Rashmi Krishna Murthy

Strategies are needed to avoid chemotherapy in early stage HER2-positive (HER2 + ) breast cancer (BC). We conducted a neoadjuvant therapy trial with zanidatamab, a dual HER2-directed bispecific antibody, in patients with 1-3 cm, node-negative HER2 + BC. Primary endpoint was pathologic complete response (pCR). Secondary endpoints were radiographic response by ultrasound and magnetic resonance imaging. US and MRI, pathologic response by residual cancer burden (RCB), rate of adverse events, feasibility of accrual and biomarkers of response. Fifteen patients with HER2 IHC 3 + , and 5 with HER2 IHC 2 + /ISH + BC were enrolled. Patients received zanidatamab 20 mg/kg every 2 weeks for 6 (n = 11) or 10 doses (n = 9). Fourteen patients also received endocrine therapy. At 6 weeks, there was a significant decrease in tumor size and volume. At surgery, six patients (30%) had pCR, meeting the prespecified pCR target, and four had limited RCB (RCB-1; 20%). Treatment was well tolerated. All patients with pCR had HER2 IHC 3+ tumors, ERBB2 amplification on WES, PAM50 HER2-high subtype, and a trend towards higher HER2 mRNA expression (p = 0.06). In conclusion, de-escalation to HER2-targeted therapy alone may be feasible. Further research is needed to refine patient selection. This study is registered at ClinicalTrials.gov (NCT05035836).

Treatments for leptomeningeal metastasis (LM) are limited and prognosis is poor. In this phase 2, nonrandomized, single-arm, multicenter study, we evaluated a tucatinib-trastuzumab-capecitabine regimen in patients with newly diagnosed LM and human epidermal growth factor receptor 2-positive (HER2⁺) breast cancer. The primary endpoint was overall survival; secondary endpoints included central nervous system progression-free survival, LM objective response, neurological symptom improvement, pharmacokinetics and safety. The trial met its prespecified interim efficacy threshold and exceeded the historical control of 4.4 months. Among 17 enrolled women, all had magnetic resonance imaging-confirmed LM, 15 (88%) were symptomatic and 8 (47%) had abnormal cerebrospinal fluid cytology. For a median follow-up of 18 months (range 9.0-26.7 months), 6 of 17 (41%) remained alive. Tucatinib reached therapeutic levels in the cerebrospinal fluid. The median overall survival was 10 months (95% confidence interval 4.1 months, not reached). The median time to central nervous system progression was 6.9 months (95% confidence interval 2.8, 13.8 months). Of 13 response-evaluable patients, 5 (38%) achieved composite LM objective response. Of 12 evaluable patients, 7 (58%) had improved neurological deficits. This prospective study suggests clinical benefit with a systemic regimen for HER2⁺ LM including objective responses, improved symptoms and extended survival. These data support systemic therapy as an approach in HER2⁺ breast cancer LM. ClinicalTrials.gov registration: NCT03501979 .

Characteristics of patients with both CNS and extracranial response

Type of Surgery and Adjuvant Therapy Received.

Somatic mutations identified by whole exome sequencing. Oncoplot representing the most common somatic mutations assessed by whole exome sequencing (WES) in tumors obtained from patients (n = 23) at the time of diagnosis. Genes with mutations occurring in five or more patients are shown.

Representativeness of Study Participants.

SUPPLEMENTARY FIGURE SF3. Box plots showing relationship between tumor mutational burden and pathological response.

Molecular Subtypes and Pathological Response.

SUPPLEMENTARY FIGURE SF2. Somatic mutations in genes commonly altered in TNBC. Oncoplot showing somatic mutations reported as commonly prevalent in other TNBC cohorts.