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Controversial topics at the St. Gallen International Consensus Session 2021

 

The St. Gallen Breast Cancer Conference 2021 was held virtually this year, sharing the latest evidence and controversies in the primary therapy of early breast cancer. The St. Gallen International Breast Cancer Consensus Session 2021 concluded the meeting, bringing together a global faculty to debate the most important evidence in breast cancer published in the last 2 years. The renowned biennial consensus focuses on the optimal treatment of women with early breast cancer and this year centered around customizing local and systemic therapies.

Beat Thürlimann, MD, Cantonal Hospital St. Gallen, St. Gallen, Switzerland, and Michael Knauer, MD, PhD, Breast Center Eastern Switzerland, St. Gallen, Switzerland, outline the key topics that were discussed as part of the session, including the more controversial issues where a consensus could not be determined. Optimizing loco-regional therapy featured heavily, with a focus on de-escalation of surgery, especially axillary lymph node dissection. Total omission of surgery in the case of clinical and radiological complete remission was also discussed, agreeing it could not be justified.

 

 

Radiation therapy (RT) in patients achieving pathological complete remission after neoadjuvant chemotherapy was voted against in clinically node-negative HER2-postive (HER2+) or triple negative breast cancer (TNBC), but was supported in the case of node-positive disease.

The use of genomic predictors to define chemotherapy needs, as well as decisions on the omission of RT were controversial topics. Disconcordance among the panelists has left many unanswered questions about the appropriate use of multi-gene panels. Major pathology topics included the routine measurement of Ki67 in early breast cancer which continues to be supported, as well as PDL-1 and tumor infiltrating lymphocyte testing in TNBC.

Recommendations were established for the neoadjuvant treatment of various patient populations. A very important topic was the necessity of anthracyclines for the treatment of HER2+ breast cancer, where a consensus on the use of these agents in node-positive disease was not reached. The optimal adjuvant therapy regimes were also discussed, including the use of cyclin depended kinase (CDK) 4/6 inhibitors. However, there were no definitive therapy recommendations for premenopausal patients with estrogen receptor (ER)-positive breast cancer with 1–3 positive nodes. There was also no agreement surrounding the appropriate cut-off for ER expression to recommend adjuvant endocrine therapy.

A clear message was established that oligometastatic breast cancer should be treated systemically and locally, with curative intent. Breast cancer in the setting of the ongoing COVID-19 pandemic was also an important discussion point, with a clear consensus established that all patients should receive the SARS-CoV-2 vaccination.

Breast reconstruction and radiation therapy consensus from AIRO

 

The indications for post-operative radiation therapy (RT) in breast cancer management have expanded with mounting evidence demonstrating survival benefits in high-risk patients. Current indications for post-mastectomy RT include involvement of ≥4 nodes, involvement of 1–3 nodes with additional risk factors for local relapse, and T3 or T4 disease, though it is often applied more broadly still.1 As a result, patients are more frequently presenting for reconstructive surgery having undergone radiation, or likely to require it in the future.

Advancements in reconstructive surgical techniques have been considerable. Autologous or implant-based methods are common following partial or complete breast removal. However, side effects of radiation, which can take months to years to fully manifest, have the potential to significantly impact the outcome of reconstructive surgery.2 Tissue injury can occur including erythema, edema, pigmentation changes, dermatitis, atrophy, and chromic skin fibrosis.2 Additionally, previous RT is associated with a significant risk of reconstructive failure and complications.

Given its influence on reconstructive outcomes, the increased use of RT has necessitated an examination of its optimal use to establish widely applicable recommendations. Icro Meattini, MD, University of Florence, Florence, Italy, outlines a consensus statement on breast reconstruction and radiation therapy from the Italian Association of Radiotherapy and Clinical Oncology (AIRO) breast cancer group, as reported at the St Gallen Breast Cancer Conference 2021.3

 

Expert oncologists were called upon in a three key-phase Delphi process to establish recommendations. Once key consensus topics were outlined, a virtual conference was held to discuss the results.

