Faculty Bibliography

Activating mutations of PIK3CA are the most frequent genomic alterations in estrogen receptor (ER)-positive breast tumors, and selective phosphatidylinositol 3-kinase α (PI3Kα) inhibitors are in clinical development. The activity of these agents, however, is not homogeneous, and only a fraction of patients bearing PIK3CA-mutant ER-positive tumors benefit from single-agent administration. Searching for mechanisms of resistance, we observed that suppression of PI3K signaling results in induction of ER-dependent transcriptional activity, as demonstrated by changes in expression of genes containing ER-binding sites and increased occupancy by the ER of promoter regions of up-regulated genes. Furthermore, expression of ESR1 mRNA and ER protein were also increased upon PI3K inhibition. These changes in gene expression were confirmed in vivo in xenografts and patient-derived models and in tumors from patients undergoing treatment with the PI3Kα inhibitor BYL719. The observed effects on transcription were enhanced by the addition of estradiol and suppressed by the anti-ER therapies fulvestrant and tamoxifen. Fulvestrant markedly sensitized ER-positive tumors to PI3Kα inhibition, resulting in major tumor regressions in vivo. We propose that increased ER transcriptional activity may be a reactive mechanism that limits the activity of PI3K inhibitors and that combined PI3K and ER inhibition is a rational approach to target these tumors.

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 receptor-positive (ER+) 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 application of such 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 improving the outcomes of patients with ER+ breast cancer, although caution must apply to their combination with other agents and in the early breast cancer setting.

OBJECTIVE:Many patients with cancer search out information about their cancer on the internet, thus affecting their relationship with their oncologists. An in-depth analysis of patient-physician communication about information obtained from the internet is currently lacking. METHODS:We audio-recorded visits of patients with breast cancer and their oncologists where internet information was expected to be discussed. Inductive thematic text analysis was used to identify qualitative themes from these conversations. RESULTS:Twenty-one patients self-reported discussing cancer-related internet information (CRII) with their oncologists; 16 audio recordings contained detectable discussions of CRII and were analyzed. Results indicated that oncologists and patients initiated CRII discussions implicitly and explicitly. Oncologists responded positively to patient-initiated CRII discussions by (1) acknowledging their limited expertise/knowledge, (2) encouraging/approving using the internet as an information resource, (3) providing information/guidance on the proper use of internet searches, (4) discussing the pros and cons of relevant treatment options, or (5) giving information. Finally, patients reacted to the CRII discussions by (1) indicating that they only used reputable sources/websites, (2) asking for further explanation of information, (3) expressing continued concern, or (4) asking for the oncologist's opinion or recommendation. CONCLUSIONS:These results indicate that the majority of patients introduce internet information implicitly, in order to guard against any threat to their self-esteem. Physicians, in turn, seem to respond in a supportive fashion to reduce any threat experienced. Future interventions may consider providing prescription-based guidance on how to navigate the internet as a health information resource and to encourage patients to bring these topics up with their oncologist.

PURPOSE/OBJECTIVE:The CLEOPATRA (Clinical Evaluation of Trastuzumab and Pertuzumab) study demonstrated superior progression-free survival (PFS) and overall survival when pertuzumab was added to trastuzumab and docetaxel. Paclitaxel given once per week is effective and less toxic than docetaxel. We performed a phase II study to evaluate the efficacy and safety of pertuzumab and trastuzumab with paclitaxel given once per week. PATIENTS AND METHODS/METHODS:Patients with metastatic human epidermal growth factor receptor 2-positive breast cancer with zero to one prior therapy were enrolled. Treatment consisted of paclitaxel 80 mg/m(2) once per week plus trastuzumab (8 mg/kg loading dose → 6 mg/kg) once every 3 weeks plus pertuzumab (840 mg loading dose → 420 mg) once every 3 weeks, all given intravenously. The primary end point was 6-month PFS assessed by Kaplan-Meier methods. RESULTS:From January 2011 to December 2013, we enrolled 69 patients: 51 (74%) and 18 (26%) treated in first- and second-line metastatic settings, respectively. At a median follow-up of 21 months (range, 3 to 38 months), 6-month PFS was 86% (95% CI, 75% to 92%). The median PFS was 19.5 months (95% CI, 14 to 26 months) overall. PFS was 24.2 months (95% CI, 14 months to not reached [NR]) and 16.4 months (95% CI, 8.5 months to NR) for those without and with prior treatment, respectively. At 1 year, Kaplan-Meier PFS was 70% (95% CI, 56% to 79%) overall, 71% (95% CI, 55% to 82%) for those without prior therapy, and 66% (95% CI, 40% to 83%) for those with prior therapy. Treatment was well-tolerated; there was no febrile neutropenia or symptomatic left ventricular systolic dysfunction. CONCLUSION/CONCLUSIONS:Paclitaxel given once per week with trastuzumab and pertuzumab is highly active and well tolerated and seems to be an effective alternative to docetaxel-based combination therapy.

