David R. Brenin

Impact of Patient Distance to Radiation Therapy on Mastectomy Use in Early-Stage Breast Cancer Patients

PURPOSE Treatment access underlies quality cancer care. We hypothesize that mastectomy rates in a rural state are independently influenced by distance to radiation therapy (XRT) and by changing XRT access through opening new facilities. PATIENTS AND METHODS Early-stage breast cancer patients diagnosed from 1996 to 2000 were identified in the Virginia state registry. Distance from patient zip code to nearest XRT facility was calculated with geographical software. Distance to XRT facility (< or = 10, > 10 to 25, > 25 to 50, and > 50 miles), American Joint Committee on Cancer tumor stage, age, race, and diagnosis year were evaluated for influencing mastectomy rate. Mastectomy use within 15 miles of five new facilities was assessed before and after opening. RESULTS Among 20,094 patients, 43% underwent mastectomy, 53% underwent lumpectomy, and therapy of 4% of patients is unknown. Twenty-nine percent of patients lived more than 10 miles from XRT facility. Mastectomy increased with distance to XRT facility (43% at < or = 10 miles, 47% at > 10 to 25 miles, 53% at > 25 to 50 miles, and 58% at > 50 miles; P < .001). Among 11,597 patients with T1 (< 2 cm) tumors, mastectomy also varied by distance (31% at < or = 10 miles, 36% at > 10 to 25 miles, 41% at > 25 to 50 miles, and 49% at > 50 miles; P < .001). In multivariate analysis, mastectomy use was independently influenced by XRT distance after adjusting for age, race, T stage, and diagnosis year. Over the study period, mastectomy rates declined from 48% to 43% across Virginia, and there were similar declines in a 15-mile area around four new radiation facilities in urban settings. However, mastectomies decreased from 61% to 45% around a new XRT facility in a rural setting. CONCLUSION Distance to XRT facility significantly impacts mastectomy use. Opportunities for increasing breast-conservation rates through improved XRT access exist.

A theory-based decision aid for patients with cancer: Results of feasibility and acceptability testing of DecisionKEYS for cancer

PurposeAppropriate utilization of treatment is a goal for all patients undergoing cancer treatment. Proper treatment maximizes benefit and limits exposure to unnecessary measures. This report describes findings of the feasibility and acceptability of implementing a short, clinic-based decision aid and presents an in-depth clinical profile of the participants.MethodsThis descriptive study used a prospective, quantitative approach to obtain the feasibility and acceptability of a decision aid (DecisionKEYS for Balancing Choices) for use in clinical settings. It combined results of trials of patients with three different common malignancies. All groups used the same decision aid series. Participants included 80 patients with solid tumors (22 with newly diagnosed breast cancer, 19 with advanced prostate cancer, and 39 with advanced lung cancer) and their 80 supporters as well as their physicians and nurses, for a total of 160 participants and 10 health professionals.ResultsThe decision aid was highly acceptable to patient and supporter participants in all diagnostic groups. It was feasible for use in clinic settings; the overall value was rated highly. Of six physicians, all found the interactive format with the help of the nurse as feasible and acceptable. Nurses also rated the decision aid favorably.ConclusionsThis intervention provides the opportunity to enhance decision making about cancer treatment and warrants further study including larger and more diverse groups. Strengths of the study included a theoretical grounding, feasibility testing of a practical clinic-based intervention, and summative evaluation of acceptability of the intervention by patient and supporter pairs. Further research also is needed to test the effectiveness of the decision aid in diverse clinical settings and to determine if this intervention can decrease overall costs.

Focused Ultrasound Ablation for the Treatment of Breast Cancer

Advances in technology and changes in our understanding of tumor biology have allowed breast cancer treatment to evolve toward less disfiguring procedures. Noninvasive ablative therapy is a natural continuation of this trend. The following paper presents the concepts underpinning focused ultrasound ablation therapy for the treatment of breast cancer and reviews the investigative experience to date in the evaluation of this promising technique.

An evaluation of a computer-imaging program to prepare women for chemotherapy-related alopecia

Objective: This study was conducted to evaluate a computer program named Help with Adjustment to Alopecia by Image Recovery (HAAIR) that was developed to provide educational support and reduce distress in women with hair loss following chemotherapy.