In total, 26 recommendations were set out across 5 topics: breast conserving surgery, postoperative radiation therapy after oncoplastic breast surgery, surgical techniques for breast reconstruction, indications for postmastectomy RT, and techniques and timing of breast reconstruction and RT.3 Key findings of the consensus included the health-related quality of life benefits associated with immediate breast reconstruction, the necessity of multidisciplinary management of high-risk patients, and the importance of an individualized approach to reconstruction.

Quality of life in monarchE: adjuvant abemaciclib in HR+ breast cancer

 

CDK 4/6 is critical in cell division regulation. Dysregulation of the cyclin D1-CDK4/6-Rb cascade, and the resulting uncontrolled cell proliferation is a key hallmark of cancer.4 CDK4/6 inhibitors have demonstrated significant survival benefits in patients with hormone receptor (HR)-positive, HER2-negative, advanced or metastatic breast cancer. When used in combination with endocrine therapy, a significant prolongation of progression-free survival is achieved in these patients.5 Currently, three CDK4/6 inhibitors are approved in the United States by the FDA for patients with advanced/metastatic breast cancer: palbociclib, ribocilcib and abemaciclib.

Substantial evidence of a clinically meaningful benefit in the advanced setting prompted investigations of these agents in early breast cancer, with hopes of similar survival improvements. Several late phase clinical trials examining the adjuvant use of CDK4/6 inhibitors in addition to endocrine therapy in early-stage HR-positive/HER2-negative breast cancer are underway, including PALLAS (NCT02513394), PENELOPE-B (NCT01864746), EarlEE-2 (NCT03081234), and monarchE (NCT03155997).

 

Controversy surrounding the use of CDK4/6 inhibitors in this setting has stemmed from the differing results achieved in these trials to date. An improvement in disease-free survival was seen with the addition of abemaciclib to standard endocrine therapy in the monarchE study, but comparable results were not seen with palbociclib in PALLAS and PENELOPE-B, despite similar patient populations being examined.6-8

Patients’ quality of life (QoL) and side effect perceptions in monarchE were presented at the St Gallen conference by Sara Tolaney, MD, MPH, Dana-Farber Cancer Institute, Boston, MA, winning the St. Gallen Oncology Conferences Best Poster Awards 2021.9 The Phase III monarchE trial assessed the efficacy of endocrine therapy with or without abemaciclib for adjuvant treatment of HR-positive HER2-negative, node-positive high-risk early breast cancer. High-risk disease was defined as having ≥4 positive lymph nodes, 1–3 positive lymph nodes with a large tumor size, histologic grade 3 disease or ≥20% Ki-67 expression in untreated breast tissue. At a median of 19 months of follow-up, the primary analyses of over 5000 patients showed that the addition of abemaciclib significantly improved disease-free survival compared to endocrine therapy alone.6

Patient-reported outcomes, recorded at randomization, throughout treatment and at follow-up, were analyzed to understand the effects of abemaciclib on patient’s QoL and symptom burden. Mixed model for repeated measures (MMRM) scores revealed no significant difference in health-related QoL reports between the two trial arms. Diarrhea was reported more commonly in patients treated with abemaciclib, however overall symptom burden was similar in both arms and most patients reported being bothered ‘a little’ or ‘not at all’ by their side effects. The findings indicate a tolerable profile for abemaciclib in early breast cancer, warranting its continued investigation in this setting.

Real-world outcomes of patients receiving neoadjuvant chemotherapy

 

Breast cancer is a heterogeneous malignancy that can be categorized based on clinical and prognostic characteristics. HER2+ and TNBC are the most aggressive subtypes, showing the highest mortality rates.10 Recognizing the differences between breast cancer subtypes and how they respond to therapy is fundamental to optimizing treatment strategies and achieving an individualized approach to disease management.

