A high-risk patient with early-stage HER2-positive breast cancer treated with extended adjuvant therapy

Presentation and investigations
A 48-year-old premenopausal female presented in July 2021 with a self-detected nodule in her left breast, which she had noticed 1 week ago. Upon physical examination, a 2 cm mass in the left breast and a 2 cm lymph node (LN) in the left axilla were palpable. Further diagnostic workup revealed an irregular-shaped mass measuring 18 x 12 mm with lobulated edges and an enlarged LN of 24 x 13.9 mm in the left axilla, without distant metastasis. Biopsy of the breast mass showed invasive carcinoma that was HER2-positive, oestrogen receptor (ER)–negative and progesterone receptor (PR)–negative, with a Ki-67 level of 50 percent. The patient was diagnosed with HER2-positive breast cancer (BC; cT1N1M0).

Treatment and response
The patient received six cycles of neoadjuvant chemotherapy (taxane plus carboplatin) with dual HER2 blockade (trastuzumab and pertuzumab [HP]) from 30 July 2021 to 17 November 2021. In December 2021, MRI showed that the breast tumour was no longer obvious, and the axillary LN shrank to 15 x 3.4 mm. Subsequently, she underwent breast-conserving radical mastectomy and axillary LN dissection. Postoperative biopsy of the breast tumour specimen indicated a pathological complete response (pCR), but a residual tumour was detected in one of the 19 excised axillary LNs showing metastasis (HER2-positive, ER- and PR-negative, Ki-67 of approximately 30 percent).

The patient then received one cycle of adjuvant trastuzumab emtansine (T‑DM1), after which she was switched back to HP due to severe thrombocytopaenia (platelet count dropped to 14 x 10⁹/L). She completed adjuvant HP in July 2022.

In December 2022, she started extended adjuvant therapy with neratinib at an initial dose of 160 mg QD, which was gradually increased to 240 mg QD, and completed treatment in December 2023. During the 1-year course of neratinib, she experienced occasional diarrhoea, with a maximum of eight daily episodes, which improved with oral loperamide PRN. The patient also experienced occasional skin rash and paronychia, which improved with symptomatic treatment.

As of September 2024, the patient undergoes regular follow-up and remains stable with no signs of tumour recurrence.

Discussion
HER2-positive BC, which accounts for 15–20 percent of all BC cases, is highly aggressive and associated with poor prognosis.¹ The current standard of care for patients with high-risk HER2-positive BC is neoadjuvant chemotherapy plus dual anti-HER2 targeted therapy.² This combination, compared with neoadjuvant chemotherapy or trastuzumab alone, has significantly improved patient outcomes, with reported pCR rates of up to 65 percent.^2,3

The NeoALTTO trial (n=455), which investigated adding dual anti-HER2 targeted therapy to neoadjuvant chemotherapy in patients with HER2-positive early-stage BC (eBC), found that patients who achieved pCR had significantly better event-free survival (EFS; 86 vs 72 percent at 3 years; 77 vs 65 percent at 6 years) and overall survival (94 vs 87 percent at 3 years; and 89 vs 77 percent at 6 years) vs non-pCR patients.³

A pooled analysis of 11 neoadjuvant trials for HER2-positive eBC (n=3,710) showed that pCR in HER2-positive patients is associated with an approximately 80 percent reduction in the risk of recurrence.1 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.¹ The 10-year analysis of the NeoALTTO trial demonstrated that non-pCR patients had a high risk of recurrence within the first 3 years after completion of neoadjuvant therapy.³ (Figure) Therefore, there remains an unmet need for preventing early relapse in this population.

Adjuvant T-DM1 for 1 year is generally recommended to reduce the risk of recurrence in non-pCR patients because it demonstrated substantial improvement in 3-year invasive disease–free survival (iDFS) vs adjuvant trastuzumab (88 vs 77 percent) in the phase III KATHERINE trial.⁴ Treatment intensification with 1-year extended adjuvant neratinib, a small-molecule irreversible pan-HER tyrosine kinase inhibitor, is also highly recommended after completion of adjuvant therapy to further prevent recurrence and improve outcomes in high-risk HER2-positive eBC patients.^5,6

The phase III ExteNET trial (n=2,840) evaluated use of 1-year extended adjuvant therapy with neratinib vs placebo in patients who completed neoadjuvant and adjuvant therapies with no evidence of disease recurrence or metastatic disease. The 2-year follow-up data showed that neratinib significantly improved iDFS vs placebo (hazard ratio, 0.67; 95 percent confidence interval [CI], 0.50–0.91; p=0.0091), and this benefit was maintained in the long-term 5-year follow-up (90.2 vs 87.7 percent; hazard ratio, 0.73; 95 percent CI, 0.57–0.92; p=0.0083).⁷ Neratinib was also associated with reductions in distant recurrence (6.4 vs 7.8 percent) and local and regional recurrence events (0.8 vs 2.5 percent]) vs placebo, which is notable given that the risk of relapse in patients with HER2-positive metastatic BC is greatest during the first 12 months after completion of trastuzumab therapy.⁷

Our patient was considered at high risk of recurrence because of nodal positivity and residual disease after neoadjuvant therapy. Since she could not tolerate adjuvant T-DM1, she continued with HP as adjuvant therapy based on its benefits reported in the APHINITY trial.⁴ Considering her increased risk of relapse, extended adjuvant neratinib was commenced within 6 months after completing adjuvant HP to improve outcomes.

Neratinib has an acceptable safety profile. The 5-year data from the ExteNET trial indicated that a 1-year course of neratinib was not associated with long-term toxicities.⁷ Diarrhoea is neratinib’s most common side effect, with 40 percent of neratinib-treated patients reporting grade 3 events (vs 2 percent with placebo).⁷ In clinical practice, most patients receiving neratinib experience diarrhoea, as observed in our patient. It tends to be less severe in patients with pre-existing constipation. Dose-escalation at treatment initiation and symptomatic treatment with oral loperamide PRN have been reported to be effective at minimizing the occurrence and severity of neratinib-associated diarrhoea both in clinical literature and in our patient.⁸

Some patients, like ours, may experience skin rash, which can be managed with topical treatments or referred to a dermatologist. In case of intolerable side effects, temporary treatment suspension until resolution may be appropriate.⁶ Educating patients upfront on possible side effects often enhances treatment compliance.

Our case illustrates the beneficial effects of initiating extended adjuvant neratinib shortly after adjuvant therapy to prevent early relapse in a high-risk HER2-positive eBC patient. Proactive antidiarrhoeal strategies have allowed our patient to complete the full treatment course without interruptions.

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NERLYNX