Rebecca K. Viscusi

Adaptive Randomization of Veliparib–Carboplatin Treatment in Breast Cancer

BACKGROUND The genetic and clinical heterogeneity of breast cancer makes the identification of effective therapies challenging. We designed I-SPY 2, a phase 2, multicenter, adaptively randomized trial to screen multiple experimental regimens in combination with standard neoadjuvant chemotherapy for breast cancer. The goal is to match experimental regimens with responding cancer subtypes. We report results for veliparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, combined with carboplatin. METHODS In this ongoing trial, women are eligible for participation if they have stage II or III breast cancer with a tumor 2.5 cm or larger in diameter; cancers are categorized into eight biomarker subtypes on the basis of status with regard to human epidermal growth factor receptor 2 (HER2), hormone receptors, and a 70-gene assay. Patients undergo adaptive randomization within each biomarker subtype to receive regimens that have better performance than the standard therapy. Regimens are evaluated within 10 biomarker signatures (i.e., prospectively defined combinations of biomarker subtypes). Veliparib-carboplatin plus standard therapy was considered for HER2-negative tumors and was therefore evaluated in 3 signatures. The primary end point is pathological complete response. Tumor volume changes measured by magnetic resonance imaging during treatment are used to predict whether a patient will have a pathological complete response. Regimens move on from phase 2 if and when they have a high Bayesian predictive probability of success in a subsequent phase 3 neoadjuvant trial within the biomarker signature in which they performed well. RESULTS With regard to triple-negative breast cancer, veliparib-carboplatin had an 88% predicted probability of success in a phase 3 trial. A total of 72 patients were randomly assigned to receive veliparib-carboplatin, and 44 patients were concurrently assigned to receive control therapy; at the completion of chemotherapy, the estimated rates of pathological complete response in the triple-negative population were 51% (95% Bayesian probability interval [PI], 36 to 66%) in the veliparib-carboplatin group versus 26% (95% PI, 9 to 43%) in the control group. The toxicity of veliparib-carboplatin was greater than that of the control. CONCLUSIONS The process used in our trial showed that veliparib-carboplatin added to standard therapy resulted in higher rates of pathological complete response than standard therapy alone specifically in triple-negative breast cancer. (Funded by the QuantumLeap Healthcare Collaborative and others; I-SPY 2 TRIAL ClinicalTrials.gov number, NCT01042379.).

The Neoadjuvant Model is Still the Future for Drug Development in Breast Cancer

The many improvements in breast cancer therapy in recent years have so lowered rates of recurrence that it is now difficult or impossible to conduct adequately powered adjuvant clinical trials. Given the many new drugs and potential synergistic combinations, the neoadjuvant approach has been used to test benefit of drug combinations in clinical trials of primary breast cancer. A recent FDA-led meta-analysis showed that pathologic complete response (pCR) predicts disease-free survival (DFS) within patients who have specific breast cancer subtypes. This meta-analysis motivated the FDAs draft guidance for using pCR as a surrogate endpoint in accelerated drug approval. Using pCR as a registration endpoint was challenged at ASCO 2014 Annual Meeting with the presentation of ALTTO, an adjuvant trial in HER2-positive breast cancer that showed a nonsignificant reduction in DFS hazard rate for adding lapatinib, a HER-family tyrosine kinase inhibitor, to trastuzumab and chemotherapy. This conclusion seemed to be inconsistent with the results of NeoALTTO, a neoadjuvant trial that found a statistical improvement in pCR rate for the identical lapatinib-containing regimen. We address differences in the two trials that may account for discordant conclusions. However, we use the FDA meta-analysis to show that there is no discordance at all between the observed pCR difference in NeoALTTO and the observed HR in ALTTO. This underscores the importance of appropriately modeling the two endpoints when designing clinical trials. The I-SPY 2/3 neoadjuvant trials exemplify this approach. Clin Cancer Res; 21(13); 2911–5. ©2015 AACR.

Trends in post-mastectomy reconstruction: A SEER database analysis

This study was performed to investigate recent trends and factors associated with immediate breast reconstruction (IBR) using a large population‐based registry. We hypothesized that rates of IBR have increased since passage of the Womens Health and Cancer Rights Act of 1998.

Introducing a Fresh Cadaver Model for Ultrasound-guided Central Venous Access Training in Undergraduate Medical Education

