Austrian Breast & Colorectal Cancer Study Group

Science from the heart of Europe

The ABCSG 42 / PALLAS study represents the largest and most ambitious research project undertaken by the Austrian Breast and Colorectal Cancer Study Group (ABCSG) to date. This randomized phase III trial evaluates the efficacy of palbociclib in combination with standard adjuvant endocrine therapy compared to endocrine therapy alone in patients with hormone receptor-positive (HR+) and HER2-negative early breast cancer. Under the leadership of ABCSG President and Coordinating Investigator Prof. Dr. Michael Gnant, along with Prof. Angela DeMichele and Prof. Erica Mayer in the USA, the study was launched globally in September 2015 and nationally in Austria in October 2015.

The PALLAS study is distinguished by extensive international participation, with over 5,700 patients from 21 countries taking part. The ABCSG, in collaboration with the Breast International Group (BIG) network, serves as the legal sponsor for all 20 participating countries outside the US. This remarkable global collaboration demonstrates the ABCSG’s ability to mobilize both academic and industrial partners around a shared research goal and to successfully coordinate and execute a project of this scale.

The study reached full recruitment in 2018. However, a key interim analysis planned for 2020 revealed that the addition of palbociclib to standard endocrine therapy did not deliver the expected benefit for patients. These findings, published in The Lancet Oncology (Mayer E et al., 2021, DOI: https://doi.org/10.1016/S1470-2045(20)30642-2), led the Independent Data Monitoring Committee (IDMC) to recommend ending the treatment phase early. Consequently, in June 2020, it was decided to transition all active patients to the follow-up phase, which will continue until 2028.

The follow-up phase of the PALLAS trial holds significant value for international breast cancer research, as it ensures the long-term monitoring of patient safety and the collection of valuable data and biological samples for future research.

The TransPALLAS program, building on the PALLAS trial data, is designed to address future questions in the treatment and understanding of early breast cancer. It includes a wide range of exploratory clinical and translational research projects, initiated through an international call for proposals, which will open new avenues for modern breast cancer therapy in close collaboration with sponsors. Among its initiatives, TransPALLAS involves the collection of additional blood samples at seven and ten years post-randomization to gain long-term insights. The first analysis of RNA sequencing data was presented in 2023 and serves as a valuable resource for further scientific endeavors.

PALLAS stands as a testament not only to the ABCSG’s scientific expertise but also to its organizational capacity to manage a project of this magnitude. Through its dedication and skill, the ABCSG has made a significant contribution to breast cancer research on a global scale, solidifying its reputation as a leading scientific organization in this field. The study has yielded important clinical findings, which have been published in prestigious journals and presented at major international cancer conferences. Moreover, it has laid the groundwork for future research projects and international collaborations.

In 2006, the largest ABCSG study started including 49 centers in Austria and 5 in Sweden. A total of 3,425 patients participated, and in August 2013 the last patient was enrolled in the study. The study investigated whether the antibody drug denosumab reduces the therapy-induced risk of osteoporosis in breast cancer patients undergoing aromatase inhibitor therapy. On March 26, 2014, the first milestone PADCD (Primary Analysis Data Cut-Off Date) was reached with 247 clinical fractures – the results are now available and are surprisingly clear. The therapy-induced risk of osteoporosis can be reduced by 50 %! Administration of 60 mg denosumab subcutaneously twice a year halved clinical fractures, and also increased bone density in the spine by 10 percent, in the hip by about 8 percent, and in the femoral neck by 6 percent – without additional toxicities. These long-awaited data were presented in 2015 at the American Society of Clinical Oncology Annual Meeting (ASCO, May 29-June 2) in Chicago and published in the renowned journal „The Lancet“.

Three years later, in 2018, the results of the secondary study objective, disease-free survival, were also available. After an average of 72.6 months follow-up, these results were statistically significant as well, and the risk of relapse was reduced by approximately 18 % by the addition of denosumab. Of the patients who received additional denosumab, 89.2 % (versus 87.3 %) were disease-free at five years and 80.6 % (versus 77.5 %) at eight years. These considerable differences are particularly noteworthy given that prospect of recovery and survival in patients with this type of breast cancer are generally quite high. These data were presented on June 4, 2018, by Prof. Dr. Michael Gnant at the American Society of Clinical Oncology Annual Meeting (ASCO, June 1-5) in Chicago.

The results of the study were published prominently in the NEJM Evidence in July 2021.

