Author:

Nicolò Morina

Abstract

Breast cancer has an intricate biology, with implications that can easily spread through the organism. This feature represented a real challenge in the past century, and the understanding of tumour mechanisms was such a mountain to climb that it was neglected for a long time. The need for a change in approach, aimed at acquiring essential knowledge that could be channelled into clinical practice, has been met by key initiatives that have developed worldwide since the 1960s. Among them, the International Breast Cancer Study Group has stood out as a beacon for decades, promoting a new vision of the field, focusing on biological issues and patient care. The longevity and important achievements of this foundation have been possible thanks to a group of inspired and committed physicians, bound by a spirit of cooperation and friendship.

Clinical research is a complex and time-consuming process. It must face a multitude of variables and obstacles to achieve results that can really have a positive impact on patient healthcare and quality of life. This is particularly true for oncological research, for which two fundamental ingredients are necessary to make it successful: meaningful scientific questions and collaboration. These factors characterize the long history of the International Breast Cancer Study Group (IBCSG), Swiss-born foundation that has fostered great advances in the treatment of breast cancer through the last four decades. The importance of the mark left by IBCSG in this field also relies in the guidance provided by passionate and wise medical doctors like Aron Goldhirsch, patiently but tenaciously proposing a revolutionary approach for oncological research.

The historical landscape of medical oncology and the birth of IBCSG

The IBCSG originated in the 1970s, due to a concomitance of different factors creating a fertile ground for something new in the medical landscape. Medical oncology had been recognized as a new branch among internal medicine subspecialties in the USA only in 1972, strongly fostered by the American physician Byrl James Kennedy (Kennedy, 1999; Muss, 2005). This event had its sudden consequences also in Europe, where Georges Mathé and Gianni Bonadonna, MDs, promoted the definition of medical oncology specialties in France and Italy, respectively. Therefore, those years were fermenting with a plethora of studies and enthusiastic initiatives with the crucial aim of connecting knowledge and expertise from distant places: an example is given by the foundation of the European Society of Medical Oncology (ESMO) in 1975 (The Asco Post, 2021).

It can be said that these winds of change were the answer to three specific problems that the whole field was facing, reflecting related innate needs. First, a lack of communication, practically translated in a missing sharing of results obtained from clinical trials by the several national cancer institutes all over the world. This led to overlapping or contradictory results, slowing down the entire cognitive process and advancement on cancer therapies and their effectiveness. Second, a matter of healthcare politics, since the outcomes of trials carried out in a specific country could meet regulatory and bureaucratic obstacles in another one. Third and probably most important, a missing focus on the biological mechanisms of cancer, which in some instances had led to an excessive use of chemotherapy drugs with their indiscriminate cytotoxic effects, despite their progressive discovery through the years represented a milestone in the treatment of tumours. This last issue would become one of the strong points advocated by Aron Goldhirsch and his colleagues. But we’ll come back to that.

This complex scenery had a disruptive effect in Switzerland, where medical oncology had established upfront compared to other countries, thanks to the gathering and cooperation of prominent physicians with a common formation in the USA. Notably, among them was Kurt Brunner, MD, who founded the Swiss Group for Clinical Cancer Research (SAKK) in 1965 (The ASCO Post, 2021). This vibrant context laid the foundations for the future IBCSG and a new paradigm in the treatment of breast cancer. Prof. Dr. Beat Thürlimann, coordinator of many clinical trials for IBCSG and president of the foundation council from 2005 to 2008, recalls that period: “Cancer research was on the upswing, on both the agendas of society and politicians, especially since the day USA had declared “war” on cancer (with Richard Nixon in 1971, a/n; Surh, 2021). All Swiss oncologists of the first generation went to America and came back importing the thinking, the science, the care, and the training of American oncologists”. Indeed, they left a significant mark in the field. “Four of them” continues Thürlimann “would be considered the Cardinals of Swiss oncology: Kurt Brunner from Bern, Hans-Jörg Senn from Saint Gallen, Georg Martz from Zurich, and Pierre Alberto from Geneva”. A fifth Cardinal would be soon added to the list, the younger Aron Goldhirsch. It was Kurt Brunner itself, who heard something both interesting and bizarre was happening in Lausanne in the late 1970s: something about an absurd guy from the Amazonas who wanted to invest in breast cancer research. He was right.

