Background: Mirvetuximab soravtansine (MIRV) is an antibody-drug conjugate comprising a folate receptor alpha (FRa)-binding antibody, cleavable linker, and the maytansinoid DM4, a potent tubulin-targeting agent. The randomized, open-label, phase III study FORWARD I compared MIRV and investigator's choice chemotherapy in patients with platinum-resistant epithelial ovarian cancer (EOC). Patients and methods: Eligible patients with 1-3 prior lines of therapy and whose tumors were positive for FRa expression were randomly assigned, in a 2 : 1 ratio, to receive MIRV (6 mg/kg, adjusted ideal body weight) or chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan). The primary endpoint was progressionfree survival [PFS, Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, blinded independent central review] in the intention-to-treat (ITT) population and in the prespecified FRa high population. Results: A total of 366 patients were randomized; 243 received MIRV and 109 received chemotherapy. The primary endpoint, PFS, did not reach statistical significance in either the ITT [hazard ratio (HR), 0.98, P ¼ 0.897] or the FRa high population (HR, 0.69, P ¼ 0.049). Superior outcomes for MIRV over chemotherapy were observed in all secondary endpoints in the FRa high population including improved objective response rate (24% versus 10%), CA-125 responses (53% versus 25%), and patient-reported outcomes (27% versus 13%). Fewer treatment-related grade 3 or higher adverse events (25.1% versus 44.0%), and fewer events leading to dose reduction (19.8% versus 30.3%) and treatment discontinuation (4.5% versus 8.3%) were seen with MIRV compared with chemotherapy. Conclusions: In patients with platinum-resistant EOC, MIRV did not result in a significant improvement in PFS compared with chemotherapy. Secondary endpoints consistently favored MIRV, particularly in patients with high FRa expression. MIRV showed a differentiated and more manageable safety profile than chemotherapy.

Imbalance of the cyclin D and cyclin-dependent kinase (CDK) pathway in cancer cells may result in diversion away from a pathway to senescence and toward a more proliferative phenotype. Cancer cells may increase cyclin D-dependent activity through a variety of mechanisms. Therapeutic inhibition of CDKs in tumors to negate their evasion of growth suppressors has been identified as a key anticancer strategy. In this review, we outline the development of CDK inhibitory therapy in breast cancer, including the initial experience with the pan-CDK inhibitor flavopiridol and the next generation of oral highly selective CDK4 and CDK6 inhibitors PD0332991 (palbociclib), LEE011 (ribociclib), and LY2835219 (abemaciclib). Data from phase I and II studies in estrogen receptorpositive (ER1) breast cancer demonstrate promising efficacy with manageable toxic effects, chiefly neutropenia. We discuss these studies and the phase III studies that are accruing or nearing completion.We describe the applicationofsuch therapy to other breast cancer settings, including HER2-positive breast cancer and the adjuvant treatment of early breast cancer. We also discuss potential concerns surrounding the combination of CDK inhibitors with chemotherapy and their effects on repair of double-strand DNA breaks in cancer cells. Oral highly selective CDK inhibitors show great promise in improvingthe outcomes of patients with ER1 breast cancer, although caution must apply to their combination with other agents and in the early breast cancer setting. The Oncologist 2015;20:483-490Implications for Practice: Cyclin-dependent kinases (CDKs) interact with cyclin D proteins to play an integral role in cell cycle progression and represent attractive therapeutic targets in many tumors, including breast cancer. A number of highly selective inhibitors of CDK4 and CDK6 (CDK4/6) are currently in clinical trial development with one agent recently approved by the U.S. Food and Drug Administration for the treatment of advanced ER+, HER2-negative breast cancer.This article reviews the role of CDK4/6 in tumorigenesis and summarizes the clinical trial experience with inhibitors of these kinases in breast cancer. Key efficacy and toxicity data from the clinical trial experience to date have been reviewed. The planned further expansion of their role in breast cancer therapies and potential concerns regarding combinations with other therapies are addressed.

This is the first study to demonstrate that capecitabine and lapatinib penetrate to a significant though variable degree in human BCBM. Drug delivery to BCBM is variable and in many cases appears partially limiting. Elucidating mechanisms that limit drug concentration and innovative approaches to overcome limited drug uptake will be important to improve clinical efficacy of these agents in the central nervous system. Trial registration ID: NCT00795678.

BACKGROUND: Pregnancy-associated breast cancer (PABC) may be defined as breast cancer diagnosed during pregnancy or within 1 year of giving birth. Conflicting data exist regarding the impact of pregnancy on clinical features and prognosis of breast cancer. METHODS: A single-institution retrospective chart review was performed of 99 patients identified with PABC between 1992 and 2007. Non-PABC controls were matched 2:1 to PABC cases by year of diagnosis and age. The differences in clinical features were compared between cases and controls using chi-square tests. Univariate and multivariate analyses were performed to assess the effect of PABC on survival. RESULTS: Of the 99 PABC cases, breast cancer was diagnosed during pregnancy in 36 patients, and after delivery in 63. PABC cases were more likely than controls to be negative for estrogen receptor (59% vs 31%, P < .0001) and negative for progesterone receptor (72% vs 40%, P < .0001). Cases were also more likely to have advanced T class (P ¼ .0271) and N class (P ¼ .0104) and higher grade tumors (P ¼ .0115). With a median follow-up of 6.3 years for cases and 4.7 years for controls, overall survival did not differ between cases and controls (P ¼ .0787). On multivariate analysis, the independent prognostic factors for overall survival were estrogen receptor status (P ¼ .0031) and N class (P ¼ .0003). The diagnosis of PABC was not an independent prognostic factor (P ¼ .1317). CONCLUSIONS: PABC is associated with more adverse tumor features than non-PABC matched for age and year of diagnosis. After correcting for pathologic features, the diagnosis of PABC is not in itself an adverse prognostic factor for survival. Cancer 2012;118:3254-9.