Development of a RSK Inhibitor as a Novel Therapy for Triple-Negative Breast Cancer

Metastatic breast cancer is an incurable disease and identification of novel therapeutic opportunities is vital. Triple-negative breast cancer (TNBC) frequently metastasizes and high levels of activated p90RSK (RSK), a downstream MEK-ERK1/2 effector, are found in TNBC. We demonstrate, using direct pharmacologic and genetic inhibition of RSK1/2, that these kinases contribute to the TNBC metastatic process in vivo. Kinase profiling showed that RSK1 and RSK2 are the predominant kinases targeted by the new inhibitor, which is based on the natural product SL0101. Further evidence for selectivity was provided by the observations that silencing RSK1 and RSK2 eliminated the ability of the analogue to further inhibit survival or proliferation of a TNBC cell line. In vivo, the new derivative was as effective as the FDA-approved MEK inhibitor trametinib in reducing the establishment of metastatic foci. Importantly, inhibition of RSK1/2 did not result in activation of AKT, which is known to limit the efficacy of MEK inhibitors in the clinic. Our results demonstrate that RSK is a major contributor to the TNBC metastatic program and provide preclinical proof-of-concept for the efficacy of the novel SL0101 analogue in vivo. Mol Cancer Ther; 15(11); 2598–608. ©2016 AACR.

Techniques for intraoperative radiation therapy for early-stage breast carcinoma

Intraoperative radiation therapy (IORT) is a method of accelerated partial breast irradiation developed to replace other longer courses of radiotherapy with a single radiation session administered at the time of breast-conserving surgery. The purpose of this review is to summarize the advantages and disadvantages of breast IORT techniques that are currently available, as well to consider potential alternative techniques for breast IORT or ultra-short course breast radiotherapy. Furthermore, we highlight the published outcomes for the IORT treatment approaches including: electron therapy, superficial photon therapy and other techniques. Potential future directions of IORT are explored including novel IORT techniques utilizing intraoperative brachytherapy with in-room imaging and rapid treatment planning.

Clinical trial priorities among surgeons caring for breast cancer patients

BACKGROUND Designing and prioritizing successful clinical trials benefits from increased community physician input. We surveyed practicing surgeons about current controversies in breast cancer surgery, reported practices of discussing trial participation, and perceived obstacles to trial participation. METHODS A 44-question survey was mailed in 2005-2006 to 2,187 randomly selected American College of Surgeons members actively seeing breast cancer patients. Responses were analyzed by surgeon sex, practice type, oncology training, professional society membership, and breast cancer patient volume. RESULTS A total of 923 responses were received, with 460 eligible responses remaining for analysis. Most surgeons infrequently or never discuss trial participation with breast cancer patients. Inadequate infrastructure presents the greatest physician obstacle to trial participation. Identifying proven indications for completion axillary dissection after positive sentinel node biopsy marks the highest-ranked research priority for surgeons providing breast care. CONCLUSIONS Understanding topics of interest among practicing surgeons and addressing common obstacles to trial participation may result in improved breast cancer patient accrual through surgeons.

Development of a high sensitivity, nested Q-PCR assay for mouse and human aromatase

Measurement of breast tissue estradiol levels could provide a powerful method to predict the risk of developing breast cancer but obtaining sufficient amounts of tissue from women is difficult from a practical standpoint. Assessment of aromatase in ductal lavage fluid or fine needle aspirates from breast might provide a surrogate marker for tissue estrogen levels but highly sensitive methods would be required. These considerations prompted us to develop an ultra-sensitive, “nested” PCR assay for aromatase which is up to one million fold more sensitive than standard PCR methods. We initially validated this assay using multiple tissues from the aromatase transgenic mouse and found that coefficients of variation for measurement of replicate samples averaged less than 5%. We demonstrated a 60-fold enhancement in aromatase message in the transgenic versus the wild type mouse breast but surprisingly, levels in the transgenic animals were highly variable, ranging from 0.4 to 27 relative units. The variability of aromatase expression in the transgenic breast did not correlate with the degree of breast development and did not appear to relate to hormonal manipulation of the MMTV promoter but probably related to lack of exhaustive inbreeding and mixed zygocity of transgenic animals. Extensive validation in mouse tissues provided confidence regarding the assay in human tissues, since nearly identical methods were used. The human assay was sufficiently sensitive to detect aromatase in a single human JAR (choriocarcinoma) cell, in all breast biopsies measured, and in 7/23 ductal lavage fluids.