The absurd guy was Daniel K. Ludwig, an American businessman who reached an empire of about 200 companies by the 1960s, including a huge project to produce paper pulp in the Amazon basin in 1967 (The New York Times, 1992). A few years later, in 1971, he founded in Lausanne the Ludwig Institute for Cancer Research (LICR), which would become the cradle of the first IBCSG studies. And therein lies the irony, since the oddest thing of this story wasn’t the Amazonian entrepreneur, but his willingness to provide resources for breast cancer clinical trials: “Actually, this was the first solid tumour to be more intensively investigated,” says Thürlimann, “because medical oncology had started with leukaemia studies, while no one dared to touch solid tumours, which were much more resistant”. The issues regarding resistance accompanied the ethical ones related to the usage of chemotherapy in clinical trials, initially as adjuvant treatment after surgery, and then as a strategy to prevent relapse in patients who didn’t show signs of the disease. American surgeon Bernard Fisher was the first following this strategy for the National Surgical Adjuvant Breast and Bowel Project (NSABP) from 1958 and throughout the 1960s and 1970s (The ASCO Post, 2013). “People were very sceptical about giving chemotherapy, and even more about giving it to ‘healthy’ tumour patients” states Thürlimann. In Europe, Hans-Jörg Senn faced similar critics while leading SAKK trials based on Leukeran®, methotrexate and fluorouracil (LMF) combination therapy administered even to lymph node-negative patients, who at the time were considered curable only through surgery (Senn et al., 1984). In the same years, Gianni Bonadonna was working with cyclophosphamide, methotrexate and fluorouracil (CMF), which would become a standard of care for the years to come (Bonadonna et al., 1976). Despite the raised controversies, these studies were groundbreaking and showed also the clear need for big cohorts of patients to get significant results. As Thürlimann reports, “the Swiss oncologists understood right from the beginning that adjuvant breast cancer research needs a lot of patients, as well as sufficient observation time to see a difference in relapses between distinct regimens and treatments. They had to think big to produce robust results in reasonable time frames: only then they would reach the patient helpfully”. This factor was the icing of the cake that led to 1977, and to the meeting that the Ludwig Institute for Cancer Research convened to establish an international collaboration in adjuvant trials for breast cancer (Forbes, Gelber, & Goldhirsch, 1987). Promoted by the Swedish oncologist Jan Stjernsward, The Ludwig (International) Breast Cancer Study Group (LBCSG) took shape, connecting Europe, America and Oceania at once.

The early years of IBCSG

On the front line of this project was Aron Goldhirsch, a young clinician based in Bern who had recently completed his internal medicine formation in Milan, and had just switched to cancer studies, convinced by the oncologist Franco Cavalli, with whom would work and later contribute to the start of the Oncology Institute of Southern Switzerland (IOSI) in Bellinzona (Beishon, 2007; R. D. Gelber et al., 2020). Within the LBCSG, Goldhirsch established a long-term collaboration and friendship with Richard Gelber, an American biostatistician based in Boston, and Alan Coates, an Australian oncologist from Sidney and one of the founders of Breast Cancer Trials Group in 1978 (Breast Cancer Trials, 2023). It was a lucky concurrence, and a game-changing combination: from the Bostonian Dana-Farber Institute, Gelber worked as Statistical Director, providing robustness to data and support in trial design to Goldhirsch and Coates, who were also strong in writing scientific papers. Indeed, the key to their connection was communication: “They communicated continuously” recalls Thürlimann. “They phoned and then e-mailed and whatnot, day and night. This way they would lead the IBCSG as a triumvirate, first informally, and then as an executive committee”.

The first four trials started between 1978 and 1981 under Goldhirsch coordination. They focused on treatment regimens differently combining CMF, the glucocorticoid prednisone, and the oestrogen receptor antagonist tamoxifen, in pre-, peri-, or post-menopausal women with node-positive breast cancer. To get how small the world is, the oestrogen receptor was discovered in 1958 by the biochemist Elwood Jensen, future medical director of LICR and supporter of the IBCSG initiative (Forbes et al., 1987; R. D. Gelber et al., 2020). Another trial on adjuvant perioperative chemotherapy was on the way in 1985, when an unexpected issue occurred. Indeed, the Ludwig institute decided to channel its resources to laboratory cancer research, suddenly discontinuing funding to clinical trials. It could have been an earthquake for the entire project; instead, it decreed the rebirth of IBCSG with a new vigour. The credit for this goes mainly to Carl Magnus Rudenstam, Head of the West Swedish Breast Cancer Study Group in Gothenburg, and Hans-Jörg Senn, who worked at SAKK. Both reassured Goldhirsch and his young colleagues: the group could not simply dissolve like that, and they would have found other means to continue. From that moment, SAKK supported the IBCSG, with Senn acting as treasurer of the group, legally established as a not-for-profit foundation in 1992 (Thürlimann & Glaus, 2023).

