NGS testing is revealing that acquired HER2 kinase domain mutations, not amplifications, are an emerging resistance mechanism in ER+ lobular breast cancer. This creates a targetable population for HER2 TKIs like neratinib or tucatinib, offering a new line of targeted therapy.
TDXD is highly emetogenic. Adding low-dose olanzapine to the standard three-drug antiemetic prophylaxis regimen is a transformative strategy that significantly reduces both acute and delayed nausea, making the potent therapy much more tolerable for patients.
When imaging is ambiguous between radiation necrosis and tumor progression in the brain, a short course of high-dose dexamethasone can serve as a diagnostic tool. Imaging improvement after steroids strongly suggests radionecrosis, potentially avoiding an invasive biopsy.
Unlike the intact blood-brain barrier, the blood-tumor barrier within brain metastases is permeable. This "leakiness" allows large molecules like the ADC trastuzumab deruxtecan (TDXD) to enter and deliver its payload, providing a mechanism for its high CNS efficacy.
The HER2CLIMB-02 trial found that adding tucatinib to TDM-1 offered only a modest 2-month PFS benefit. This came at the cost of substantially increased toxicity, including transaminitis and diarrhea, suggesting the two agents are better used sequentially for most patients.
For patients with otherwise well-controlled disease who develop isolated oligoprogression in the brain, evidence suggests a better survival outcome from adding local therapy (like SRS) and continuing the current effective systemic therapy, rather than switching the systemic regimen entirely.
The DESTINY-Breast11 trial showed a neoadjuvant regimen of TDXD followed by THP achieved a 67.3% pathologic complete response (pCR) rate in high-risk HER2+ breast cancer. This is the highest pCR rate seen in a registrational trial, signaling a potential new standard of care.
With new CNS-active drugs dramatically improving survival after a brain metastasis diagnosis, some experts are now advocating for routine screening brain MRIs in high-risk patients. The goal is to detect asymptomatic lesions early, potentially preventing catastrophic neurologic events like seizures.
Retrospective data reveals a four-fold increase in radiation necrosis when antibody-drug conjugates (ADCs) like TDXD or TDM-1 are given within weeks of stereotactic radiosurgery (SRS). Clinicians should pause ADC treatment for at least one cycle around SRS to mitigate this serious complication.
A dramatic epidemiological shift has occurred in HER2+ breast cancer. Due to highly effective adjuvant therapies preventing recurrence, the majority of new metastatic cases (two-thirds) are now de novo, a complete reversal from 15 years ago when relapsed disease dominated.
Data from DESTINY-Breast09 shows TDXD plus pertuzumab dramatically improved progression-free survival in first-line metastatic HER2+ breast cancer. This unprecedented efficacy raises new questions about optimal treatment duration and the potential for de-escalated maintenance therapy after induction.
To manage the risk of interstitial lung disease (ILD) with TDXD, experts now recommend routine screening with high-resolution chest CT scans every 6-12 weeks. This practice aims to catch asymptomatic, grade 1 ILD early, allowing for treatment holds and steroid intervention, which may preserve the option to rechallenge.