Collecting real-world outcomes from diverse patient populations provides a huge contribution to the understanding of real-life treatment patterns and patient outcomes. Larger sample sizes and longer follow-ups can support the investigation of rare and long-term outcomes. Bernardo Rapoport, MD, The Medical Oncology Centre of Rosebank, Johannesburg, & University of Pretoria, Pretoria, South Africa, discusses the results from a real-world assessment of outcomes in patients with breast cancer receiving neoadjuvant chemotherapy.11

The retrospective study enrolled 273 patients receiving taxane and anthracycline-based chemotherapy, with or without trastuzumab. Pathological complete response (pCR), defined in the study as the complete disappearance of invasive cancer in the breast and tumor cells in the axillary lymph nodes, was assessed and pCR rates were compared across patient subsets.

 

The study found that achieving a pCR following neoadjuvant chemotherapy was associated with improved disease-free survival, with 96% of patients achieving a pCR remaining disease free after 4-years, compared to 74% of patients who did not.

Univariate analyses revealed several factors to be associated with pCR rate, including tumor size, molecular subtype, age, hormone receptor status, Ki67 expression and disease stage. TNBC and HER2-positive patient subsets were associated with a higher pCR rate. The results are consistent with outcomes reported in clinical trials and demonstrate the benefits of neoadjuvant chemotherapy in a real-world setting.

References

  1. A Niwińska, J Gałecki. Current indications and methods of postoperative radiation therapy — repetition before the exam. Oncol Clin Pract. May 2016; 12(1):18–24.
  2. J A Nelson, J J Disa. Breast Reconstruction and Radiation Therapy: An Update. Plast Reconstr Surg. Nov 2017; 140(5S Advances in Breast Reconstruction):60S–68S.
  3. I Meattini, N Rocco, M Bernini, et al. Breast reconstruction and radiation therapy: consensus statements of the Italian association of radiotherapy and clinical oncology (AIRO) breast cancer group. [Conference presentation abstract]. St Gallen Breast Cancer Conference 2021, 17–21st Mar 2021.
  4. Y Wu, Y Zhang, H Pi, et al. Current Therapeutic Progress of CDK4/6 Inhibitors in Breast Cancer. Cancer Manag Res. May 2020; 12: 3477–3487.
  5. C Messina, C Cattrini, G Buzzatti, et al. CDK4/6 inhibitors in advanced hormone receptor-positive/HER2-negative breast cancer: a systematic review and meta-analysis of randomized trials. Breast Cancer Res Treat. Nov 2018; 172(1):9–21.
  6. J A O’Shaughnessy, S Johnston, N Harbeck, et al. Primary outcome analysis of invasive disease-free survival for monarchE: abemaciclib combined with adjuvant endocrine therapy for high risk early breast cancer. [Conference presentation abstract]. San Antonio Breast Cancer Symposium 2020, 8–11 Dec 2020.
  7. Loibl S, Marmé F, Martin M, et al. Phase III study of palbociclib combined with endocrine therapy (ET) in patients with hormone-receptor-positive (HR+), HER2-negative primary breast cancer and with high relapse risk after neoadjuvant chemotherapy (NACT): First results from PENELOPE-B. Presented at: 2020 Virtual San Antonio Breast Cancer Symposium 2020; December 8–11, 2020.
  8. E Mayer, A Dueck, M Martin, et al. Palbociclib with adjuvant endocrine therapy in early breast cancer (PALLAS): interim analysis of a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. Feb 2021; 22(2):212–222.
  9. S Tolaney, I Blancas, Y H Im, et al. Patients’ quality of life and side effect perceptions in monarchE, a study of abemaciclib plus endocrine therapy in adjuvant treatment of HR+, HER2-, node-positive, high-risk, early breast cancer. [Conference presentation abstract]. St Gallen Breast Cancer Conference 2021, 17–21st Mar 2021.
  10. A Johansson, C Trewin, K V Hjerkind, et al. Breast cancer‐specific survival by clinical subtype after 7 years follow‐up of young and elderly women in a nationwide cohort. Int J Cancer. Mar 2019; 144(6):1251–1261.
  11. B L Rapoprt, T Smit, L Heyman, et al. Her-2 positive and TNBC patients receiving neoadjuvant chemotherapy are associated with a high pathological complete response rate – results from real-world outcomes in a multidisciplinary setting. [Conference presentation abstract]. St Gallen Breast Cancer Conference 2021, 17–21st Mar 2021.

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