Aron Goldhirsch and the IBCSG identity

The trials could then proceed, and they would be more than twenty over the next years, with endocrine therapy as a major common thread. At the same time, a progressive and revolutionary change of approach and perspective towards breast cancer and patients characterized the IBCSG experience, and this is thanks to Aron Goldhirsch, who at this point deserves more than a few words from those who knew him personally. Prof. Dr. Monica Castiglione, coordinator of many IBCSG trials from 1985 and CEO of the group until 2008, collaborated closely with Goldhirsch: “I first knew Aron in Bern, while I was finishing my specialization in internal medicine, asking myself what to do next. I used to meet him in the canteen, and there he proposed that I join medical oncology. It was wonderful to work with him, since he was pouring out ideas from every pore, and became a lifelong friend”. Beat Thürlimann spends important words describing Goldhirsch: “Aron was an institution. He represented not only research, but also medicine and patient care”. Gifted with a superfine mind, he apparently felt no need to sleep much, gaining time to read literature (or answering phone calls from colleagues in the middle of the night). “This made him a walking lexical, coupled with an incredible practical experience due to the many patients he met,” continues Thürlimann. “When he saw a problem, he was immediately looking for the questions and reasons behind it”. And here lays the key to the longevity of IBCSG and the changes it has fostered: this mindset was shared within the group. Goldhirsch was aware of that, summarizing the concept in one sentence: we have the same spirit. Which made everything easier, even international interactions. “It was an exalting experience,” says Castiglione, “We were a group of friends, working really hard and having fun in the process”. Thanks to this spirit, IBCSG became a hotbed of ideas and innovation, basic elements for the above-mentioned change of approach in the field. Indeed, one of the points Goldhirsch cared most about was the biology of cancer. “Throughout the many clinical trials, we were always adding factors to learn more about the tumour: understanding its biological mechanisms was more important than the questions behind the single trial,” confirms Thürlimann, who continues: “Aron insisted on introducing an obligation to preserve the pathological material of all patients participating in IBCSG studies, taking him more than a decade to reach this aim. He recognised the opportunity to make clinical-biological research a standard and a unique source of knowledge on breast cancer; one of the events that kick-started what we now call precision medicine”. This vision tackled the general lack of interest in the study of the disease, to which the simple testing of new drugs and compounds was preferred: something that also Bernard Fisher had already observed in the past (The ASCO Post, 2013).

The relevance of breast cancer biology was accompanied by another fundamental topic, strongly promoted by Goldhirsch, Coates and Gelber: patients’ quality of life. It was clear that the effectiveness of therapies should consider the effects on the wellness of women suffering from the tumour. Dr. Fedro Alessandro Peccatori, based in Milan at Istituto Europeo di Oncologia (IEO) and collaborator of IBCSG for recent studies, underlines that “this patient-centred vision was not a slogan, it came from Aron’s direct experience; this idea found several allies outside the IBCSG, from Franco Cavalli to Umberto Veronesi, Giovanni Paganelli and Roberto Orecchia at IEO”. But how to assess such a subjective parameter as quality of life? The answer was the development of a complex and multi-factorial system consisting of the following features: individual investigations of benefits, adverse events and toxicity of a treatment; comparisons of big cohorts of patients with different therapies or regimens; biostatistical analyses of collected data. This system, called Q-TWiST (quality-adjusted time without symptoms of disease or toxicity), was based on the TWiST observation developed by Kurt Brunner for advanced cancer, and it was the first concrete attempt to put patient care at the centre of medical oncology (Richard D Gelber et al., 1996).

The St. Gallen Consensus Conferences

Issues such as this were the subject of intense discussion in a parallel experience, which arose at the same time as the IBCSG and was closely linked to it: the St. Gallen International Breast Cancer Conference. Initiated by Hans-Jörg Senn, later joined by Goldhirsch, Gelber and Coates, the St. Gallen consensus was held every 2-3 years, gathering breast cancer experts from all over the world. It was a basin of ideas, debates and comparisons, where all the potential controversies in the quest for the optimal solutions and approaches would emerge and be potentially channelled in a constructive dialogue. Indeed, the outcome of the conferences had never been precise guidelines, but recommendations instead, acknowledging the complexity of adjuvant therapies and the differences between distinct healthcare systems (Beishon, 2007; Thürlimann & Glaus, 2023).