OBJECTIVES/OBJECTIVE:Most research examining the impact of patients seeking online health information treats internet information homogenously, rather than recognizing that there are multiple types and sources of available information. The present research was conducted to differentiate among sources and types of internet information that patients search for, intend to discuss with their doctors, and recall discussing with their doctors, and to determine how accurate and hopeful patients rate this information. METHODS:We surveyed 70 breast cancer patients recruited from the waiting rooms of breast medical oncology and surgery clinics. The main variables in the study were as follows: (1) the sources and types of online information patients have read, intended to discuss, and actually discussed with their doctors, and (2) how accurately and hopefully they rated this information to be. RESULTS:Patients read information most frequently from the websites of cancer organizations, and most often about side effects. Patients planned to discuss fewer types of information with their doctors than they had read about. They most often intended to discuss information from cancer organization websites or WebMD, and the material was most often about alternative therapies, side effects, and proven or traditional treatments. Some 76.8% of total participants rated the information they had read as very or somewhat accurate, and 61% rated the information they had read as very or somewhat hopeful. SIGNIFICANCE OF RESULTS/CONCLUSIONS:Internet information varies widely by source and type. Differentiating among sources and types of information is essential to explore the ways in which online health information impacts patients' experiences.

The demonstrated efficacy of pharmacologic antiestrogen therapy in treating hormone receptor-positive breast cancer has changed the landscape of treatment for the majority of women with metastatic disease, providing them with a well-tolerated therapeutic alternative to surgical oophorectomy and chemotherapy. A multitude of clinical trials have evaluated the various endocrine agents alone or in combination. Studies have established ovarian suppression as key for the management of premenopausal metastatic breast cancer patients, and aromatase inhibitor therapy as first-line treatment for their postmenopausal counterparts. Fulvestrant (Faslodex, AstraZeneca) has also been found to be efficacious and has been studied in the first-line and second-line settings. De novo and acquired endocrine therapy resistance represent a major challenge to the ongoing treatment of patients with hormone receptor-positive disease; strategies to circumvent or delay resistance, including the use of combination endocrine therapy and endocrine therapy with agents targeting various growth-factor signaling pathways, represent an active area of investigation. This review provides a summary of the various landmark trials that have established our current standards of practice in the management of patients with hormone receptor-positive metastatic breast cancer. A discussion of future directions and ongoing studies is also provided.

Tivozanib is a potent selective tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3. This Phase Ib study investigated the safety/tolerability, pharmacokinetics (PK), and activity of tivozanib with weekly paclitaxel in metastatic breast cancer (MBC). MBC patients with no prior VEGFR TKI treatment received daily oral tivozanib (3 weeks on, 1 week off) with weekly paclitaxel 90 mg/m(2). Standard 3 + 3 dose escalation was used; tivozanib cohorts (C) included C1 0.5 mg, C2 1.0 mg, and C3 1.5 mg. Assessments included Response Evaluation Criteria in Solid Tumors response, PK, and vascular function. Eighteen patients enrolled. Toxicities in >20 % of patients included fatigue, alopecia, nausea, diarrhea, peripheral sensory neuropathy, and hypertension. Grade 3/4 toxicities in >15 % of patients included fatigue and neutropenia. Maximum tolerated dose was tivozanib 1.5 mg with paclitaxel 90 mg/m(2). Four patients withdrew because of toxicity and one due to progressive disease. Thirteen patients were evaluable for response: four (30.8 %) had confirmed partial response; four had stable disease ≥6 months (30.8 %). PK data suggest no influence of paclitaxel on tivozanib concentrations. Tivozanib plus weekly paclitaxel was tolerable at all dose levels, supporting their combination at full dose. Activity in this small population was encouraging.