Michael DiGiovanna

Neoadjuvant Trastuzumab Induces Apoptosis in Primary Breast Cancers

Purpose Greater understanding of the cellular response in trastuzumab-treated patients will provide insight into the clinical management of patients. Patients and Methods We performed a neoadjuvant trial in 35 patients with locally advanced HER-2/neu overexpressing breast cancers who received weekly trastuzumab given as a single agent for the first 3 weeks, followed by a combination of trastuzumab and docetaxel for 12 weeks before surgery. Sequential core biopsies were taken at baseline and within weeks 1 and 3 after the first dose of trastuzumab. Clinical response to trastuzumab was assessed by tumor measurements on day 22 before chemotherapy. Core biopsies were assessed by immunohistochemistry for cell cycle and proliferation (Ki67, p27, phosphorylated [p] -MAPK), apoptosis and survival (apoptotic index, p-Akt), epidermal growth factor receptor, and total and p-HER-2. Results There was early tumor regression with a median decrease of −20.0% (range. 0% to 60.4%) after only 3 weeks of trastuzumab, and eig...

Abstract P6-06-37: Predicting improvements in survival based on improvements in pathologic response rate to neoadjuvant chemotherapy in different breast cancer subtypes

Background: Individuals with excellent pathologic response (complete response or minimal residual cancer burden, pCR+RCB-I) to neoadjuvant chemotherapy have prolonged survival, and several chemotherapy regimens have resulted in improved pathologic response rates. However, how to estimate expected improvements in disease free survival (DFS) in a clinical trial based on improvement in pathologic response remains uncertain. The purpose of this study was to develop a statistical tool to estimate improvements in DFS based in improvements in pCR/RCB-I in triple negative (TNBC) and HR+/HER2- breast cancer subtypes. Methods: 387 clinical stage II (73%) and III (23%) breast cancers who received neoadjuvant T/FAC chemotherapy at MD Anderson Cancer Center were included in this analysis (N = 127 TNBC, N = 260 HR+/HER2-). Patients received adjuvant endocrine therapy if HR+. To evaluate the association between pCR rate and survival we used within-subtype stratified bootstrap analysis with biased resampling from the two response groups (pCR and RCB-I) to generate 500 bootstrapped populations with a range of different response rates. Survival was based on the Kaplan-Meier estimator with its variance obtained from the bootstrap standard error. Power was estimated as the probability of no overlap in the 95% log confidence intervals of survival in 500 bootstrap replicates of populations of different sizes and response rates. Results: Excellent pathologic response (pCR or RCB-I), was observed in 50% and 23% in the TNBC and ER+/HER2- cohorts respectively. The median follow-up was 7.6 years (range 0.1 to 13.4 years); 48 and 59 relapses occurred in the TNBC and HR+ subtypes, respectively. Bootstrap analysis showed a linear dependence of the 5-year DFS on the pCR/RCB-I rate, with a slope of 0.472 for TNBC suggesting a 4.7% improvement in DFS for every 10% increase in response rate. A more modest slope of 0.129 was observed for ER+/HER2- cancers. The sample size of a randomized 2-arm study required to show with 80% power a statistically significant improvement in 5-year DFS that corresponds to 75% response rate compared to baseline response rate of 50% and 23% in TNBC and ER+/HER2- would be 1144 and 1688 cases respectively. We are providing an open-access web-based calculator to estimate improvements in DFS and for sample size calculations for randomized clinical trials with combined endpoints of pCR/RCB-I and survival. Conclusions: We observed a linear increase in DFS with increase in pathologic response rate in the evaluated cohort. The slope depends on breast cancer subtype - it is greater in TNBC than in ER+ cancers - and expected to be influenced by the stage distribution in the study population. These results could help provide a basis for powering studies with combined response and survival endpoints. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-06-37.

