St. Gallen International Breast Cancer Conference 2023 - Day 3

HER2+ breast cancer and real-world evidence and interview with Professor Harbeck

The 18^th St. Gallen International Breast Cancer Conference 2023 was held at the Austria Centre Vienna, from 15—18 March. This is the third and final article covering important highlights from this conference.

Professor Nadia Harbeck of LMU University Hospital, Munich provided her thoughts on the key developments in breast cancer management from the conference, as well as future directions of therapy.

The role of real-world breast cancer data in research and patient management

Real-world data has offered a significant contribution to this year's meeting. Better health-related quality of life (QoL) and physical and social functioning outcomes come hand in hand with patients’ involvement in their treatment decision-making process.

Neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI), is approved for use in patients with HR+/HER2+ early breast cancer (eBC) who have completed adjuvant trastuzumab within the prior year. The most common and debilitating adverse event with neratinib use is diarrhoea, often leading to discontinuation. Ongoing studies are assessing the incidence and management of diarrhoea in the real-world setting. The DIANER phase 2 study, currently recruiting across Europe, will evaluate the incidence of diarrhoea within the first three cycles of neratinib using the three best prophylaxis strategies reported from the CONTROL study. Interim analysis results will be available when 36 patients have completed three cycles of neratinib²¹. ELEANOR is the first non-interventional study to collect real-world data on the use of neratinib in Germany, Austria and Switzerland. These data were discussed in the previous article²². An ongoing post-authorisation safety study (PASS) at 50 European sites, Nerlyfe, reported diarrhoea incidence within the first three months of adjuvant neratinib treatment and an extended phase (4–12 months). Secondary outcomes include the characterisation of diarrhoea patterns, treatment maintenance, and the impact of treatment-related diarrhoea on QoL. In parallel, the Nerlyfe-Ancillary study will observe prospective data on cancer recurrence at two years (invasive disease-free survival (IDFS), overall survival (OS))²³.

The 21-gene recurrence assay^® (RS) has been validated to predict the estimated risk of recurrence at nine years and the benefit of chemotherapy (CT) in ER+ HER2– eBC. However, the benefits of adjuvant CT depend on menopausal status (data from RxPONDER²⁴). Real-world analysis of the clinical and economic impact of RS in early-stage node-positive BC patients showed a 55% reduction in CT administration, with economic savings of over €1 million. This figure will likely be underestimated as it does not account for the QoL and indirect societal costs²⁵. Descriptive real-world data from Brazil showed that in patients with eBC (n=278) following neoadjuvant chemotherapy (NACT), pathologic complete response (pCR) occurred in 27.4%, in whom OS was lower than those without pCR (44.2% vs 62.3%). In patients with tumour stages one and two (T1, T2), 5-year OS was lower in pCR than in non-pCR patients; the inverse was found in T3 patients²⁶.

Real-world information on managing side effects in patients undergoing treatment for breast cancer was an important theme among posters presented at SGBCC 2023

HR+ BC accounts for 80% of eBC. Adjuvant endocrine therapy (ET) is the backbone of treatment, improving OS and distant recurrence-free survival (DRFS). ET has significant side effects leading to discontinuation, poorer clinical outcomes, and increased public health burden. Adherence to ET, measured in a German study, found average ET adherence over five years to be 72%. Further analysis is required to determine the impact on OS and DRFS²⁷. Despite advances in adjuvant ET treatment, node-positive, HR+/HER– eBC is associated with a considerable risk of recurrence. Using the same high-risk criteria used in the MonarchE study²⁸, descriptive analysis of this patient population in Scotland confirmed poor long-term outcomes and a clinically unmet need for improved treatments. The increasing burden of nodal disease was associated with a worse 10-year IDFS and OS, adversely affected by postmenopausal status and larger tumour size²⁹.

Real-world data evaluating socioeconomic outcomes in patients taking CDK4/6 inhibitors are limited. A study of British patients (n=154) found that ribociclib, in combination with aromatase inhibitors, was associated with a change in socioeconomic status in patients with HR+/HER2– advanced BC. PFS was comparable to the MONALEESA-2 study³⁰. Retrospective real-world data from Serbia found that compared to the clinical trial setting, patients with HR+/HER2+ BC treated with CDK4/6 inhibitors had a lower frequency of adverse events (AEs) and dose modifications, with no difference between palbociclib or ribociclib³¹.

