Author:

Tiziana Moriconi

Abstract

The advancements in medical treatment for breast cancer over the past century have been enormous. For instance, we can consider the significant progress made from the earliest forms of endocrine therapy, such as ovarian ablation, first described in 1896, to surgical adrenalectomy and hypophysectomy, which were performed in the mid-20th century. However, the more recent history of advanced breast cancer (ABC) is not as filled with success as the history of early-stage breast cancer. Since the 80s, the hope of reducing recurrence rates through new molecules and the stigma associated with metastatic breast cancer, where it was challenging to see an increase in overall survival, led to a concentration of investments in adjuvant therapies for early-stage settings. This left a significant portion of patients behind, perpetuating a vicious cycle. In this article, we briefly review the scientific advancements from the 1960s to the 1990s, and then delve into the events of the first two decades of the 2000s, which saw the birth of a cultural movement to improve the treatment of ABC. Fatima Cardoso, MD, one of the key figures in that revolution, guides us through the reconstruction of those events.

Introduction

Historically, breast cancer has always been the most frequent cancer in women worldwide and one of the leading causes of cancer-related death in women, primarily due to complications from advanced breast cancer. Advanced breast cancer, as defined by the ABC Guidelines, incorporates inoperable locally advanced and metastatic (mBC) or stage IV breast cancer (when the cancer has spread from the breast to other organs in the body), and it is considered incurable. It is currently estimated that 5-10% of patients are diagnosed at the metastatic stage of the disease, in developed countries - 50-80% in developing countries - and that approximately 30% of early breast cancer (eBC) patients may recur with mBC even if treated with the optimal available therapies (Cardoso et al., 2018; O’Shaughnessy, 2005; Unger-Saldana, 2014). Since the birth of medical oncology, mortality from breast cancer has remarkably reduced, but until very recently, these advances have almost exclusively concerned early-stage disease (Caswell-Jin JL et al., 2024). Our aim is to explore how advanced breast cancer has been treated from the earliest available medical therapies to recent years in the 21st century and to answer some questions: when, how, and why did the conception and treatment of the advanced disease begin to change? Who are the protagonists of this change in Europe?

The First Molecules That Could Slow Progression Of The Disease (1960-1980)

The beginning of this story coincides with the development of the first chemotherapy drugs and early endocrine therapies (discussed in other articles on Oncopedia, referenced as: Fricker, 2023; Monfardini, 2024). In both cases, Europe played a leading role: in chemotherapy, through the studies of Gianni Bonadonna's group in Italy, and in endocrine therapies, with studies conducted especially by British researchers.

We are in the midst of the 1960s in Italy: few agents are used (mainly cyclophosphamide, vinblastine, procarbazine) in patients with advanced tumours, and there is still much scepticism about the efficacy of cancer chemotherapy. The first turning point occurs in 1968, when Gianni Bonadonna, then dealing with patients with advanced-stage neoplasms at the 'Reparto C' of the Istituto Tumori in Milan (INT), receives the first vials of a new drug to initiate Phase I-II clinical trials. The new drug was adriamycin, developed by the chemist Federico Arcamone, and it demonstrated the ability to induce regression in several neoplastic diseases, including breast cancer (Monfardini, Balducci, 2021). Adriamycin (doxorubicin) marked the beginning of a new approach to the medical treatment of tumours and remains a cornerstone treatment to this day: it was approved for metastatic breast cancer in 1974 in the USA and ushered in the era of studies on anthracyclines, which have improved survival for mBC, although not greatly (survival is here understood in terms of duration of life instead of survival rate). The same goes for other chemotherapy agents developed during those years such as vinorelbine, created by the pharmacist Pierre Potier in France, where it was approved for metastatic breast cancer in 1989 (Pavlidis, 2024).