A pilot study of the immunogenicity of a 9-peptide breast cancer vaccine plus poly-ICLC in early stage breast cancer

BackgroundBreast cancer remains a leading cause of cancer death worldwide. There is evidence that immunotherapy may play a role in the eradication of residual disease. Peptide vaccines for immunotherapy are capable of durable immune memory, but vaccines alone have shown sparse clinical activity against breast cancer to date. Toll-like receptor (TLR) agonists and helper peptides are excellent adjuvants for vaccine immunotherapy and they are examined in this human clinical trial.MethodsA vaccine consisting of 9 MHC class I-restricted breast cancer-associated peptides (from MAGE-A1, −A3, and -A10, CEA, NY-ESO-1, and HER2 proteins) was combined with a TLR3 agonist, poly-ICLC, along with a helper peptide derived from tetanus toxoid. The vaccine was administered on days 1, 8, 15, 36, 57, 78. CD8+ T cell responses to the vaccine were assessed by both direct and stimulated interferon gamma ELIspot assays.ResultsTwelve patients with breast cancer were treated: five had estrogen receptor positive disease and five were HER2 amplified. There were no dose-limiting toxicities. Toxicities were limited to Grade 1 and Grade 2 and included mild injection site reactions and flu-like symptoms, which occurred in most patients. The most common toxicities were injection site reaction/induration and fatigue, which were experienced by 100% and 92% of participants, respectively. In the stimulated ELIspot assays, peptide-specific CD8+ T cell responses were detected in 4 of 11 evaluable patients. Two patients had borderline immune responses to the vaccine. The two peptides derived from CEA were immunogenic. No difference in immune response was evident between patients receiving endocrine therapy and those not receiving endocrine therapy during the vaccine series.ConclusionsPeptide vaccine administered in the adjuvant breast cancer setting was safe and feasible. The TLR3 adjuvant, poly-ICLC, plus helper peptide mixture provided modest immune stimulation. Further optimization is required for this multi-peptide vaccine/adjuvant combination.Trial registrationClinicalTrials.gov(posted 2/15/2012): NCT01532960. Registered 2/8/2012.https://clinicaltrials.gov/show/NCT01532960

Intraoperative breast radiation therapy with image guidance: Findings from CT images obtained in a prospective trial of intraoperative high-dose-rate brachytherapy with CT on rails

PURPOSE Intraoperative radiation therapy (IORT) is an increasingly popular approach to breast conserving therapy in the treatment of early-stage breast cancer. A drawback to IORT compared with postoperative adjuvant radiation therapy is that it is not performed using image guidance. Our aim was to report on how our institutions unique IORT workflow integrates CT image guidance and how these CT images were used intraoperatively to change applicator positioning. METHODS AND MATERIALS We retrospectively reviewed the first 29 patients who participated in a prospective clinical trial of breast IORT at our institution. All patients underwent lumpectomy, multicatheter balloon placement, intraoperative CT scan, and high-dose-rate brachytherapy treatment delivery to 12.5 Gy to 1 cm from the balloon surface. This report focuses on the intraoperative CT findings that led to clinical changes, followed by repeat CT for IORT treatment planning. RESULTS After initial intraoperative CT, 7 patients underwent an additional intraoperative CT scan (24.1%). In 6 patients, the initial intraoperative CT scan identified large air cavities and/or poor tissue conformity. This defect could be improved in all patients with adjustment of the balloon applicator before planning and delivering IORT. Intraoperative CT scan was used in one patient to localize a biopsy clip and aided in excision to negative margin. CONCLUSIONS In our study, intraoperative CT identifies actionable findings in breast IORT, including residual tumor or errors in applicator positioning, in almost 25% of patients. Clinical results of the described trial will serve to further validate this image-guided approach to IORT.