In Memoriam: José Baselga's Journey in Cancer Medicine

CLINICAL CANCER RESEARCH | OBITUARY

In Memoriam: Jose Baselga’s Journey in Cancer Medicine Rakesh Kumar1,2,3, Gabriel N. Hortobagy4, Joan Albanell5,6,7, Joaquín Arribas8,9, and Larry Norton10

Breast cancer continues to register one of the most common Early Years incidence and deaths among female cancers. However, during the A Catalan by birth, Jose Baselga was born on July 3, 1959 in a family last three decades, breast cancer treatment benefited from a sea-change with long roots in medicine. His grandfather was a rural physician in for specific subtypes. These successes led to increases in the period of Cardona, Spain, and his father an occupational physician in Barcelona. cancer remission, reduced therapeutic resistance, inhibition of drug Jose completed his basic degree in Medicine at the Universitat toxicity, and resulting in almost life-long remission in some cases. Autonoma de Barcelona in 1982. Soon after, he started his residency These gains in prolonging the life of patients with breast cancer are training in Internal Medicine at the Hospital Vall d’Hebron in the largely attributed to targeted therapies and ever-evolving combination same city. During this time, Jose’s desire to excel in oncology made it modalities by the bold effort of basic and clinical scientists and evident that he planned to seek advanced training abroad. One of his practicing oncologists (1–3). The records of these advances in clinical childhood friends and a colleague in medicine residency, Antonio cancer research and combination targeted therapeutics would be Gonzalez Fernandez, remembers Jose, “as a good student among the sketchy in the absence of untiring and transforming scientific effort top ten. However, by far he was the one with a clear plan to advance his of our colleague Dr. Jose Baselga, who died on March 21, 2021 in career in oncology.” Passionate about it, Josedidnothesitatetodrophis Cerdanya, Spain. To illustrate a fulfilling career in cancer medicine and residency in Barcelona to restart at the Kings County Hospital Center in his contributions to clinical cancer research, here we will attempt to Brooklyn, New York City. His partial residency in Spain was an bring out a few, less-known features of Jose’s journey in clinical cancer advantage to Jose among internal medicine residents coming from their research and treatment, and how these advances shaped the field of training in medical school. This advantage, along with his intelligence combination cancer therapeutics with a direct impact on the life of and tireless capacity to work, led to an appointment as a chief resident. patients with breast cancer. We will begin with Jose’s early formative At the time this was significant because Josewasthefirst non-American years and decisive turning point(s) along his expedition in cancer to hold such a position at the Kings County Hospital. medicine and accentuate how Jose maintained a two-way flow of meaningful scientific questions between the laboratory and clinical settings, with a singular motive to improve the treatment of breast – cancer. The Turning Point Memorial-Sloan Kettering Cancer Center Years 1Cancer Biology Program, Rajiv Gandhi Centre for Biotechnology, Thiruva- After completing his residency training in 1989, Jose was admitted nanthapuram, Kerala, India. 2Department of Human and Molecular Genetics, to the Medical Oncology fellowship training program at Memorial- Virginia Commonwealth University School of Medicine, Richmond, Virginia. Sloan Kettering Cancer Center (MSKCC, New York, NY). During his 3Department of Medicine, Hematology-Oncology, Rutgers New Jersey Medical fellowship, Jose immensely benefited from the joint mentorship School, Newark, New Jersey. 4Department of Breast Medical Oncology, The provided by Larry Norton and the late John Mendelsohn, as well as 5 University of Texas MD Anderson Cancer, Houston, Texas. Cancer Research working in the Mendelsohn’s Research Laboratory of Receptor Biol- Program, Hospital del Mar-CIBERONC, Barcelona, Spain. 6Universitat Pompeu Fabra, Barcelona, Spain. 7Clara Campal Comprehensive Cancer Center, Barce- ogy. At that time, the laboratory was intensively pursing the hypothesis lona, Spain. 8Hospital del Mar Medical Research Institute and CIBERONC, that the growth of tumor cells with high epidermal growth factor Barcelona, Spain. 9Vall d’Hebron Institute of Oncology, Barcelona, Spain. receptor (EGFR) with an extracellular autocrine loop could be effec- 10Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, tively inhibited by anti-EGFR–blocking antibodies (1, 4–6). These New York. research questions caught Jose’s attention and imagination, leading to Photo compliments of Memorial Sloan-Kettering Cancer Center, New York, NY. his intense integration in basic science and preclinical research projects – ’ Corresponding Author: Rakesh Kumar, Cancer Biology Program, Rajiv Gandhi with Rakesh Kumar and Hideo Masui, respectively (7 9). Jose s Centre for Biotechnology, Thycaud Post, Poojappura, Thiruvananthapuram training in translational oncology began while he worked with John 695014, India. E-mail: [email protected] Mendelsohn in the laboratory, and Larry Norton in the clinic. Jose — Clin Cancer Res 2021;27:3499–502 recognized two concepts more widely deprecated than appreciated at the time. These concepts became the motivation of much of his doi: 10.1158/1078-0432.CCR-21-1624 groundbreaking work over the next decades. The first concept learned 2021 American Association for Cancer Research. by Jose was an understanding that the molecules responsible for

