Nevertheless, the necessity remains to define a mechanistic basis because of this fast progression and formulate substitute therapeutic strategies. strong course=”kwd-title” Keywords: Breasts Cancers, Estrogen Receptor-Positive Breasts Cancer, Fast Disease Development, CDK and CDK Inhibitors Introduction In normal mobile division, different cyclin reliant kinases (CDKs) control the transition in one phase from the cell cycle to some other by binding to cyclin protein subunits and overcoming particular molecular checkpoints. verified, such observations might alter the algorithm for following therapy in sufferers with disease progression in CDK4/6i. Nevertheless, the necessity continues to be to define a mechanistic basis because of this rapid progression and formulate alternative therapeutic strategies. strong class=”kwd-title” Keywords: Breast ML401 Cancer, Estrogen Receptor-Positive Breast Cancer, Rapid Disease Progression, CDK and CDK Inhibitors Introduction In normal cellular division, various cyclin dependent kinases (CDKs) control the transition from one phase of the cell cycle to another by binding to cyclin protein subunits and overcoming specific molecular checkpoints. CDK4 and CDK6 (CDK4/6), in complex with the D class of cyclins, regulate the transition from the early G1 to late G1 phase, while cyclin E, in complex with CDK2, regulate the transition from the late G1 phase to the S phase. The key substrate for these two different complexes is the retinoblastoma (Rb) protein, which is sequentially phosphorylated in early and late G1 by cyclin D1/CDK4/6, followed by cyclin E/CDK2 complexes. The resulting hyperphosphorylated Rb is deactivated, allowing the dividing cell to bypass the G1-S phase cell cycle checkpoint. Overexpression of the G1 cyclins accelerate the transition through the G1-S phase checkpoint, and the subsequent cellular proliferation impacts disease prognosis 1, 2, 3, 4. CDK inhibitors arrest cellular proliferation in response to various conditions. Activating aberrations, such as gene amplification and translocation of cyclins, as well as loss of function of Rb and CDK inhibitors, are common in cancer, making CDKs logical cancer therapy targets 5. Recently, selective CDK4/6 inhibitors (CDK4/6i) have been shown to block the growth of estrogen receptor-positive (ER+) breast cancer cell lines 6, but have low activity as single agents for the treatment of breast cancer 7. Combining CDK4/6 inhibition (palbociclib) with endocrine therapy (letrozole) significantly improved progression-free survival (PFS) from 10.2 to 20.2 months (p=0.0004) when compared to letrozole alone as first-line therapy for the treatment of patients with advanced ER+, HER2-negative (ER+/HER2-) disease. This treatment combination had an acceptable toxicity profile, which included reversible neutropenia 8. Although the study was not powered to assess overall survival (OS), the near doubling in PFS did not translate into significant improvement in OS, with a median of 37.5 months ML401 for the letrozole plus palbociclib arm, and 33.3 months in the letrozole alone arm (p=0.42). At our institution, a patient with bone-only disease, who developed cyclic neutropenia, and also had prolonged disease stability for 12 months while treated on a randomized, double-blind trial of first-line hormone therapy +/- a CDK4/6i, was noted to have increased uptake on bone scans with a rising CA15-3, prompting study drug discontinuation and the initiation of second-line therapy with everolimus and exemestane. After 2 months of second-line therapy, the patient exhibited atypical, rapid disease progression which also included visceral organ involvement. Given this patient’s history of a well-controlled disease status while on study but rapid, secondary disease progression after only 2 months of second-line therapy, we further explored the rate of rapid, secondary disease progression in other patients treated at our cancer center following CDK4/6i trial discontinuation. Methods Using an IRB-approved protocol at the University of Texas MD Anderson Cancer Center, cases of patients who were removed from trials of hormone therapy +/- a CDK4/6i were identified and evaluated for patient outcomes during subsequent treatment after study discontinuation. Only patients who discontinued CDK4/6i therapy due to disease progression are included in this analysis. The data collected included the number of therapies received MPL prior to entering the CDK4/6i clinical trial, subsequent treatment regimen after discontinuing CDK4/6i, start and stop dates for subsequent systemic therapy, reason for discontinuation, and date of last follow-up or patient death. One CDK4/6i-based clinical trial was identified with enrollment durations long enough to have patients who developed disease progression. This trial was a double-blind, first-line therapy trial of CDK4/6i versus placebo in combination with an aromatase inhibitor (AI) for the treatment of advanced ER+/HER2- breast cancer. Patients enrolled in this placebo-controlled trial were allowed, per ML401 protocol, to be unblinded if requested by the treating physician.