Bidirectional Text Messaging to Monitor Endocrine Therapy Adherence and Patient-Reported Outcomes in Breast Cancer

INTRODUCTIONnUp to 40% of patients with breast cancer may not adhere to adjuvant endocrine therapy. Therapy-related adverse effects (AEs) are important contributors to nonadherence. We developed a bidirectional text-message application, BETA-Text, that simultaneously tracks adherence, records symptoms, and alerts the clinical team.nnnPATIENTS AND METHODSnWe piloted our intervention in 100 patients. The intervention consisted of text messages to which patients responded for 3 months: daily, evaluating adherence; weekly, evaluating medication-related AEs; and monthly, regarding barriers to adherence. Concerning responses prompted a telephone call from a clinic nurse. The primary objective was to assess patient acceptance of this intervention using self-reported surveys. To compare participants with the general population at our institution, we assessed 100 consecutively treated patients as historical controls using medical record review.nnnRESULTSnWe approached 141 consecutive patients, 100 (71%) of whom agreed to participate and 89 of whom completed the intervention. A majority of patients reported that the intervention was easy to use (98%) and helpful in taking their medication (96%). Four patients discontinued therapy before 3 months, and 93% of patients who continued therapy took ≥ 80% of their medication. The frequency of AEs reported by participants via text was higher than that reported in clinical trials: hot flashes (72%), arthralgias (53%), and vaginal symptoms (35%). Approximately 39% of patients reported one or more severe AE that prompted an alert to the provider team to call the patient.nnnCONCLUSIONnA daily bidirectional text-messaging system can monitor adherence and identify AEs and other barriers to adherence in real time without inconveniencing patients. AEs of endocrine therapy, as detected using this texting approach, are more prevalent than reported in clinical trials.

Mutation based treatment recommendations from next generation sequencing data: a comparison of web tools

Interpretation of complex cancer genome data, generated by tumor target profiling platforms, is key for the success of personalized cancer therapy. How to draw therapeutic conclusions from tumor profiling results is not standardized and may vary among commercial and academically-affiliated recommendation tools. We performed targeted sequencing of 315 genes from 75 metastatic breast cancer biopsies using the FoundationOne assay. Results were run through 4 different web tools including the Drug-Gene Interaction Database (DGidb), My Cancer Genome (MCG), Personalized Cancer Therapy (PCT), and cBioPortal, for drug and clinical trial recommendations. These recommendations were compared amongst each other and to those provided by FoundationOne. The identification of a gene as targetable varied across the different recommendation sources. Only 33% of cases had 4 or more sources recommend the same drug for at least one of the usually several altered genes found in tumor biopsies. These results indicate further development and standardization of broadly applicable software tools that assist in our therapeutic interpretation of genomic data is needed. Existing algorithms for data acquisition, integration and interpretation will likely need to incorporate artificial intelligence tools to improve both content and real-time status.

Abstract P5-11-03: Development of an interactive text messaging tool to improve adherence with adjuvant endocrine therapy: Breast cancer endocrine therapy adherence (BETA) pilot study

