The David A. Karnofsky Memorial Award, ASCO’s highest scientific honor, went this year to Dr. Martine J. Piccart, who is internationally recognized for her unflagging dedication and innovative approaches to the development of drugs and regimens that will truly make a difference in the lives of patients with breast cancer.
CHICAGO-The David A. Karnofsky Memorial Award, ASCO’s highest scientific honor, went this year to Dr. Martine J. Piccart, who is internationally recognized for her unflagging dedication and innovative approaches to the development of drugs and regimens that will truly make a difference in the lives of patients with breast cancer. Dr. Piccart is a professor of oncology at the Universit libre de Bruxelles, director of medicine at the Jules Bordet Institute (Belgium), a member of the Belgian Royal Academy of Medicine, cofounder and chair of the Breast International Group (BIG), president of the European Society for Medical Oncology (ESMO), president-elect of the European Cancer Organisation (ECCO), and a past president of the European Organisation for Research and Treatment of Cancer (EORTC). She has served as the principal investigator or co-principal investigator on numerous landmark trials, including HERA, MINDACT, and ALLTO.
Motivated by her mother’s battle with breast cancer, Dr. Piccart has been actively involved in breast cancer research for the past 30 years. In her Karnofsky Award lecture, entitled “Academic Medical Research Worldwide, Quo Vadis?” she enumerated lessons to be learned from the past several decades of breast cancer research, and outlined her vision for the shape effective research will need to take in the years to come. Tying together the many ideas she set forth was her conviction that academic researchers must play the role of the guardian who ensures that patients’ needs remain the top priority in all research. She noted that, given the current trend of reduction in federal funding of clinical research in the United States, what she had to say would have increasing relevance in this country, as well as in Europe.
Dr. Piccart described the years right before her entry into medicine-the 1960s and 1970s-as the “golden age” of academic research. The time required then to take a protocol from initial concept to the first patient was only 3 to 9 months, and the chief focus of clinical research was on public health. These years were followed by the “silver” and “bronze” ages, which have been characterized by the growth of bureaucracy, the increasing involvement of regulatory bodies, limited or no government involvement (except in the United States), and more “business-oriented” trials. The time required to activate a trial protocol has expanded to 15 to 36 months, and costs have also escalated tremendously-largely due, she said, to excessive and compulsive monitoring.
To counteract these tendencies, Dr. Piccart founded the Breast International Group in 1996. With BIG, she hoped that collaboration among researchers across continents would help speed trial activation and accelerate the development of the novel and effective treatments patients needed and wanted. Initially just active in Europe, BIG soon grew to involve academic research centers from around the world and now numbers 49 member groups. BIG has run some of the most important large breast cancer trials of the past 15 years, including BIG 1-98, HERA, ALLTO, MINDACT, and APHINITY.
Dr. Piccart shared some of the important lessons she and her colleagues have learned from these large trials. With BIG 1-98, the importance of fighting back against the pharmaceutical industry’s preference for one-size-fits-all trials became clear. In this trial, the pharmaceutical company was just interested in a straightforward comparison of the new drug (letrozole [Femara]) vs tamoxifen. The investigators, however, had other interests, including questions about the sequencing of the drugs. Ultimately, the investigators prevailed, and the trial went forward with four arms, including two that involved sequences of the two agents.
In HERA, the lesson learned took the form of a mistake to be avoided in the future: Underfunding of translational research resulted in a very slow and inefficient biomarker discovery process-and consequently in a missed opportunity to identify patients who were resistant to trastuzumab (Herceptin), and those who were cured without trastuzumab.
With regard to neoadjuvant trials, Dr. Piccart noted that there are three assumptions that are commonly made-but that they are not all, or always, valid. The first of these assumptions is that neoadjuvant trials can predict the success of chemotherapeutic agents and endocrine agents. This assumption, she said, has proven largely true, at least with respect to taxanes and aromatase inhibitors. The second assumption-that neoadjuvant trials can predict the success of new targeted agents-has proven sometimes valid (as in the case of trastuzumab) but other times not valid (as in the case of lapatinib [Tykerb] or bevacizumab [Avastin]). However, the third assumption-that neoadjuvant trials can identify clinically useful markers-so far has not been borne out. There have been false-positive signals or no signals at all in biomarker research in neoadjuvant trials. In fact, Dr. Piccart noted that biomarker research to improve the tailoring of anti-HER2 therapy has so far been quite disappointing.
How can the deficiencies in neoadjuvant trials be rectified? Dr. Piccart shared several lessons that BIG researchers have learned over the years. First, she emphasized that optimal trial design requires lengthy discussions involving all parties. Second, safety issues must be adequately addressed. And finally, it must be possible to kill the trial “in utero” if the drug performs poorly.
The research model of the future, Dr. Piccart said, would have to be one of collaboration between academic researchers and the pharmaceutical industry (something that may well come to be the case in the United States, as well as in Europe). In this model, the database would reside at the academic institutions, so that it might continue to live on after the trial’s primary endpoints have been reached. Safety data would be shared with the pharmaceutical company right away. Efficacy data would only be seen by a statistician who does not sit on the trial’s steering committee; once endpoints have been reached, the efficacy data would be transferred to the pharmaceutical company, while continuing to live on at the academic centers.
Dr. Piccart is convinced that an “academia/pharma” hybrid model of this sort can be very successful. Strengths of the model include its tendency to reduce commercial bias and conflicts of interest, reduced costs for the pharmaceutical company, and considerable benefits for patients (full transparency of all results and an increased likelihood of long-term follow-up). However, the model also has vulnerabilities. It can only be successful, she said, if academic researchers are in the driver’s seat and exhibit strong leadership; also essential to its success is a willingness on the part of the pharmaceutical industry to trust the academics.
Dr. Piccart pointed out that there are numerous “burning questions” in the area of breast cancer treatment, and that the pharmaceutical industry is not particularly interested in many of these. It is only with a model in which academic researchers take the lead, she said, that we will have the nondrug and “cheap drug” trials that are badly needed, that the performance of breast cancer drugs in older women will be investigated, that the needs of women in the developing world will be addressed, and that progress will be made in the area of metastatic breast cancer.