The St. Gallen conferences marked the milestones that the IBCSG and clinical breast cancer research experienced over the years, characterized by wrong paths, trial failures, reconsiderations and new attempts. Overall, these process slowly but constantly led to a paradigm shift. As the knowledge on tumour biology increased, principles of therapy and trial design changed. “In the 1970s-1980s, treatments were given according to the menopausal status,” says Thürlimann “with chemotherapy for pre-menopausal patients, and tamoxifen for post-menopausal ones; this because we lacked sufficient knowledge at that time”. Next, once recognized the essential role of oestrogen receptors beyond the menopausal condition, therapies were adjusted according to the risk of cancer recurrence: the higher the risk, the stronger the treatment. But even this approach, despite being so reasonable at first, was not successful as thought, leading to a crucial turnaround in 2007: from a risk-adapted therapy to a personalised one, tailored on biological targets identified via tissue collection as predictive (rather than prognostic) factors; risk of relapse would be considered secondarily (Goldhirsch et al, 2005; Goldhirsch et al, 2006). This new view, together with the call to the de-escalation of treatments fostered from 2010, strongly influenced the subsequent trials.

The main achievements of IBCSG

Throughout this long process, IBCSG gave an important contribution by leading seminal studies. As already mentioned before, the first generation of trials focused on the usage and timing of chemotherapy and endocrine therapies, with various drug combinations in distinct populations of patients, chosen according to their age, menopausal status and presence of a node-positive or -negative breast cancer. Among these, trial IV tested one year of hormonal therapy alone (tamoxifen) in women more than 65 years old, observing an impressive significant reduction in tumour recurrence and mortality over the years. In the 1990s, the group achieved key results with trial VIII, introducing ovarian function suppression (OFS) through a compound named goserelin in pre-menopausal women with node-negative cancer. This study highlighted the enormous benefits related to the treatment, especially when preceded by combined chemotherapy in young women, thus opening a new path for trials focusing on OFS and the inhibition of a key player in the synthesis of oestrogens, the aromatase enzyme, through drugs like exemestane. Two of these were planned in 2002: the SOFT (Suppression of Ovarian Function Trial) and TEXT (Tamoxifen and Exemestane Trial), for pre-menopausal women with endocrine-responsive breast cancer. Both represented an important landmark, since they showed that in addition to tamoxifen, OFS alone or in combination with exemestane cause a significant increase of disease-free and overall survival, despite a higher frequency of adverse events compared to tamoxifen alone (Francis et al., 2018).

Another strand of studies consisted of surgical trials, carried out since 1993. As underlined by Dr. Castiglione, they had a great impact on patients’ quality of life, since they helped to understand when it is possible to avoid or reduce the surgical clearance of axillary lymph nodes.

Between the 1990s and the early 2000s, the IBCSG supported the formation of the Breast International Group (BIG), a consortium of several groups set up to meet the need for more patients to investigate the effectiveness of new breast cancer drugs, like taxanes (docetaxel) and the emerging monoclonal antibodies (trastuzumab). For both, seminal trials started in 1998 and 2002 (Piccart-Gebhart et al., 2005; Sonnenblick et al., 2015). Since the increasing biological knowledge of breast cancer was also causing a fragmentation of the disease, with a subsequent reduction of patient populations, this initiative proved to be of particular importance, with international mutual collaboration as the key to significant results.

Conclusion

In 2021, IBCSG merged with the not-for-profit European Thoracic Oncology Platform (ETOP), giving rise to the ETOP IBCSG Partners Foundation. The group is pursuing relevant studies in the field, like the POSITIVE trial, aiming to investigate if the interruption of endocrine therapy to allow pregnancy leads to higher risks of breast cancer recurrence (Partridge et al., 2023). Still, the conditions to perform solid and useful studies are not favourable. Thürlimann is clear: “As Aron himself said, we are doing research in a hostile environment. There is little support for de-escalation and small trials that can still answer important questions.” This opinion is shared by Castiglione: “The costs for trials are extremely high, thus it is very difficult to maintain the independency of academic studies, also due to the monopolies of pharmaceutical companies.” The open questions are many, and the future of the field is challenging, but Aron Goldhirsch, who passed away in 2020, highlighted one of the keys to face it: giving patients a voice. While enriching the knowledge on breast cancer biology, the care to the wellbeing of women suffering from it should always be the landmark. An identifying trait of IBCSG, which has tried to walk this path with a unique approach, as simple as rare: the same spirit.

Acknowledgements

An important thanks goes to Pr. Dr. Beat Thürlimann, for his availability in terms of time and kindness, and the great contribution to the reconstruction of IBCSG history. Special thanks to Pr. Dr. Monica Castiglione and Dr. Alessandro Fedro Peccatori, for their precious support to the validation and reinforcement of facts.

A final thanks to Dr. Anita Hiltbrunner, Director of the ETOP IBCSG Partners Foundation, for her great willingness to provide the book “International Breast Cancer Study Group: History of Research and Friendship Across Borders”, a useful source of information for the study of the different trials led by the group.

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