St. Gallen International Breast Cancer Conference 2023 - Day 2

Updates in HER2+ breast cancer: adjuvant therapies, early-stage data, and tumour heterogeneity

The 18^th St. Gallen International Breast Cancer Conference 2023 was held at the Austria Centre Vienna, from 15—18 March. This is the second in a series of three articles covering important highlights from this conference.

Updates in HER2+ breast cancer

HER2+ breast cancer (BC) remains an exciting space due to the number of ongoing trials, recent research findings, and the interesting debate on the case for de-escalating therapies.

A presentation by Nadia Harbeck covered the current state of (neo)adjuvant treatment of HER2+ BC¹³. Trastuzumab in the adjuvant setting reduces mortality in patients with HER2+ by a third, with a relapse rate independent of HR status. The timing of relapse differs depending on HR status, which needs to be considered when looking at long-term data to determine the magnitude of the benefit. For most HER2+ patients, neoadjuvant therapy is the standard therapy, individualised based on pathologic complete response (pCR) status, and escalated with neratinib. Not everyone needs neoadjuvant therapy, but the decision needs to be made after surgery when the nodal status is known.

Several trials, such as the APHINITY trial¹⁴, have highlighted that longer follow-up is needed for patients with no pCR, the impact of HR status, the impact of TDM-1 on the residual tumour, and for those with pCR to determine relapse rates.

Sub-group analysis from the ExteNET trial shows the benefit of one year of neratinib in HR+ patients within the first year after adjuvant trastuzumab-based therapy in patients with no pCR¹⁵. However, this trial had a high-grade 3+ diarrhoea rate. The phase 3b/4 ELEANOR study is being conducted in German-speaking countries to assess adherence to neratinib with this additional year of treatment¹³. Interim results show that by starting neratinib at half dose and escalating to full dose over three weeks, the diarrhoea rate decreases substantially, with a high rate of patient acceptance.

In the ADAPT programme in HR-/HER2+ tumours, 12 weeks of paclitaxel and trastuzumab gave a 90% pCR rate¹⁶. Excellent patient outcomes were reported after five years, and almost all patients in the paclitaxel arm did not receive further chemotherapy (CT) after surgery. These trials make a good case for individualised, de-escalated therapies in patients with pCR.

HER2 status has important implications for treatment selection and sequencing in early stages of breast cancer

There is also a good deal of excitement over ongoing data from several early-stage trials as presented by Martine Piccart¹⁷. These target several areas, such as HER2 and HER3, expanding the antibody-drug conjugate (ADC) family, engaging immune cells, and reinforcing the HER and HR pathway blockade. In metastatic HER2+ breast cancer, the current therapeutic target is HER2. This may change in the future as new emerging treatments target the cancer cell and its microenvironment (anti-CTLA-4, anti-PD(L)1, new anti-HER2, anti-NKG2A, anti-HER3 and anti-ER). Post-neoadjuvant trials are challenging the current standards of care with T-DM1. Based on the DESTINY Breast-05, ASTEFANIA, and COMPASS trials T-DM1 could be replaced by TdxD, TDM-1 plus atezolizumab, or TDM-1 plus tucatinib.

Based on the BR004, HER2Climb05, Patina, HeredERA, and Epik-82 trials, variations in the trastuzumab/pertuzumab (HP) combination are possible. For example, adding atezolizumab to HP in the induction phase, tucatinib in the maintenance phase, palbociclib or giredestrant for ER+ tumours, and alpelsib in PI3K mutations. Further trials are needed to prove the clinical benefit, as so many add-on treatments may also generate toxicity. Other emerging new treatments include bispecific antibodies. KLN06 is directed at specific HER2 domains (II and IV) combined with docetaxel as neoadjuvant therapy in early BC has shown a pCR rate of 50%.

The potential mechanisms of ADCs and their contributions to toxicity are explained in a recent article in Cancer Cell¹⁸. T-DUO (SYD985) in the phase III Tulip trial reached the primary endpoint of progression-free survival (PFS) but no overall survival (OS) benefits or quality of life, with a 19% discontinuation rate due to ocular toxicities. HER-3-directed therapies are also in different stages of development, showing encouraging results.