Italian real-world data evaluating treatment patterns and survival outcomes in patients with non-metastatic BC after primary systemic therapy (n=146) suggest caution in de-escalating postoperative regional node irradiation (RNI) in patients with 1–3 residual lymph nodes. According to their local practice, these patients would not usually receive RNI. Large databases of real-world data are needed, and existing guidelines should be strictly followed³².

In the NeoPowER trial, no increase pertuzumab related cardiotoxicity was found in patients with HER2+ BC (n=158) who received pertuzumab (P), trastuzumab (H), and standard chemotherapy (CT) as neoadjuvant treatment. Cardiac events occurred in patients who received anthracyclines and HER2 inhibitors. These data are important for de-escalation studies for HER2+ when anthracyclines could be omitted³³.

Real-world data from single centres or countries or from large datasets are providing important contextual information to improve patient management

Debating real-world data and updates in treatment regimens

Combining this real-world data and the updates in treatment regimens for HER2+ BC, a thought-provoking debate between Sybille Loibl and Stephen Chia was made for treatment escalation or de-escalation, respectively, after a pCR in all BC types³⁴.

While the surrogate pCR is associated with stable long-term clinical outcomes, it is based on older, shorter treatment regimens and not dual anti-HER2. pCR has considerably improved since these older studies, which were around 29% for HER2+ BC. In the newer KEYNOTE-522 study, the pCR rate was 65%. However, in this study, the difference in pCR with or without pembrolizumab was only 2%, with higher pembrolizumab-associated toxicity. Calculations on the cost savings from de-escalation were enormous, reaching into the billions of dollars in the United States. Both speakers agreed that more data is required; to select patients at high-risk despite achieving pCR and identify patients who would benefit from drug optimisation regimens, reducing treatment, toxicity and cost burden.

Global implications of clinical research in breast cancer

Finally, a global perspective session pointed out that most trials are being run in Europe and North America, which is disappointing in the context of data presented by representatives from Asia, Africa and LATAM regions³⁵. This session highlighted the need for all populations to be included in clinical trials, as the populations are genetically diverse with different resources. Patients with BC in Asia and LATAM present at a younger age than in the western world, with a high prevalence of HER-enriched subtypes in Asia and higher mortality in LATAM. African patients present very late with aggressive disease. Researchers in these low- middle-income regions need more infrastructure and financial support.

