metastatic breast cancer following progression with an endocrine-based regimen based on data from SOLAR-1.4 Even today, there are various novel PI3K inhibitors in breast cancer, such as inavolisib (GDC-0077), coming down the pipe- line—the development of which may not have been possible if not for the SOLAR-1 results. If there was no SOLAR-1, André said, the PI3K field would not have expanded.

Based on the conclusion of SOLAR-1, André under- scored a few key takeaways. “First, going to confer- ences and discussing with colleagues is crucial. This is where everything starts,” he said. “Second, good pharmacology in oncology is key, because most of the targets we are hitting also exist on normal cells. Monitoring the trial is [also] very important.”

Other noteworthy trials André has been involved with include the observational SAFIR01/UNICANCER trial (NCT01414933) and the phase 2 SAFIR02- Breast trial (NCT02299999). The results of these studies demonstrated that the use of next-generation sequencing (NGS) to identify abnormalities could improve outcomes of those with breast cancer.

Specifically, reports from the SAFIR01 trial, which André and colleagues published in Lancet Oncology in 2014, showed the feasibility of running multigene sequencing and copy number analysis to enable medi- cine personalization for metastatic breast cancer.5 In SAFIR02-Breast, findings published in Nature in 2022 highlighted evidence that the use of genomics to allocate treatment could provide a benefit to this patient population.6

This research also elucidated some of the genes that may be involved in cancers developing resistance to current treatments, including RB1 mutations augmenting resistance to endo- crine therapy. Additionally, André and colleagues noted that apolipoprotein B mRNA editing catalytic polypeptide-like enzymes may also be involved in diseases becoming resistant to breast cancer treatment. Genomically characterizing disease metastasis also highlighted the amplification of the gene code for PD-L1 in a subset of patients with breast cancer who could derive higher benefits from anti–PD-1 agents.

“The [SAFIR02-Breast] trial was supported by philanthropy. It showed how it’s important to donate for cancer [research]. In this case, it was only the donors who made this trial positive,” André said. “The results of this trial are used in daily practice because we [now] use NGS in our daily practice.... In most countries across the world, it’s the trial that provided some evidence about whether we should use [NGS], [as well as] how to use it.”

Applying and Sharing Knowledge With Future Researchers

Across his career, there has been one specific patient case that has stuck with André more than others. Here, he had the opportunity to apply his genetic and molecular research to make a tangible impact on his patient’s life.

A patient with breast cancer presented with hard-to-treat disease. Following a colleague’s recommendation, André used whole-genome copy number analysis to identify a potential therapeutic target. The analysis revealed that this patient had very high FGFR1 amplification, which André described as rare in breast cancer. With his colleagues, André collaborated to determine a suitable treatment course for this patient. They arranged a trip for this patient to Amsterdam in the Netherlands around 2008 to help her receive access to an FGFR inhibitor. She ultimately responded to therapy, and treatment yielded tumor shrinkage.

“[Treating] this patient was the starting point of the program of using genomic analysis for metastatic breast cancer. [It] was also an example of [applying] this new medicine that is based on under- standing the biology of the disease to better treat the patient,” André said. “She was the first patient [in whom] we used high-throughput molecular tools to under- stand the disease and then give treatment according to what we understood.”

Today, applying the findings from his molecular-based studies to help optimize patient care is just one facet of André’s work. As a professor of medicine, he looks to share his understanding of biomarkers and genomic analysis with a new generation of researchers. Handling the responsibility that accom- panies one’s involvement in education comes with time, he says. As he adapted to this leadership posi- tion, he realized that the growth and sustainability of his institution, as well as the future of patient care, were dependent on his ability to train the next wave of scientists and oncologists. At Gustave Roussy, André oversees the work of approximately 20 young colleagues. In addition to explaining the material to his students, he aims to reassure them and instill confidence in their research abilities.

“In terms of science, the young generation knows better than us. There is now artificial intelligence and new tools [available]. But myself? I’m not educated for that,” André said. “But we can help them navigate the complexity of their career development and reas- sure them that the institution is supportive.”

Additionally, André said that aspiring oncologists should remember the level of impact their work could have, as something like a positive phase 3 trial can make a difference for millions of people each year. “Because we are in a field where people are usually modest, they don’t step back to realize that anything they do could have a huge worldwide impact,” André said. “This is something that people, [especially] when they are young, need to realize.”

References

1. Wang X, Ding J, Meng LH. PI3K isoform-selective inhibitors: next-generation targeted cancer therapies. Acta Pharmacol Sin. 2015;36(10):1170-1776. doi:10.1038/aps.2015.71

2. André F, Ciruelos E, Rubovszky G, et al. Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer. N Engl J Med. 2019;380(20):1929-1940. doi:10.1056/NEJMoa1813904

3. Harding JJ, Bauer TM, Tan DSW, et al. Characterization and phase I study of CLR457, an orally bioavailable pan-class I PI3-kinase inhibitor. Invest New Drugs. 2019;37(2):271-281. doi:10.1007/s10637-018-0627-4

4. FDA approves alpelisib for metastatic breast cancer. FDA. May 24, 2019. Updated May 28, 2019. Accessed August 15, 2024. https:// tinyurl.com/2rc3btwc

5. André F, Bachelot T, Commo F, et al. Comparative genomic hybridisation array and DNA sequencing to direct treatment of metastatic breast cancer: a multicentre, prospective trial (SAFIR01/ UNICANCER). Lancet Oncol. 2014;15(3):267-274. doi:10.1016/ S1470-2045(13)70611-9

6. André F, Filleron T, Kamal M, et al. Genomics to select treatment for patients with metastatic breast cancer. Nature. 2022;610:343-348. doi:10.1038/s41586-022-05068-3