Background: Given excellent survival outcomes in breast cancer, there is interest in de-escalating the amount of chemotherapy delivered to patients. This approach may be of even greater importance in the setting of the COVID-19 pandemic. Methods: This concurrent mixed methods study included (1) interviews with patients and patient advocates and (2) a cross-sectional survey of women with breast cancer served by a charitable nonprofit organization. Questions evaluated interest in de-escalation trial participation, perceived barriers/facilitators to participation, and language describing de-escalation. Results: Sixteen patient advocates and 24 patients were interviewed. Key barriers to de-escalation included fear of recurrence, worry about decision regret, lack of clinical trial interest, and dislike for focus on less treatment. Facilitators included trust in physician recommendation, toxicity avoidance, monitoring for progression, perception of good prognosis, and impact on daily life. Participants reported that the COVID-19 pandemic made them more likely to avoid chemotherapy if possible. Of 91 survey respondents, many (43%) patients would have been unwilling to participation in a de-escalation clinical trial. The most commonly reported barrier to participation was fear of recurrence (85%). Few patients (19%) considered clinical trials themselves as a barrier to de-escalation trial participation. The most popular terminology describing chemotherapy de-escalation was “lowest effective chemotherapy dose” (53%); no patients preferred the term “de-escalation.”. Conclusions: Fear of recurrence is a common concern among breast cancer survivors and patient advocates, contributing to resistance to de-escalation clinical trial participation. Additional research is needed to understand how to engage patients in de-escalation trials.