Purpose: The G 1 -S checkpoint of the cell cycle is frequently dysregulated in breast cancer. Palbociclib (PD0332991) is an oral inhibitor of CDK4/6. Based upon preclinical/phase I activity, we performed a phase II, single-arm trial of palbociclib in advanced breast cancer.Experimental Design: Eligible patients had histologically confirmed, metastatic breast cancer positive for retinoblastoma (Rb) protein and measureable disease. Palbociclib was given at 125 mg orally on days 1 to 21 of a 28-day cycle. Primary objectives were tumor response and tolerability. Secondary objectives included progression-free survival (PFS) and assessment of Rb expression/localization, KI-67, p16 loss, and CCND1 amplification.Results: Thirty-seven patients were enrolled; 84% hormonereceptor (HR) þ /Her2 À

Conflict of interest: AD serves as principal investigator for clinical trials for which the University of Pennsylvania receives research funding from Novartis, Pfizer, Genentech, Calithera, and Menarini. JJDM received consultant fees from Novartis and Loxo Pharmaceuticals. SWS received consultant fees from Becton Dickinson and research funding from Cook Biotech and SillaJen. LAC received consultant fees for expert testimony on behalf of Imerys related to talc, and for consulting on behalf of Eli Lilly related to asbestos.

B cells undergo a random process of V(D)J recombination to generate the many distinct receptors needed to recognize a vast array of antigens. An inevitable consequence of this random process is the production of autoreactive B cells ( 1 ). An important mechanism for tolerizing autoreactive B cells is receptor editing ( 2 ). Receptor editing results in the alteration of B cell receptor specifi city and is achieved by ongoing Ig gene rearrangement, most commonly at the light chain loci ( 3 -5 ). Light chain rearrangement proceeds in an ordered fashion as B cells develop in the bone marrow, with genes recombining fi rst, followed by rearrangement of the recombining sequence (RS) and ( 6, 7 ). The RS (also known as the deleting element [KDE] in humans) is a noncoding gene segment located 25 kb downstream of C in the locus that is rearranged during continued Ig light chain gene rearrangement ( 8,9 ).Because of the unique structure of the locus, primary V -J rearrangements that are nonfunctional or autoreactive can be replaced via " leap-frogging " recombination of unrearranged upstream V and downstream J gene segments to form new light chains ( Fig. 1 a ). Additional rearrangement attempts can be made through recombination at the second allele or at . Recombination of RS to upstream V gene segments or a recombination signal sequence within the J -C intron results in the deletion or inversion of C and functional inactivation of the locus ( Fig. 1 a ). Because RS rearrangements do not encode any functional proteins ( 10 ), monitoring RS rearrangement provides a specifi city-independent means of measuring repeated rearrangement attempts at (receptor editing).The original studies characterizing RS recombination postulated that it served to promote rearrangement by either repressing rearrangement or activating the locus ( 7, 11 ). However, -expressing B cells can form without undergoing RS rearrangement, indicating that RS is not required for the production of ( 12 ). When RS rearrangement is prevented in RS knockout mice, receptor editing is ineffi cient and autoreactive B cells are found among peripheral cells ( 13 ) Continued antibody gene rearrangement, termed receptor editing, is an important mechanism of central B cell tolerance that may be defective in some autoimmune individuals. We describe a quantitative assay for recombining sequence (RS) rearrangement that we use to estimate levels of antibody light chain receptor editing in various B cell populations. RS rearrangement is a recombination of a noncoding gene segment in the antibody light chain locus. RS rearrangement levels are highest in the most highly edited B cells, and are inappropriately low in autoimmune mouse models of systemic lupus erythematosus (SLE) and type 1 diabetes (T1D), including those without overt disease. Low RS rearrangement levels are also observed in human subjects with SLE or T1D.

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Depressed anti-HER2 Th1 response is a novel immune correlate to recurrence in patients with completely treated HER2-positive IBC. These data underscore a role for immune monitoring in patients with HER2-positive IBC to identify vulnerable populations at risk of treatment failure.