While treatments targeting HER2 are the standard for managing HER2+ BC, trials exploring related targets are showing promising initial results

Aleix Prat continued the HER2-focused session by covering how the impact of the HER2 heterogeneity affects treatment decisions¹⁹. A study by Filho and colleagues found no pCR in the HER2 group of patients, compared to 55% in the non-heterogeneous group (p=0.0001)²⁰. Translational research has tried to link biological heterogeneity to clinical outcomes. The HER2-enriched tumours are more prevalent in the HR- setting (75%) and only in 30% when patients are HR+. There are 15% of tumours in HR–/HER2+ that are basal-like and look like triple-negative tumours. The biological drivers of higher pCR are HER2-enriched, ERBB2-high, with high proliferation and high levels of immune cells. Conversely, the drivers of low pCR are luminal tumours, ESR1-high, HER2+ heterogeneity and high tumour burden. Results from the trastuzumab arm of the ALTTO trial showed that HER2+ tumours with more immune and luminal features had better disease-free survival (DFS) and OS than the other subtypes. The CALGB40601 trial evaluated almost 700 biomarkers and RNA-based gene expression. Overall, 31% of biomarkers were associated with pCR; only 7% were associated with relapse-free survival (RFS), and only 3% were associated with pCR and RFS.

The immune signatures, especially the B cell signatures, were associated with better outcomes and more probability of pCR. However, these signatures correlated to the HER2-enriched subtype and were associated with a better chance of pCR but worse RFS. The biology driving pCR is different to the biology that drives prognosis, which is also reflected in clinic. By integrating all the translational data from the tumour microenvironment, there is an argument that HR status has no role in prognosis, supported by a recent meta-analysis and the final analysis of the 10-year survival APT trial, where HR status loses significance for predicting outcome.

In the HR– setting, no patients with basal disease in the ADAPT trial achieved a pCR, and the KRISTINE trial showed these patients need CT. The POETIC trial found that not all HR+/HER2+ tumours are endocrine-sensitive. HR+/HER2+ basal-like tumours are aggressive from a prognostic perspective and require CT, so de-escalation should be used with caution. Genomic multi-feature scores should precede receptor status to predict pCR and prognosis better.

References

1. Anderson B. The ESO Umberto Veronesi Memorial Award Lecture 2023: A global approach to breast cancer management. Presented at the St Gallen International Breast Cancer Conference 2023, 15-18 March. Vienna. Opening Ceremony.
2. World Health Organization. Global breast cancer initiative implementation framework: assessing, strengthening and scaling up of services for the early detection and management of breast cancer. 2023. Available at: https://www.who.int/publications/i/item/9789240065987. Accessed 20 March 2023.
3. Cardoso F. How to avoid unnecessary mastectomies – a global discussion. Presented at the St Gallen International Breast Cancer Conference 2023, 15-18 March. Vienna. Interactive Session 1.
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8. Poortmans P. Access to evidence based radiation therapy for patients with early breast cancer. Presented at the St Gallen International Breast Cancer Conference 2023, 15-18 March. Vienna. Session 1.
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29. Hall PS. Patient Characteristics, Treatment and Long-term Outcomes from a Real-World Population of Early Breast Cancer Patients at High risk of Recurrence in Scotland. Presented at the St Gallen International Breast Cancer Conference 2023, 15-18 March. Vienna. Poster P016.
30. Hall P. Socioeconomic Outcomes With Ribociclib in Patients With HR+, HER2– Advanced Breast Cancer (ABC) in UK Real-world Settings. Presented at the St Gallen International Breast Cancer Conference 2023, 15-18 March. Vienna. Poster P084.
31. Kovacevic MM. Real-World Experience with CDK4/6 Inhibitors for Metastatic HR+/HER2− Breast Cancer at a Single Cancer Center. Presented at the St Gallen International Breast Cancer Conference 2023, 15-18 March. Vienna. Poster P082.
32. Meattini I. De-escalation of radiation therapy after primary systemic therapy in non-metastatic breast cancer: patterns of recurrence from a real-world single-centre cohort of patients. Presented at the St Gallen International Breast Cancer Conference 2023, 15-18 March. Vienna. Poster P106.
33. Canino F. Cardiac safety of pertuzumab, trastuzumab and standard chemotherapy as neoadjuvant treatment for HER2 positive breast cancer: real world data from NeoPowER trial. Presented at the St Gallen International Breast Cancer Conference 2023, 15-18 March. Vienna. Poster P120.
34. Loibl S, Chia S. If you achieve pCR after neoadjuvant, do you need adjuvant therapy? Presented at the St Gallen International Breast Cancer Conference 2023, 15-18 March. Vienna. Debate 3.
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