Treatment decisions in post-neoadjuvant HER2-positive early breast cancer

Patients HER2-positive (HER2+) breast cancer (BC) who achieve pathological complete response (pCR) have significantly better event-free survival (EFS), yet pCR cannot overcome the prognostic impact of baseline tumour size and nodal status. At an industry-sponsored symposium, Professor Michael Untch of Obstetrics and Gynaecology Department of Helios Hospital in Berlin, Germany, discussed considerations behind treatment decisions in post-neoadjuvant HER2+ early BC and data supporting the use of neratinib, an irreversible, small-molecule pan-HER tyrosine kinase inhibitor (TKI), in this setting.

Importance and limitations of pCR
HER2+ BC, which accounts for 15–20 percent of all BC cases, is highly aggressive and associated with poor prognosis. [Comput Struct Biotechnol J 2021;20:333-342] The current standard of care for patients with high-risk HER2+ BC is neoadjuvant chemotherapy plus dual anti-HER2 targeted therapy, which is associated with pCR rates of up to 65 percent. [Front Oncol 2023;13:1066007]

Nevertheless, a substantial proportion of patients do not achieve pCR after neoadjuvant therapy, and the presence of residual disease is independently prognostic of decreased EFS and increased risk of recurrence, especially in patients with larger tumour size and primary nodal involvement. [J Clin Oncol 2023;41:2998-3008]

Furthermore, traditional poor prognostic features, namely, large tumour size and positive nodal status, remain important even after pCR. After a median follow-up of 61.2 months, the 5-year Kaplan-Meier estimates of overall survival (OS) were lower for patients with clinical tumour size 3–4 vs cT 1–2 and those with positive vs negative clinical nodal status. (Figure 1) [Cancer Res 2020;80(4_Suppl):P5-06-02]

“These findings have diminished my previous euphoria, when I used to think that if a patient has pCR that means she will survive – this turned out to be not true,” shared Untch.

ExteNET: Extended adjuvant neratinib after trastuzumab-based Tx
Neratinib is an oral, small-molecule, irreversible pan-HER TKI indicated in adults with HER2+ early BC who have completed adjuvant trastuzumab-based therapy ≤1 year ago. [Nerlynx Hong Kong Prescribing Information, September 2022] “Neratinib has been approved in Europe for many years and what we have learnt is that we should not wait too long before giving patients neratinib after finishing adjuvant treatment, in which case we can see significantly better long-term invasive disease-free survival [iDFS] and OS,” advised Untch.

In the phase III ExteNET trial (n=2,840), neratinib significantly reduced the risk of 5-year disease recurrence by 42 percent (5-year invasive disease-free survival [iDFS]: hazard ratio [HR], 0.58; 95 percent confidence interval [CI], 0.41–0.82; p_two-sided=0.002) vs placebo. (Figure 2) Among patients with residual disease after neoadjuvant treatment (non-pCR subgroup; n=295), absolute 5-year iDFS and 8-year OS gains with neratinib were 7.4 percent (HR, 0.60; 95 percent CI, 0.33–1.07) and 9.1 percent (HR, 0.47; 95 percent CI, 0.23–0.92), respectively. [Clin Breast Cancer 2021;21:80-91.e7]

In addition, ExteNET demonstrated a lower 5-year cumulative incidence of first central nervous system (CNS) recurrences with neratinib vs placebo (0.7 vs 2.1 percent), and more patients in the neratinib group were alive without a CNS recurrence at 5 years (98.4 vs 95.7 percent; HR for CNS-DFS, 0.41; 95 percent CI, 0.18–0.85). The potential CNS benefit was consistently shown across various high-risk subgroups, including non-pCR and node-positive patients. (Figure 3)

“Across the adjuvant setting trials, ALTTO, APHINITY and KATHERINE, we have not seen any HER2-directed therapy prevent CNS metastases. On the other hand, there was a much lower cumulative incidence of first CNS recurrence with neratinib vs placebo in ExteNET, including in non-pCR patients,” commented Untch.   '

Conclusion
HER2+ BC is associated with an increased recurrence risk and poor prognosis. Even in patients who achieve pCR, chance of recurrence remains high. Extended adjuvant treatment with neratinib after trastuzumab-based therapy significantly reduces the risk of invasive recurrence and prolongs iDFS. In particular, there was consistent numerical benefit seen in iDFS, OS, and CNS events in patients with residual disease following neoadjuvant treatment, who would be considered at heightened risk of disease recurrence.