Long-Term Outcomes of Adjuvant Denosumab in Breast Cancer
M. Gnant et al.
NEJM Evidence, Published November 18, 2022
DOI: 10.1056/EVIDoa2200162

 A standard treatment for postmenopausal breast cancer is to administer endocrine breast cancer therapy for five years after surgical removal of the tumor. The result of the ABCSG 16/S.A.L.S.A study shows that continuing therapy with the aromatase inhibitor anastrozole for an additional two years is sufficient. A further extension to five years is not required, as the therapy result does not improve, but side effects (especially fractures) are increased. A total of 3,484 postmenopausal breast cancer patients at more than 70 Austrian centers participated in the study between 2004 and 2010, making it one of the largest clinical trials in Austria. Participants had early hormone receptor-positive breast cancer (stage I-III) and, after five years of standard endocrine therapy, received an additional two or five years of the aromatase inhibitor anastrozole as extended endocrine therapy. These long-awaited ABCSG 16/S.A.L.S.A data were presented in 2017 at the San Antonio Breast Cancer Symposium (SABCS, Dec. 5-9) by Coordinating Investigator and ABCSG President Univ.Prof. Dr. Michael Gnant, and were even included in the congress’ highlight report.

The results of the study were published prominently in the New England Journal of Medicine in July 2021.

Duration of Adjuvant Aromatase-Inhibitor Therapy in Postmenopausal Breast Cancer
M. Gnant et al.
N Engl J Med 2021;385:395-405
DOI: 10.1056/NEJMoa2104162

ABCSG has long focused its clinical research on innovative neoadjuvant therapies. The first successes became apparent in 2004, when the positive effect of neoadjuvant therapy was demonstrated in ABCSG 14: Doubling the number of chemotherapy cycles before surgery from 3 to 6 resulted in significant improvements. Pathological complete response (pCR), according to which previously existing tumor manifestations were no longer detectable, increased from 7 to 18 %.

These investigations were continued in study 24, which included 536 patients in Austria. According to this study, the proportion of patients with pCR increased to 24 % in the epirubicin + docetaxel + capecitabine group. This is 50 % more than in patients treated with the standard therapy epirubicin + docetaxel, where in 16 % of patients living cancer cells were no longer detected.

More recently, it was detected that this bisphosphonate increases the prospects of preventing recurrences in women with early breast cancer – i.e., it also has an antitumor effect. Compared to endocrine therapy alone, the prospects for reducing the risk of recurrence improve and survival increases dramatically: more than 98 % of the participants in study 12 were still alive 5 years after diagnosis, even without adjuvant chemotherapy.

This result led to considerable international attention and was one of the scientific highlights at ASCO 2008, as well as in 2010 and 2011. The renowned journal “The Lancet Oncology” also published the 62-month follow-up data of the study in its June 2011 issue.

The 84-month data have since confirmed these results: The probability of recurrence can be reduced by 28 % with zoledronate, and the overall survival of patients improves by around 36 %.

The second study result, presented in San Antonio, is also of great importance to female cancer patients. Many suffered from osteoporosis, a side effect of successful cancer treatment. ABCSG succeeded in proving that the addition of the bisphosphonate zoledronic acid to standard therapy can prevent this effect and thus significantly reduces the risk of bone fractures.

Two further ABCSG research results were presented at the Breast Cancer Symposium in San Antonio/Texas (SABCS) 2008, one of the most important meeting points of the international elite of cancer researchers, which have since attracted worldwide attention.

Firstly, the new treatment concept for hormone receptor-positive women after surgery. They now receive 2 years of the antiestrogen tamoxifen, which was already used for treatment, and subsequently 3 years of the aromatase inhibitor anastrozole. This “switch therapy” reduces the risk of developing new tumors by 40 %!

The aim of the study was to investigate whether prolonging therapy by a total of 8 years after surgery could increase patients’ chances of cancer survival.

The results were clear: the women benefited from prolonged endocrine therapy with the aromatase inhibitor to an unexpectedly high extent. As a result, the recurrence of breast cancer was reduced by 36 %.

The major breakthrough for ABCSG was the realization that the chances of breast cancer survival prior to menopause increase significantly if a combined endocrine therapy is administered after surgical intervention instead of the classic chemotherapy. The ABCSG 5 study gained international recognition when it was published in 2002; it was decisively taken into account when defining the “International Guidelines for Adjuvant Therapy of Primary Breast Carcinoma.”

This was the first major success of the Austrian study group and, above all, a success for the patients, who have since benefited from an endocrine therapy with considerably fewer side effects.