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.

In neoadjuvant settings, ctDNA monitoring allows for real-time therapy adjustment. Data from the iSpy platform shows 80% of hormone-positive patients clear ctDNA with half the chemotherapy, enabling de-escalation, while the remaining 20% can be identified for escalated treatment.

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.

With pirtobrutinib, time to next treatment often exceeds progression-free survival. This discrepancy exists because disease progression is frequently slow and asymptomatic, meaning clinicians do not need to switch therapies immediately upon seeing radiographic changes, allowing for longer treatment duration.

For patients with oligometastatic disease who achieve a deep PSA response (e.g., to zero), oncologists consider finite treatment durations (e.g., 18-24 months) followed by observation. This "do less harm" approach challenges the standard of continuous therapy until progression, aiming for long-term treatment-free intervals.

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.

In metastatic breast cancer, approximately one-third of patients are unable to proceed to a second line of therapy due to disease progression or declining performance status. This high attrition rate argues for using the most effective agents, such as ADCs, in the first-line setting.

The PR21 trial showed better overall survival for docetaxel followed by Lutetium, despite similar progression-free survival. The likely reason is not drug superiority but patient behavior: a higher percentage of patients complete the second therapy when starting with chemo, highlighting how treatment fatigue significantly impacts survival.

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.