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growth regulation were more suitable targets for anticancer therapy complete remission and four partial remissions in 45 patients with than the subsequent downstream processes of mitoses. The second was HER2-overexpressing metastatic breast cancer - and average response that recombinant monoclonal antibodies (mAbs) could be useful durations were only a few months, this was a critical publication agents for this purpose. Soon, Jose, along with his mentors, demon- because it demonstrated some activity of mAb as an emerging class of strated superior antitumor activity of EGFR-blocking mAbs and drugs. The pharmacokinetic assays mastered during this trial were doxorubicin in experimental models (8), further catalyzing his deter- important in designing subsequent dose schedules, which formed the mination for several forward-looking clinical trials. Moreover, the basis for further investigation. This seminal publication confirmed that notion of sequential blockade emerged from this work: that simulta- a biomarker could be used to stratify patients for a given study. More neously attacking growth factor receptors (and, later, signal transduc- importantly, the publication provided a pathway for the development tion therefrom) and mitosis itself could be synergistic. This idea, of anti-HER2 therapy in conjunction with antimitotic chemotherapy. motivated by studies of feedback loops and alternative pathways in There was evidence of profound synergy with this combination the laboratory of Neal Rosen at MSKCC (New York, NY), was neither treatment rather than the modest benefit as a single-agent targeted obvious in those days nor popular, but Jose was not of the type to be treatment. In fact, Jose’s collaborative laboratory work documented dismayed. In 1993, he first authored a prescient paper on this topic, the power of combination treatment (21). Simultaneously, he showed showing synergy between doxorubicin and an anti-EGFR mAb (9). that HER2 overexpression was a predictive marker for paclitaxel This work continued in the demonstration in a phase I trial: that sensitivity (22) This, together with the demonstration that HER2- anti-EGFR chimeric antibody cetuximab combined productively directed therapy enhances the effect, was the basis for inclusion of with cisplatin (10). In addition, with his characteristic enthusiasm, paclitaxel in the pivotal trial first-authored by Denis Slamon that put Jose was deeply involved in germinal studies of the taxanes and trastuzumab on the map and established the foundation for its clinical dose-dense sequential therapy, both of which evolved further to applications up to the present day (23). Through these seminal studies, good effect (11–13). Jose became one of the early leaders in the development of trastuzu- At the time that Jose was getting involved in translational oncology, mab, leading to one of the earliest clinical trials of this life-saving the significance of a second member of the EGFR family, the HER2/c- antibody, in combination with cisplatin (24). The concept was enor- Neu/ErbB-2 oncogene was emerging. HER2 was beginning to be at the mously successful and trastuzumab became one of the major con- forefront of a surface oncogene that is upregulated in breast and many tributors to prolonging the lives of patients with HER2-positive other solid tumors (14, 15). One of these studies was from Marc J. Van metastatic breast cancer. More importantly, the combination of tras- de Vijver (14) – who subsequently came to MSKCC on a sabbatical in tuzumab with cytotoxic therapy led to decreased recurrence rates and John Mendelsohn’s laboratory. During this time, Marc J. Van de significantly increased survival rates for patients with nonmetastatic Vijver, along with Rakesh Kumar and John Mendelsohn, defined the HER2-positive disease (25, 26). Jose’s work also contributed to the details of EGFR trafficking and activation by an extracellular autocrine clinical development of pertuzumab, another HER-2–directed mAb, pathway, providing an additional rational for using anti-EGFR– becoming the current standard treatment for HER2-positive breast blocking antibodies to interrupt an autocrine growth stimulatory cancer. The collaboration among Jose, Larry Norton, and John Men- loop (6). As the scientific community was aware of John Mendelsohn’s delsohn represented one of the earliest examples of targeted therapy in inhibitory anti-EGFR studies, a similar approach was attempted for breast oncology and catapulted Jose into a position of prominence as HER2 by many laboratories, even though there was no known HER2 one of the leading translational investigators in breast cancer treat- ligand. This led to the development of growth-inhibitory anti-HER2 ment. A significant outcome of Jose’s work is the notion of sequential mAbs against an extracellular region of HER2 receptor in breast tumor blockade therapies. cells with upregulated HER2 (16, 17). One such antibody, mAb4D5, was developed by Genentech (17) and later humanized as rhuMAb Transforming Oncology at Vall HER2/trastuzumab (Herceptin) to treat patients with breast cancer d’Hebron with HER2 upregulation (18). At the time, the mechanism of action of mAb4D5 was not fully understood. Because of the scientific interests of Jose’s passion for translational cancer research, nurturing excellence the laboratory and informal discussions with Marc J. Van de Vijver, in academic medicine and love for his native country, prompted his Rakesh Kumar, and John Mendelsohn, in collaboration with return to the Vall d’Hebron University Hospital with a vision in mind: H. Michael Shepard from Genentech, demonstrated the effectiveness creating a comprehensive cancer center in his hometown Barcelona. In of mAb4D5 to inhibit the phosphorylation of HER2 on tyrosine 1996, he chaired the Oncology and Hematology Department at Vall residues as well as HER2 downregulation from the cell surface in d’Hebron and subsequently, became the first director of the Vall breast cancer cells with upregulated HER2 (19). As Jose was working d’Hebron Institute of Oncology (VHIO, Barcelona, Spain). The man- with patients at MSKCC’s breast cancer program in the early to mid- date of the institute was to create a center wherein preclinical and 1990s and because Mendelsohn’s laboratory was also studying certain translation sciences are intermingled with oncology practices. To this aspects of HER2 biology in breast tumor cells, it was natural that he was end, Jose quickly recruited Josep Tabernero, the current VHIO interested in the emerging evidence that HER2, not uncommonly director, as well as Joaquin Arribas and Joan Albanell (both also overexpressed in breast cancer, was potentially a therapeutic target as trained at MSKCC, New York, NY), to lay the foundation in basic and well as a prognostic biomarker. Working clinically in the breast cancer translation cancer, respectively, at Vall d’Hebron. As there was no program in the early to mid-1990s and due to Jose’s involvement with precedence of a research laboratory at Vall d’Hebron, the team started anti-EGFR mAbs with Larry Norton and John Mendelsohn, the their research programs from a small empty room at the general concept of blocking cell surface receptor-tyrosine kinases by antire- hospital, publishing the first set of growth factor research manuscripts ceptor mAbs encouraged the young Baselga to explore strategies to in 1998 (27, 28). These early successes were instrumental for the first inhibit HER-2 in patients with breast cancer along with his mentors. major expansion of preclinical and translational research programs In 1996, Jose was the first author of the first phase II trial of single- and positioned the Vall d’Hebron as a preferred site for phase I studies agent trastuzumab (20). While the response rate was modest - one and a hub for international cancer clinical trials, many of which were