Another turning point was the development of tamoxifen, the first hormone therapy approved for mBC, which arrived around the same time as adriamycin. It was the early 1970s, still in Europe but on the other side of the English Channel. The story is particularly fascinating, but it is not our aim to recount it. We simply remember some key figures: Arthur Walpole, then head of the fertility regulation program at the pharmaceuticals division of chemical company ICI, in Alderley Park (which became first Zeneca, and then AstraZeneca in the 1990s); Dora Richardson, the chemist who synthesised tamoxifen; and Moira Cole, who conducted the first breast cancer trial at the Christie Hospital on 46 postmenopausal women with mBC. The important aspect is that tamoxifen introduced into oncology the concept of personalising treatment according to biological markers: in this case, the expression of oestrogen receptors. Tamoxifen was initially approved in 1973 in the UK (under the name Nolvadex) for palliative treatment in postmenopausal women with mBC, and in 1977 by the FDA in the USA; it proved to be efficacious in about half of the cases of mBC and improved survival, although in a limited way (V. Craig Jordan, 2021; Fricker, 2023). During those years, research was underway in Switzerland, the United Kingdom, and the USA to identify other endocrine agents capable of inhibiting aromatase, the enzyme that catalyses the final phase of oestrogen biosynthesis. The goal was to reduce oestrogen levels in postmenopausal women with advanced breast cancer. The first selective aromatase inhibitor (AI) available for the treatment of breast cancer in the UK was formestane, introduced in the 1980s. This research subsequently led to the development of a new generation of highly potent AIs with greater specificity by three companies: anastrozole from AstraZeneca in the United Kingdom, letrozole from Novartis in Switzerland, and exemestane from Pfizer in the United States (Fricker, 2023), all approved in the second half of the 1990s.

Despite these advances, it was becoming increasingly clear that slowing disease progression was not sufficient in the advanced setting. Michael Baum, a British surgical oncologist at University Hospital in Cardiff, came to this realisation quite early. In the mid-1970s, Baum was the first to compare chemotherapy to endocrine treatment in women with advanced breast cancer, also evaluating quality of life. He found that “the length of survival was the same for tamoxifen and chemotherapy, but the quality of life was much better with tamoxifen”. Nevertheless, Baum believed that “there was a greater opportunity to make a difference in early breast cancer” (Fricker, 2023), and this same hope was also guiding trials on chemotherapy as adjuvant therapy.

The Big Difference Between eBC And mBC

According to Fatima Cardoso, Medical Oncologist, Director of the Breast Unit at the Champalimaud Clinical Centre and President of the Advanced Breast Cancer Global Alliance, in Lisbon, Portugal, from this point onwards, retracing the history of ABC as one would do for eBC is much more difficult, for three main reasons:

1. The research environment used the metastatic setting almost exclusively to gain drug approval and quickly move to the early setting;
2. Almost all trials in ABC were pharma-led and usually small, including phase III trials. They didn't have the proper endpoints - initially focused on response rate, which is a weak endpoint, instead of more long-term endpoints such as Progression-free survival (PFS) and Overall Survival (OS) - and didn't answer many clinically relevant questions. There was—and still is—very little academic research in the metastatic setting;
3. People involved in drug development were also involved in international trials. We did have important investigators in Europe, but the leading ones were almost always in the USA. This also makes it difficult to identify the European physician-scientists who marked the route.

Over time, several independent trials have been conducted by the EORTC (European Organisation for Research and Treatment of Cancer), founded in 1962 as GECA (Groupe Européan de Chimiothéarapie Anticancéreuse). Within the EORTC, the trials were initially conducted by the Breast Cancer Group (BCG), and since 1996 by the Breast International Group (BIG), a global network founded by Martine Piccart (former EORTC President and BCG Chair) and Aron Goldhirsch (Cufer et al., 2012). Unlike the United States, however, Europe lacks a centralised funding agency, apart from the European Commission, which issues few calls for proposals and often does not fund clinical trials. Additionally, national agencies typically do not fund international projects (Cardoso, 2009). This accentuates a significant difference between early and advanced breast cancer, as Cardoso emphasises: “In the early setting, very large trials run by cooperative groups can be found; conversely, it remains challenging to find trials in the metastatic setting that are not led by pharmaceutical companies, even today”.

