Phase 2 ddCMF chemo (alkylator + antifolate + thymidylate synthase inhibitor) in older breast cancer

Memorial Sloan Kettering Cancer Center is running this Phase 2 feasibility study testing dose-dense CMF (cyclophosphamide, methotrexate, and 5‑fluorouracil) as an anthracycline-sparing alternative to AC (doxorubicin/cyclophosphamide) for patients age 70 and older with early-stage breast cancer. Cyclophosphamide is a DNA-alkylating agent, methotrexate inhibits DHFR (blocking folate-dependent DNA synthesis), and 5‑fluorouracil inhibits thymidylate synthase; in Cohort 1, ddCMF for 4 cycles is followed by paclitaxel (a microtubule/tubulin inhibitor) either every 2 weeks or weekly, in the adjuvant or neoadjuvant setting. Cohort 2 focuses on early-stage triple-negative breast cancer in the neoadjuvant setting, adding ddCMF after patients have already started standard carboplatin/paclitaxel with or without pembrolizumab (Merck). The key angle is pragmatic geriatric oncology: can a “dose-dense” CMF backbone preserve curative-intent intensity while avoiding anthracycline cardiac risk that can be more consequential in older adults? Today’s care for higher-risk early TNBC commonly uses neoadjuvant chemo including taxane + carboplatin with pembrolizumab when eligible, followed by surgery and risk-adapted adjuvant therapy; for other higher-risk early breast cancers, adjuvant or neoadjuvant anthracycline/taxane regimens are common, with CMF historically used when anthracyclines are undesirable.