Due to cumulative toxicity concerns with TDXD, particularly ILD, clinicians express more comfort with the shorter 4-cycle neoadjuvant course from DESTINY-Breast11 than the prolonged 14-cycle adjuvant therapy in DESTINY-Breast05, favoring front-loading the treatment.

Positive data from both DESTINY-Breast09 (TDXD-based) and PATINA (CDK4/6i maintenance) create a new dilemma. With similar PFS outcomes, the first-line choice for metastatic HER2+/HR+ patients now hinges on toxicity profiles and patient preference rather than a single efficacy winner.

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.

DESTINY-Breast09 data shows that complete responses with TDXD+pertuzumab can take 8-10 months to develop. This suggests the regimen is not just a short induction strategy and may offer the greatest benefit for durable remission in lower-burden patients, countering the instinct to de-escalate.

For RAS wild-type metastatic colorectal cancer, oncologists may prefer starting with a trastuzumab/tucatinib regimen over TDXD. This sequencing strategy preserves TDXD as a later option, as there is currently no data supporting tucatinib's efficacy after a patient has progressed on TDXD.

A subtle finding in the DESTINY-Breast11 trial, where TDXD alone underperformed TDXD followed by THP, suggests that taxane-based chemotherapy might remain effective even after a patient's HER2-positive cancer becomes resistant to the antibody-drug conjugate TDXD.

To mitigate long-term toxicity from TDXD, oncologists are proposing an "induction/maintenance" approach. Patients receive TDXD for an initial period to achieve maximal response, then switch to a less toxic maintenance regimen for a "chemotherapy holiday," improving quality of life.

In HR+/HER2- early breast cancer, registry data shows only the MammaPrint High-2 (ultra-high risk) subgroup derives significant benefit from adding anthracycline-based chemotherapy. This NCCN-adopted finding allows for therapy de-escalation in MammaPrint High-1 patients, sparing them unnecessary toxicity.

The high efficacy of neoadjuvant TDXD in high-risk HER2+ breast cancer presents a compelling argument to avoid initial surgery for patients with reasonably sized tumors. There is currently no data to support using adjuvant TDXD for patients who undergo surgery first.