Meet Professor Nadia Harbeck

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.
4. Grössmann N, Del Paggio JC, Wolf S, Sullivan R, Booth CM, Rosian K, et al. Five years of EMA-approved systemic cancer therapies for solid tumours—a comparison of two thresholds for meaningful clinical benefit. European Journal of Cancer. 2017;82:66-71.
5. Douillard J-Y. ESMO Magnitude of Clinical Benefit Scale as a tool for treatment decision and prioritization: Focus on Gastro-Intestinal Cancers. https://oncologypro.esmo.org/content/download/135149/2507045/file/WORLDGI2018_75_douillard.pdf. Accessed 20 March 2023.
6. Biganzoli L, Cardoso F, Beishon M, Cameron D, Cataliotti L, Coles CE, et al. The requirements of a specialist breast centre. The Breast. 2020;51:65-84.
7. Cardoso F, Macneill F, Penault-Llorca F, Eniu A, Sardanelli F, Nordström EB, et al. Why is appropriate healthcare inaccessible for many European breast cancer patients? – The EBCC 12 manifesto. The Breast. 2021;55:128-135.
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.
9. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353(16):1659-1672.
10. Weber W. Surgery of patients with early breast cancer: Quo vadis? Presented at the St Gallen International Breast Cancer Conference 2023, 15-18 March. Vienna. Session 1.
11. Connolly R. What’s new in systemic treatment of patients with early breast cancer. Presented at the St Gallen International Breast Cancer Conference 2023, 15-18 March. Vienna. Session 1.
12. André F. Translational research priorities for patients with early breast cancer. Presented at the St Gallen International Breast Cancer Conference 2023, 15-18 March. Vienna. Session 1.
13. Harbeck N. Current adjuvant and neoadjuvant approaches. Presented at the St Gallen International Breast Cancer Conference 2023, 15-18 March. Vienna. Session 8.
14. Piccart M, Procter M, Fumagalli D, de Azambuja E, Clark E, Ewer MS, et al. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up. J Clin Oncol. 2021;39(13):1448-1457.
15. Chan A, Moy B, Mansi J, Ejlertsen B, Holmes FA, Chia S, et al. Final Efficacy Results of Neratinib in HER2-positive Hormone Receptor-positive Early-stage Breast Cancer From the Phase III ExteNET Trial. Clin Breast Cancer. 2021;21(1):80-91.e87.
16. Nitz U, Gluz O, Graeser M, Christgen M, Kuemmel S, Grischke EM, et al. De-escalated neoadjuvant pertuzumab plus trastuzumab therapy with or without weekly paclitaxel in HER2-positive, hormone receptor-negative, early breast cancer (WSG-ADAPT-HER2+/HR-): survival outcomes from a multicentre, open-label, randomised, phase 2 trial. Lancet Oncol. 2022;23(5):625-635.
17. Piccart M. Emerging new treatments in HER2 positive breast cancer. Presented at the St Gallen International Breast Cancer Conference 2023, 15-18 March. Vienna. Session 8.
18. Colombo R, Rich JR. The therapeutic window of antibody drug conjugates: A dogma in need of revision. Cancer Cell. 2022;40(11):1255-1263.
19. Prat A. ER positive vs ER negative: tackling diversity in HER2 positive breast cancer Presented at the St Gallen International Breast Cancer Conference 2023, 15-18 March. Vienna. Session 8.
20. Filho OM, Viale G, Stein S, Trippa L, Yardley DA, Mayer IA, et al. Impact of HER2 Heterogeneity on Treatment Response of Early-Stage HER2-Positive Breast Cancer: Phase II Neoadjuvant Clinical Trial of T-DM1 Combined with Pertuzumab. Cancer Discov. 2021;11(10):2474-2487.
21. González-Santiago S. Randomized Phase II trial evaluating three anti-diarrhoeal prophylaxis strategies in patients with HER2+ / HR+ early breast cancer treated with extended adjuvant neratinib (DIANER GEICAM/2018-06). Presented at the St Gallen International Breast Cancer Conference 2023, 15-18 March. Vienna. Poster P006.
22. Bartsch R. Interim analysis of ELEANOR (n=200): a multi-national, prospective, non-interventional study (NIS) among patients with HER2+ and HR+ early breast cancer (eBC) treated with extended adjuvant neratinib. Presented at the St Gallen International Breast Cancer Conference 2023, 15-18 March. Vienna. Poster P014.
23. Harbeck N. A real-world prospective observational multi-national study in adult patients with breast cancer treated with extended adjuvant neratinib: NERLYFE study. Presented at the St Gallen International Breast Cancer Conference 2023, 15-18 March. Vienna. Poster P009.
24. Kalinsky K, Barlow WE, Gralow JR, Meric-Bernstam F, Albain KS, Hayes DF, et al. 21-Gene Assay to Inform Chemotherapy Benefit in Node-Positive Breast Cancer. N Engl J Med. 2021;385(25):2336-2347.
25. Browne IM. Real-world analysis of the clinical and economic impact of 21-gene recurrence score (RS) testing in early-stage node positive breast cancer in Ireland. Presented at the St Gallen International Breast Cancer Conference 2023, 15-18 March. Vienna. Poster P008.
26. Antonini M. Real World Evidence of the Impact at Neoadjuvant Chemotherapy Treatment on the Prognosis of Patients with Early Breast Cancer. Presented at the St Gallen International Breast Cancer Conference 2023, 15-18 March. Vienna. Poster P131.
27. Dannehl D. Retrospective modeling of adherence to endocrine therapy in early breast cancer using real-world claims data. Presented at the St Gallen International Breast Cancer Conference 2023, 15-18 March. Vienna. Poster P010.
28. Johnston SRD, Toi M, O'Shaughnessy J, Rastogi P, Campone M, Neven P, et al. Abemaciclib plus endocrine therapy for hormone receptor-positive, HER2-negative, node-positive, high-risk early breast cancer (monarchE): results from a preplanned interim analysis of a randomised, open-label, phase 3 trial. Lancet Oncol. 2023;24(1):77-90.
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.
35. Barrios C, Xu B, Gamal H, Bretel D. Global Perspective on breast cancer treatment. Presented at the St Gallen International Breast Cancer Conference 2023, 15-18 March. Vienna. Session 10.