Introduction Over the past decade, medical students have witnessed a decline in the opportunities to perform technical skills during their clinical years. Ultrasound-guided central venous access (USG-CVA) is a critical procedure commonly performed by emergency medicine, anesthesia, and general surgery residents, often during their first month of residency. However, the acquisition of skills required to safely perform this procedure is often deficient upon graduation from medical school. To ameliorate this lack of technical proficiency, ultrasound simulation models have been introduced into undergraduate medical education to train venous access skills. Criticisms of simulation models are the innate lack of realistic tactile qualities, as well as the lack of anatomical variances when compared to living patients. The purpose of our investigation was to design and evaluate a life-like and reproducible training model for USG-CVA using a fresh cadaver. Methods This was a cross-sectional study at an urban academic medical center. An 18-point procedural knowledge tool and an 18-point procedural skill evaluation tool were administered during a cadaver lab at the beginning and end of the surgical clerkship. During the fresh cadaver lab, procedure naïve third-year medical students were trained on how to perform ultrasound-guided central venous access of the femoral and internal jugular vessels. Preparation of the fresh cadaver model involved placement of a thin-walled latex tubing in the anatomic location of the femoral and internal jugular vein respectively. Results Fifty-six third-year medical students participated in this study during their surgical clerkship. The fresh cadaver model provided high quality and lifelike ultrasound images despite numerous cannulation attempts. Technical skill scores improved from an average score of 3 to 12 (p<0.001) and procedural knowledge scores improved from an average score of 4 to 8 (p<0.001). Conclusion The use of this novel cadaver model prevented extravasation of fluid, maintained ultrasound-imaging quality, and proved to be an effective educational model allowing third-year medical students to improve and maintain their technical skills.

The role of genetic testing in patients with breast cancer a review

Importance In the United States from 2009 to 2013, the incidence of breast cancer was the highest of any cancer and the death rate was second to that of lung cancer. Approximately 5% to 10% of breast cancers are inheritable. Observations BRCA1 and BRCA2 germline mutations account for up to 30% of inheritable breast cancers and are the most commonly assessed mutations in patients presenting with early-onset breast cancer, triple-negative breast cancer, bilateral breast cancer, and a family history of breast cancer. Less common non-BRCA mutations have also been identified and contribute to hereditary breast cancer syndromes. Although established in BRCA mutations, indications and interpretations of genetic testing in non-BRCA mutations are not well defined. Furthermore, costs associated with genetic testing are highly variable and dependent on laboratory pricing, insurance coverage, and individual risk factors. Conclusions and Relevance Genetic testing is a powerful tool that allows for the detection of BRCA and non-BRCA germline mutations in individuals with high risks of breast cancer, which in turn aids in the individualization of treatment. Given the magnitude of this disease, it is of great benefit for physicians, including general surgeons, to understand the indications, interpretations, and costs associated with genetic testing in patients with breast cancer. Cost is an especially important part of the genetic testing process and point of discussion with patients.

Development of a fresh cadaver model for instruction of ultrasound-guided breast biopsy during the surgery clerkship: pre-test and post-test results among third-year medical students.

BACKGROUND The aim of our study was to determine if a fresh cadaver model is a viable method for teaching ultrasound (US)-guided breast biopsy of palpable breast lesions. METHODS Third-year medical students were assessed both preinstruction and postinstruction on their ability to perform US-guided needle aspiration or biopsy of artificially created masses using a 10-item checklist. RESULTS Forty-one third-year medical students completed the cadaver laboratory as part of the surgery clerkship. Eight items on the checklist were found to be significantly different between pre-testing and post-testing. The mean preinstruction score was 2.4, whereas the mean postinstruction score was 7.10 (P < .001). CONCLUSIONS Fresh cadaver models have been widely used in medical education. However, there are few fresh cadaver models that provide instruction on procedures done in the outpatient setting. Our model was found to be an effective method for the instruction of US-guided breast biopsy among medical students.

37 – Assessment and Designation of Breast Cancer Stage

Abstract Staging of breast cancer is critical for making treatment decisions as well as for prognosis. Staging systems have evolved over time, and most providers caring for patients with breast cancer use American Joint Commission on Cancer staging. This chapter also provides a review of multicentric and multifocal characteristics of breast cancer.

Learning preferences of surgery residents: A multi-institutional study

Background. The VARK model categorizes learners by preferences for 4 modalities: visual, aural, read/write, and kinesthetic. Previous single‐institution studies found that VARK preferences are associated with academic performance. This multi‐institutional study was conducted to test the hypothesis that the VARK learning preferences of residents differ from the general population and that they are associated with performance on the American Board of Surgery In‐Training Examination (ABSITE). Methods. The VARK inventory was administered to residents at 5 general surgery programs. The distribution of the VARK preferences of residents was compared with the general population. ABSITE results were analyzed for associations with VARK preferences. χ2, Analysis of variance, and multiple linear regression were used for statistical analysis. Results. A total of 132 residents completed the VARK inventory. The distribution of the VARK preferences of residents was different than the general population (P < .001). The number of aural responses on the VARK inventory was an independent predictor of ABSITE percentile rank (P = .03), percent of questions correct (P = .01), and standard score (P = .01). Conclusion. This study represents the first multi‐institutional study to examine VARK preferences among surgery residents. The distribution of preferences among residents was different than that of the general population. Residents with a greater number of aural responses on VARK had greater ABSITE scores. The VARK model may have potential to improve learning efficiency among residents.