Survivorship Improves For The Very First Time (1990-2000)

To see a significant increase in the survival of women with mBC, we have to wait for the development of trastuzumab (brand name Herceptin), a humanised murine monoclonal antibody. This drug, the second in its class overall and the first for breast cancer, was approved in September 1998 in the USA and in August 2000 in Europe. The development of trastuzumab is an extraordinary American story that began in 1979, when Robert Weinberg, PhD (then an assistant professor at the Massachusetts Institute of Technology), identified the neu gene (later known as ERBB2), which is involved in multiple cancer pathways (Bazell, 1998). At that time, there was great excitement in the fields of molecular biology and genetics: just three years earlier, Michael Bishop and Harold Varmus had discovered that genes within our own bodies can trigger cancer, forever changing the world of cancer biology (“the cellular origin of retroviral oncogenes'' for which they received the Nobel Prize in Physiology or Medicine in 1989) (Sawyers, 2019). It took five years from the discovery of the neu oncogene to the identification of the protein produced by that gene, HER-2, and credit for this goes to German scientist Alex Ullrich, who was working at Genentech, a biotechnology firm in San Francisco (Daniel F. Hayes, 2019). Ullrich played a leading role, and together with Dennis Slamon, a practising oncologist at UCLA's Jonsson Cancer Center, published their first results in Science in 1987: cancers overexpressing HER-2 are more likely to recur and spread more quickly (Slamon et al., 1987). The road to the development of trastuzumab was still long, full of mistakes, obstacles, and strokes of luck. But, eventually, Ullrich, Slamon, and American biologist Michael Shepard (also at Genentech) invented this groundbreaking targeted therapy. As reported by Genentech (1998) in the press release announcing FDA approval, “in 1992, the Herceptin antibody, combined with chemotherapy, was given to the first trial group of 15 women, all considered terminally ill. By 1996, 900 women were involved in Phase III clinical trials”. “That was the first trial to show a significant improvement in survival: five months benefit in survival, which at the time was unseen with the available treatments”, Cardoso comments.

A Lot of Questions Go Unanswered

So, first came trastuzumab, then pertuzumab, another monoclonal antibody, and then T-DM1 (ado-trastuzumab emtansine), an antibody–drug conjugate where the HER2-targeted antibody trastuzumab is chemically linked to the cytotoxin emtansine (also called DM-1). They all quickly transitioned to the early setting, leaving a plethora of unanswered questions in the metastatic setting, as highlighted by Cardoso. For instance: is it beneficial to continue trastuzumab beyond progression? “This was observed in clinical practice - she says - just changing the partner drug: We initiated treatment with trastuzumab and a chemotherapy drug, and later modified the chemotherapy regimen while continuing trastuzumab. We noticed an important difference in patient survival and quality of life, but when we tried to prove the efficacy of continuing trastuzumab in randomised trials, we failed because recruitment was slow in both the USA and Europe. I think nobody wanted to randomise the patients because we could see in clinical practice that, once you stop blocking the HER-2 pathway, the tumour progresses faster, and death occurs much sooner”. The only trial presented was that of the German Breast Group (GBG, founded in 2003), a very important and independent cooperative group in Europe, but it was not able to show an overall survival benefit because it was stopped early and did not meet the statistical endpoint (von Minckwitz et al.). Consequently, regulatory agencies did not - and still do not - approve continuing trastuzumab beyond progression in many countries around the world, “which has terrible consequences for patients, especially in countries where availability of newer and expensive anti-HER-2 agents is very limited - Cardoso complaints - Another unanswered question for many years concerned the best trastuzumab regimen: every three weeks or weekly? Should we use a higher dose at the beginning or not? It took a long time to understand how to best use this drug in the metastatic setting. Similar problems have also affected chemotherapy regimens”.

The Great Stigma Revealed: First Steps Toward Change (2000-2013)

A single statistic highlights the situation: from 2000 to 2013, only 7% of the 15 billion dollars invested in breast cancer research by government and nonprofit funders in North America and the United Kingdom went to MBC-focused research (MBC Alliance Report, 2014). “They simply did not want to invest money in the metastatic setting - Cardoso says - It has been very hard to convey the message that we need to answer questions important for patients that are not all drug-related. For instance: is it worthwhile to identify metastases early? Should we treat metastatic disease with radiation or surgery?”.

In 2005, however, something important happened. An American patient organisation, Living Beyond Breast Cancer (LBBC), conducted the first nationwide survey on the psychosocial needs of women with metastatic breast cancer (MBC), “Silent Voices”, revealing the stigma of the disease: they felt abandoned by physicians, without information on their specific needs, and were isolated from other patients with early-stage breast cancer (Living Beyond Breast Cancer, 2006). At the same time in Europe, a few clinicians, including Cardoso, began to try to understand how things had changed for the early setting. “We needed to have large trials and level 1 evidence, and we needed to aim higher and better for these patients - Cardoso recalls - I was looking for support and I found it only thanks to Alberto Costa (co-founder and Director of the European School of Oncology from its foundation in 1992 to 2015). ‘We have to do something to change’, he said to me”.