Introduction: Approximately 75% of stage I-III breast cancers are hormone receptor (HR) positive for which the standard of care is 5-10 years of adjuvant endocrine therapy, which has been shown to reduce recurrences and improve survival. Unfortunately, up to 40% of patients may not take the prescribed medication daily or may discontinue it early. Mobile health technology provides an opportunity to develop new innovative tools to identify women who are not taking medication as prescribed, to understand their barriers for adherence and to facilitate communication with providers to improve adherence. Methods: The objective of the BETA study was to develop a new bi-directional text messaging application that simultaneously assesses patient adherence to endocrine therapy and provides direct communication to the provider team. Our primary endpoint was to assess feasibility of the application and the secondary endpoints included adherence, side effects and their severity, and quality of life (QOL). The intervention consisted of 3 types of text messages to which patients responded: 1) daily, evaluating adherence, 2) weekly, evaluating medication-related side effects and their severity, and 3) monthly, evaluating barriers to taking the medication. After 3 months of participation, patients completed surveys assessing the tolerability and financial burden of the intervention and adherence to medication. Patients were eligible if they had stage I-III, HR-positive breast cancer, owned a cell phone, and were initiating endocrine therapy. Target enrollment is 100 patients. For comparison, 100 consecutive patients meeting the above criteria were identified retrospectively as historical controls; adherence was assessed via chart review. Results: Between November 2014 and May 2015, 62 patients (mean age 53.5 years) were enrolled and 25 had completed the study. Of those approached, 66% participated. Of those who completed the study, the application was found to be helpful by 63%; specifically, 76% felt the intervention was a reminder to take the medication, 96% felt it was easy to use, and 71% wanted to continue receiving text messages after the study ended. On average, patients spent 12 minutes with the application per week, 0% felt it took up too much time, and only 1 patient incurred text messaging fees. No patients withdrew from the study and only 1 patient did not adhere to treatment (as defined by ≥ 80% adherence). None of the enrolled patients discontinued endocrine therapy, compared to 9% of historical controls. Side effects were common: hot flashes/night sweats (61% of patients), joint aches/pains (56%), and vaginal symptoms (29%) were reported. Severe side effects (reported by 29% of patients) prompted a return phone call to the patient. The study is ongoing and final results will be available by December 2015. Conclusion: We developed a new bi-directional text messaging intervention to assess adherence to endocrine therapy that provides real-time feedback to providers. Patients found the application helpful, easy to use, and not time consuming. Our tool is scalable for large population-based trials. Citation Format: Epstein LN, Jhaveri AP, Han G, Abu-Khalaf MM, Hofstatter EW, Sanft TB, DiGiovanna MP, Silber AL, Adelson KB, Chung GG, Pusztai L, Gross CP, Mougalian SS. Development of an interactive text messaging tool to improve adherence with adjuvant endocrine therapy: Breast cancer endocrine therapy adherence (BETA) pilot study. [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 P5-11-03.

Abstract 3879: Patient preferences for disclosure of incidental genetic information discovered through high-throughput sequencing

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PAnnINTRODUCTION: Several high throughput next generation sequencing platforms that search for targetable genetic alterations in cancer are now available in the clinic. However, a large number of germline variants may also be detected during testing, some of which may predispose a patient to diseases other than cancer. If, and how, to disclose these incidental genetic findings is controversial. The purpose of this study was to assess patient preferences regarding disclosure of incidental genetic findings.nnMETHODS: We developed a cross-sectional questionnaire study of ambulatory breast oncology patients. Patients completed a 45 item questionnaire, including their disclosure preferences about various hypothetical scenarios of incidental genetic findings found during tumor profiling. Basic descriptive statistics and the proportional odds logistic regression were used for analysis. RESULTS: Of 351 patients approached between February-May 2014, 199 (56%) responded. Participants had a mean age of 55 (29-80), and most were Caucasian (75%), had Stage 0-III disease (61%), were college-educated (53%) and comfortable with basic genetic information (69%). Sixty-eight percent of respondents desired tumor profiling even if they were found to carry a mutation that could cause a disease other than cancer. While 74% initially indicated they would want to know all genetic information found, only 47% of respondents wanted to know about variants of uncertain significance when specifically questioned. Only 12% expressed preference not to learn about a mutation that was potentially heritable. Most patients (82%) preferred to know if they had a mutation that increased their risk of a serious but preventable illness (eg heart disease), but only 57% desired information for mutations that always caused a serious and unpreventable illness (eg Alzheimers dementia). Interestingly, 62% of patients desired tumor profiling even if there was only a 1% chance it would help their treatment, yet 54% endorsed significant concern about the potential risk of incidental findings impacting their ability to obtain health insurance. Ultimately, 59% of respondents indicated that they would agree to undergo tumor profiling if offered by their doctor; Caucasians (OR 4.1, CI 2-8.3) and those with prior knowledge of tumor profiling (OR 2.6, CI 1.3-5.1) were more likely to agree, while cancer stage, treatment, marital status, education, income, family history and other demographic factors were not significant.nnCONCLUSIONS: A majority of breast cancer patients express interest in pursuing tumor profiling. The potential for incidental genetic findings does not appear to significantly dissuade patients from pursuing this technology, nor does the potential for learning about germline traits that could impact family members. However, there is remarkable variability in disclosure preferences of specific types of incidental findings.nnCitation Format: Melinda L. Yushak, Sara Bouberhan, Gang Han, Lianne Epstein, Sarah Mougalian, Maysa Abu-Khalaf, Gina Chung, Michael DiGiovanna, Tara Sanft, Lajos Pusztai, Erin Hofstatter. Patient preferences for disclosure of incidental genetic information discovered through high-throughput sequencing. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3879. doi:10.1158/1538-7445.AM2015-3879