Abstract P6-04-10: Clinicopathological and molecular characteristics of pleomorphic invasive lobular carcinoma of breast

Background: Pleomorphic invasive lobular carcinoma (PILC) is described as a distinct morphological variant of invasive lobular carcinoma (ILC) but its clinical behavior is not well characterized. PILCs have loss of E-cadherin similar to ILCs but have distinct morphological features like nuclear contour irregularity, a single prominent nucleolus, increased hyperchromasia and more frequent mitoses. In addition, some studies have reported that PILCs have acquired further molecular alterations such as gain of HER2/neu, amplification of c-myc and loss of p53. To the best of our knowledge there have been no studies evaluating Phosphoinositide 3 kinase/Akt/mammalian (or mechanistic) target of rapamycin (PI3K/Akt/mTOR) pathway in PILC. We hypothesize that there is increased activation of PI3K/Akt/mTOR pathway in PILC compared to ILC. Activation of the PI3k/Akt/mTOR pathway was evaluated by quantifying protein expression of phosphatase and tensin homolog (PTEN) and phosphorylated-S6 kinase1 (p-S6K1). PTEN is a negative regulator of the PI3K pathway and its loss/decreased expression (by mutation or allelic imbalance) activates downstream signaling. Loss (or decrease) of PTEN expression has been reported to be associated with PI3K pathway activation in more than 50% of ER+ breast tumors. Since PI3K pathway can be activated by other mechanisms in addition to PTEN loss, we hypothesized that evaluation of pS6K1 may predict activation of this pathway more than PTEN protein expression alone. Methods: We conducted a retrospective translational study at the University of Arizona Cancer Center. Our Pathology database was searched to identify PILCs from 2012-2014. Two investigators reviewed the pathology reports independently and abstracted clinocopathological data. Formalin-fixed paraffin embedded (FFPE) primary PILCs were stained for PTEN and pS6K1 expression. Expression of PTEN and pS6K1 was quantified by long score methodology as low (≤ 10), moderate (11-50) or high (≥ 50) expression. Results: We identified 19 patients with PILC. All tumors were either moderately (n=10) or poorly differentiated (n=9). Estrogen receptor (ER) was positive in all, progesterone receptor (PR) was positive in 11(52%) and HER2 was negative in all tumors. Proliferation index (Ki67) was elevated in all tumors (median 32%, range 20-70%). Lymph nodes were involved with metastatic carcinoma in 7 patients (negative in 9 and unknown in 3). The 21-gene recurrence score assay (Oncotype Dx) was performed in 10 patients and demonstrated higher scores (median 23, range 6-36) with the majority being in the intermediate or high range (8/10). Expression of PTEN and p-S6K1 was quantified on 10 FFPE tumor tissues. PTEN expression was high in all while pS6K1 was high in 8 and low in 2 tumors. Conclusion: PILCs are a biologically distinct group of ILC. Clinicopathological characteristics suggest they would have a more clinically aggressive behavior (higher grade, high proliferative index and 21 gene recurrence score). In addition, our results indicate that PI3k/Akt/mTOR pathway in activated in majority of these tumors and that PTEN is not the key regulator of this pathway. Genomic profiling is currently underway to further analyze other causes of pathway activation. Citation Format: Segar J, Baker AF, MacKerricher W, Nagle R, Livingston R, Clarke K, Ley M, Viscusi R, Gonzalez V, LeBeau L, Chalasani P. Clinicopathological and molecular characteristics of pleomorphic invasive lobular carcinoma of breast. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-04-10.

Abstract P2-13-27: Nipple sparing mastectomy: Risks of wound complication in the setting of neo-adjuvant or adjuvant chemotherapy and/or radiation therapy

Background: Surgical care of breast cancer has evolved significantly over the past 40 years. Nipple sparing mastectomy (NSM) and skin sparing mastectomy (SSM) have become an increasingly used surgical management for women with malignant breast disease. To date, there are limited recommendations about the role of NSM in patients receiving aggressive adjuvant therapy. The purpose of this investigation is to determine whether NSM in the setting of neo-adjuvant or adjuvant chemotherapy and/or radiation therapy increased the risks for wound complications. Methods: A retrospective chart review of nipple sparing mastectomies at a single institution was performed from 2007 to 2014. Multiple data points including neo-adjuvant or adjuvant chemotherapy and/or radiation therapy, obesity, smoking history, and type of reconstructive surgery were examined in detail. Results: We counted the procedures by breasts affected and identified 76 NSM in the time period which met criteria. Of the 76 NSMs, 27 breasts received neo-adjuvant(20) or adjuvant chemotherapy and/or radiation(7) therapy. 21 breasts in the NSM group developed wound complications including skin flap necrosis (5), total nipple necrosis and loss (11) hematoma (2) infection(2) and seroma(1). The complications were seen in 11 in the non adjuvant treated setting (14%) and 9 (33%) in the adjuvant therapy setting. Conclusions: Nipple sparing mastectomy are emerging as safe and adequate options for the management of malignant breast disease. Our results show there is a significant risk of wound complication associated with neo-adjuvant and adjuvant chemotherapy and radiation therapy in the setting of nipple sparing mastectomy. We are pursuing the development of new surgical techniques and guidelines to reduce these risks in these high risk patients. Citation Format: Selyne Samuel, Rebecca Viscusi, Amy Waer, Victor Gonzalez, Pavani Chalasani, Craig Hurst, Ethan Larson, Robert Livingston, Michele Ley. Nipple sparing mastectomy: Risks of wound complication in the setting of neo-adjuvant or adjuvant chemotherapy and/or radiation therapy [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-13-27.