The first step was the creation of the ESO - ABC Task Force, involving people from all over the world, including the president of the European Breast Cancer Coalition Europa Donna, Stella Kyriakides. The first publication of the ABC Task Force, in 2007, issued 12 recommendations on how to best manage this disease based on the limited knowledge available (ESO-MBC Task Force, 2007). That work led to the establishment of the 1st International Consensus Guidelines Conference on ABC (ABC 1), held in Lisbon in November 2011 with the true involvement of all healthcare professionals and patients, not just clinicians. The result was the publication of the 1st international guidelines for the management of ABC in 2012, which were truly patient-centred (Cardoso et al., 2012).

Meanwhile, on the other side of the ocean, three initiatives were shaking the trees. In 2009, Ms. Shirley A. Mertz, a patient with metastatic breast cancer and advocate, led a group of other patients to the US Congress, obtaining a resolution to designate October 13 as National Metastatic Breast Cancer Awareness Day, with the aim of shining a spotlight on the lack of knowledge and treatments. Also in 2009, a new survey on metastatic patients was published, this time financed by the pharmaceutical company Pfizer. The BRIDGE Survey (Bridging Gaps, Expanding Outreach – Metastatic Breast Cancer Patient Survey) was conducted in the US, UK, France, Spain, Poland, Belgium, Argentina, Mexico, and Egypt, involving 950 women. In addition to highlighting the stigma, the survey revealed that 78% of women living with mBC had never participated in a clinical trial, and 56% of these women had never been invited to consider a clinical trial (Mayer et al., 2009). The third important initiative was the formation of the MBC Advocacy Working Group, which published the first Consensus Report of its inaugural meeting, also sponsored by Pfizer (MBC Advocacy Working Group, 2009). A few years later, in 2013, the MBC Alliance was born in the USA: a unique coalition of nonprofit groups, advocates, individuals living with metastatic breast cancer, and industry partners.

The Birth Of The ABC Global Alliance In Europe (2014-2016)

Returning our attention to Europe, from that first Consensus Conference in 2011, things really began to change here as well. “I have to say that patient organisations changed their minds faster than anyone else - Cardoso continues - Subsequently, there was very intense work to change the mindset of cooperative research groups to start focusing on the metastatic setting”. With success: in 2014, the Breast International Group launched AURORA EU, the first large, multinational, collaborative metastatic breast cancer molecular screening programme. “Moreover, we finally started having results that changed the survival of metastatic disease, and pharma companies also started to change their mentality. After a while, we realised that there was a great movement that wanted to change things, and that's how the Advanced Breast Cancer Global Alliance was created”. It was born in 2016 as a new project of ESO, and it was based in Europe: an independent non-profit multi-stakeholder organisation dedicated exclusively to improving and extending the lives of women and men living with ABC. Currently, the ABC Global Alliance (which works as a federation, since its members are organisations, not individuals) has more than 200 members in over 90 countries worldwide, and since 2019 it is no longer under the aegis of ESO but is now independent.