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based on Jose’s research studies at MSKCC. Examples of such studies concept of dual anti-HER2 antibody in the absence of chemother- included, the pivotal phase III trial on trastuzumab and paclitaxel in apy for selected patients with HER2-positive metastatic breast HER2-positive advanced breast cancer (23), new cetuximab trials (29), cancer. He was also a leading force in SOLTI, an innovative breast and an International phase I trial of gefitinib (also known as ZD1839; cancer research organization in Spain, with links in France, the refs. 30, 31). Jose was also a pathbreaker in attracting large philan- Netherlands, and Italy, with about 400 members at approximately thropic donations for the center, the first of which was for the 100 research sites. Also noteworthy, was Jose’s extensive collabo- construction and equipment of an oncology research building. At the ration with Breast International Group (BIG) where his vision, national level, he soon became the president of Solid Tumor Inten- energy, and extensive connections contributed substantially to the sification (SOLTI) group and turned it into a leading consortium of development and conduct of multiple clinical trials that affected the international breast cancer research (29), while collaborating with practice of clinical oncology. other European leaders, such as the European Cooperative Trial in Jose’s contributions to cancer medicine were enhanced by his Operable Breast Cancer (ECTO; ref. 32). Over the next very few years, ability to remain connected with all stakeholders. Josewasavery his center became one of the guiding lights of translational research in active member of the major professional societies where he served oncology in Europe. Laboratory research flourished, and the center in several leadership positions: Jose served as the president of the attracted outstanding trainees that today populate many cancer centers European Society of Medical Oncology (ESMO) and the American around the world. The center also focused on multidisciplinary Association for Cancer Research (AACR). His tenure in these approaches to managing malignant disease, which resulted in societies was highly productive and accelerated the incorporation improved clinical outcomes. Jose’s translational research team was of genomic science into modern cancer investigation. In his native enormously prolific, publishing basic and translational observations in Catalunya, Jose founded the Fundaciod ’Estudis i recerca leading peer-reviewed journals in Europe and North America. During Oncologica (FERO). Jose coauthored about 400 peer-reviewed his first ten years in Barcelona, Jose evolved from a very promising research articles and reviews in peer-reviewed journals. In addition, oncologist at MSKCC to an internationally acclaimed leader in cancer he was the founding co-Editor-in-Chief of Cancer Discovery,oneof medicine while remained connected with his mentors, Larry Norton at the flagship journals of the AACR. Jose was also recognized by MSKCC and John Mendelsohn at the University of Texas MD numerous professional associations and institutions. In 1992, he Anderson Cancer Center (MDACC). It is important to note that prior received a Young Investigator Award from the American Society of to Jose’s departure to Chair the Department of Medical Oncology at Clinical Oncology and one year later, he received the prestigious Vall D’Hebron University Hospital in Barcelona in 1996, and even Career Development Award from the same organization. Other after as a collaborator, Jose contributed meaningfully to the overall awards were achieved in 2004 as an elected Member of the Amer- breast cancer clinical research program at MSKCC. ican Society of Clinical Investigation; 2007, the American Italian Cancer Foundation Prize for Scientific Excellence in Medicine; Completing the Cycle to the United 2008, the Rei Jaume Prize in Medical Investigation from the Generalidad Valenciana y la Fundacion Valenciana de Estudios States Avanzados and the Rosenthal Family Foundation Award from the Jose demonstrated his strength to master the art of establishing large American Association for Cancer Research; 2010, the Gold medal oncology programs and taking laboratory findings to the bedside. He from the Queen Sofia Spanish Institute in New York; 2011, the decided