Abstract P3-14-02: Patterns of the use of primary systemic therapy in the United States

Background: Primary systemic therapy (PST) is an accepted alternative to adjuvant systemic therapy of breast cancer. It provides equivalent survival, increased breast conservation rates, and prognostic information. Methods: This analysis assesses patterns of PST use based on information collected by the National Cancer Database (NCDB), a joint project of the American College of Surgeons and the American Cancer Society which captures data on over 70% of all diagnosed breast cancer patients in the U.S. Using the b-participant use file of the NCDB, we evaluated regional, patient, and tumor factors associated with PST use. Results: The NCDB captured 621,319 patients treated with PST from 2006 to 2010. Of these, 7.4% received systemic therapy pre-operatively, and 3.6% in both the pre- and post-operative settings. Factors correlating with timing of therapy are shown in the table. PST use increased steadily from 7.0% to 7.8% (p<0.001) from 2006 to 2010. PST was significantly more frequently used in younger, African-American, Hispanic, low-income, uninsured patients with larger, node positive tumors, living in large metropolitan areas in the West and treated in academic centers. These factors remained significantly and independently associated with PST on multivariate analysis. View this table: Conclusion: PST appears to be underutilized, received by only 7.8% of all patients, 36% of T3-T4 tumors, and 26.0% of clinically node positive patients. However, its rate of use has increased over the past years. There is also significant regional variation in the use of PST, independent of patient and tumor factors. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-14-02.

Abstract P6-06-09: Baseline assessment of left ventricular function for breast cancer patients undergoing anthracycline and/or trastuzumab: What is the prevalence of baseline dysfunction?

Background: It is unclear if all breast cancer patients require baseline left ventricular function (LVEF) assessment prior to anthracycline chemotherapy, and the approach is variable in clinical practice. While some oncologist do not obtain baseline LVEF assessment in breast cancer patients under the age of 65 without known cardiac risk factors, others continue to perform baseline LVEF assessment in all breast cancer patients who will be receiving adjuvant anthracycline chemotherapy. We sought to determine the prevalence of left ventricular dysfunction in breast cancer patients prior to anthracycline and /or trastuzumab therapy, and to identify the cardiac risk factors associated with a low LVEF. Methods: We performed a retrospective analysis of the Yale Equilibrium Radionuclide Angiography (ERNA) database, which also included self-reported cardiac risk factors. We identified 702 patients who had a baseline ERNA scan prior to anthracycline and/or trastuzumab therapy for an initial diagnosis of stages I-IV BC between July 2003 and May 2013. Our objective was to determine the prevalence rate of an abnormal baseline LVEF defined as Results: Median age was 51(range 26-86); 637 (91%) patients were 65 years of age or younger. BMI Conclusion: The prevalence of abnormal baseline LVEF in patients being considered for anthracycline and/or trastuzumab therapy is small. Age, BMI, pre-existing cardiac risk factors and coronary artery disease were not associated with LVEF Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-06-09.