When We Finally Started Having Good Results

It is important to note that, between 1995 and 2013, median survival for MBC remained approximately 2–3 years in developed countries (Caswell-Jin et al, 2018; Cardoso et al., 2018). The anti-HER2 agents lead to a substantial improvement in survival, but only for HER2-positive mBC. For ER-positive mBC, the most frequent subtype, overall survival remained almost stable since the early nineties (Cardoso et al., 2012). The game changer for this subtype was the development of cyclin-dependent kinase (CDK) 4/6 inhibitors, a new class of drugs for patients with ER+/HER2- mBC, in the early 2010s. This advancement is primarily due to Sir Paul Nurse (United Kingdom), who identified CDK as one of the key regulators of the cell cycle. This discovery earned him the Nobel Prize in Physiology or Medicine in 2001 (Nurse, 2002). The first CDK 4/6 inhibitor was Palbociclib (developed by Pfizer, approved by the FDA in 2015 and by EMA in 2016), followed by ribociclib (by Novartis, approved in 2017 in both the US and the EU) and abemaciclib (by Eli Lilly, approved in 2017 in the USA and in 2018 in the EU). European researchers participated significantly in the Phase III trials that led to their approvals. “With the CDK 4/6 inhibitors, the trials started to become bigger and powered to see an overall survival benefit, therefore able to provide level 1 evidence. It took a long time, and it is still a matter of debate, for researchers and pharma to understand that what truly matters to patients is overall survival and quality of life, not just progression-free survival - Cardoso emphasises - Today we have a median survival of five to six years for two of the ABC subtypes: HR+/HER2-, and HER2+. Instead, the median survival for triple-negative subtypes is still 18 months, although there has been some progress in recent years. Now we have immunotherapy with pembrolizumab and ADCs like sacituzumab govitecan: both improve survival, and we hope to increase this median survival to at least three years”.

When Quality Of Life Finally Started To Improve

The quality of life (QoL) had not even improved until about 10 years ago; on the contrary, it appears to have decreased slightly from 2004 to 2012 (Cardoso et al., 2018). According to the survey “Here & Now” conducted by Novartis in 2013 in the UK, eight out of ten patients felt that QoL was the biggest area in need of improvement in mBC care (Harmer, 2013). In 2015, another survey by Pfizer showed that emotional support and QoL improvements were the top two needs of mBC patients (Breast Cancer Center Survey, Pfizer, 2015). Recommendations on how to improve QoL were summarised in the Global Status of MBC Decade Report 2005-2015 (a one-of-a-kind paper, published by the ABC Global Alliance and ESO in 2018, in collaboration and with the support from Pfizer): in particular, healthcare professionals were required to collaborate in delivering a multidisciplinary, holistic, and personalised approach to caring for patients with MBC (Cardoso et al., 2018). “We fought for these patients to be treated within a multidisciplinary team, where there are psycho-oncologists and palliative care experts as well as surgical oncologists and radiation oncologists. We also needed - and still need - a QoL tool specific for ABC to assess the quality of care in the metastatic setting, since all available tools were developed for early breast cancer. This tools is currently in an advanced stage of development by the Quality of Life and the Breast Cancer Groups of the EORTC. Finally, we also needed to verify the quality of care that patients with mBC receive. To do that, we needed quality indicators for the metastatic setting”. It is important to note that standards required for establishing high-quality breast cancer centres in Europe have existed since 2000 (EUSOMA, 2000), but for many years they applied only to eBC. Recently, thanks to a joint effort from EUSOMA and the ABC Global Alliance, the quality indicators of mBC have been developed and published and are currently being implemented in the certification process (Cardoso et al., 2023).

Conclusions

For 20 years, there has been a movement in Europe that has continued to push for improvements in the condition of patients living with mBC. During this time, significant changes have occurred. In the USA, between 2014 and 2020, 13% of all breast cancer research funding was allocated to MBC. Consequently, the proportion of funding for MBC research nearly doubled during this period compared to 2000-2013. The annual investment in MBC research grew from $249 million in 2014 to $337 million in 2020, marking a 25% increase above the inflation rate (Flowers et al., 2023). Today, there are three additional guidelines for mBC, alongside those of the ABC Global Alliance. But many needs remain unmet. We cannot yet call mBC a chronic disease, since patients live years not decades with this disease, according to Cardoso. However, currently, this is a realistic goal, at least in HER2-positive and hormone-dependent subtypes. According to experts from the ABC Global Alliance, one of the most crucial needs is epidemiological data, adequately collected by cancer registries. Nowadays, cancer registries only collect diagnosis and death, not relapses, making it impossible to know how many patients are living with mBC in the world. “If you do not know how many patients exist in each country, how can you properly allocate resources”, asks Cardoso. Currently, the ABC Alliance has several ongoing projects and has started to work on the new ABC Global Charter, outlining updated goals for the next decade, 2025-2035 (ABC Global Alliance, 2024).

Acknoledgement

We thank Dr Fatima Cardoso, Medical Oncologist, Director of the Breast Unit at the Champalimaud Clinical Centre (Lisbon, Portugal) and President of the Advanced Breast Cancer Global Alliance, for the guidance and final revision of the article.

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