to continue the cycle of his international career by returning to Laurea Honoris Causa (honorary doctorate) from the Universitat de the United States. In 2010, he became the Chief of the Division of Valencia (Spain); 2012, the Joseph B. Martin Award from Massa- Hematology and Oncology at the Massachusetts General Hospital in chusetts General Hospital, Boston, MA; in 2014 he became a Boston, MA, and in 2013, he was recruited to his starting point at member of the National Academy of Medicine; 2016, the John MSKCC. This 24-year span now led Jose as Physician-in-Chief and Wayne Clinical Research Lecture Award at the Society of Surgical later, Chief Medical Officer until 2018. In 2019, Jose joined the Oncology,theXXVIIICataloniaInternationalPrize;2017,the multinational pharmaceutical company, AstraZeneca as Global Direc- Lifetime Achievement Award by the Euan Society for Medical tor of Oncology Research. Oncology; and in 2021, the AACR dedicated a Clinical Symposium in his honor during the annual meeting. In addition to science and medicine, Jose loved life and lived Beyond Institutions intensely: he was, along with his wife Sylvia Garriga, an avid and As a key opinion leader, Jose had important advisory roles at several expert skier, and enjoyed travel, outdoor sport activities, and the finer large pharmaceutical companies with concomitant development of aspects of life. His passion for life and transformative capacity was anticancer agents. He also led some of the seminal phase III trials with manifested in everything he touched. Another asset of Jose was his new agents from early phase I, to pivotal phase III trials leading to deep involvement in mentoring students, residents, fellows, and regulatory approvals. His early interest in the HER family eventually younger colleagues, while always making a point about how to pursue extended into the PI3K/AKT/mTOR signaling pathways that he the best science and bring their best version together. He was very codirected with Gabriel Hortobagyi - the definitive clinical trial of generous to share his professional and personal experiences with his everolimus (an mTOR inhibitor), leading to regulatory approval by the colleagues and mentees alike and served as an excellent collaborator European Medicines Agency (EMA) and FDA and incorporation into who loved to work hard with insights about the best way to move the standard of care for breast cancer. Jose had an extensive network of forward in numerous team science projects. In some way, Jose clinical and translational collaborations around the globe. It is worth continued the legacy of his laboratory research mentor, late John mentioning the work that he and Luca Gianni did as outstanding Mendelsohn, in enabling his mentees and younger colleagues to leaders of the Michelangelo Foundation - a group that conducted novel achieve their dreams in cancer medicine. and creative breast cancer clinical trials with targeted agents, such as Besides clinical cancer research, it is important to emphasize Jose’s The ECTO trial. Jose’s involvement in this foundation led to the unremitting commitment toward the excellence in the quality of

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patient care by bringing the most promising laboratory findings to the together clinicians and scientists in their efforts to enhance cancer cure bedside. His legacy will remain alive at the institutions he served, and rates and quality of life. globally by the treatments he developed. Jose was a relentless force in translational research, who brought out the best from people around Acknowledgments ’ you with a human touch and respect for others. Baselga s death has The authors thank Prof. Pranela Rameshwar, Rutgers New Jersey Medical School robbed the world of a great mind, and a man of vision who dedicated (Newark, NJ) for her critical reading of the manuscript. his professional life to the search for better understanding of the cancer problem and whose persistence contributed significantly to bringing Received May 3, 2021; accepted May 6, 2021; published first June 11, 2021.

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3502 Clin Cancer Res; 27(12) June 15, 2021 CLINICAL CANCER RESEARCH

Rakesh Kumar, Gabriel N. Hortobagy, Joan Albanell, et al.

Clin Cancer Res 2021;27:3499-3502.

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