Abstract P3-02-11: Screening Magnetic Resonance Imaging (MRI) of the breast in women at increased lifetime risk for breast cancer: A retrospective single institution study.

Abstract Background: Multiple factors are associated with an increased lifetime risk of breast cancer, including inheritance of an abnormal BRCA 1/2 gene, history of lobular carcinoma in situ (LCIS) or atypical hyperplasia, family history of breast cancer or previous chest wall radiation. In 2007, the American Cancer Society released updated guidelines for breast cancer screening based on risk stratification. These guidelines added annual MRI screening to mammography for women with greater than or equal to a 20–25% lifetime risk. Breast MRI screening trials have consistently demonstrated a higher sensitivity of MRI for malignancy compared with mammography, with an additional cancer yield from MRI of approximately 3%. The purpose of this study was to evaluate MRI screening outcomes in women with an increased risk for breast cancer evaluated in an established breast subspecialty clinic within the University of Wisconsin (UW) Hospital and Clinics. Methods: Patients (Pts) were included if they were seen by a UW breast center nurse practitioner, medical or surgical oncologist between 1/1/2007–3/1/2011 with a diagnosis code of: family history of breast or ovarian cancer, genetic susceptibility to malignant neoplasm or genetic carrier, Hodgkin's disease, LCIS, or atypical hyperplasia. Pts with a co-existing diagnosis of invasive breast cancer or ductal carcinoma in situ prior to initial encounter were excluded. Demographic information, breast cancer risk factors, estimated lifetime risk of breast cancer and screening recommendations were abstracted from the medical record. Results of subsequent breast imaging examinations (including breast MRI, diagnostic and screening mammography, and image-guided biopsies) were analyzed with the use of the mammography information system (PenRad™). Results: Of 276 women who met the inclusion criteria, 148 underwent at least 1 screening breast MRI. The majority of MRI screened pts were premenopausal (82%) and Caucasian (96.6%) with a mean age of 42.5 (range 20–68) at their initial encounter. Eighty five percent had a first degree relative with breast cancer and 72.3% of pts undergoing MRI screening had a documented lifetime risk of breast cancer of 20% or greater using a validated model. Within this MRI-screened cohort, 18.2% had a known genetic predisposition to breast cancer. Over the time assessed, 307 MRIs were performed in the 148 pts. Biopsy was recommended and performed based on the results of the MRI in 31 of 307 exams (10%). Ten cancers were detected for a positive predictive value based on biopsy performed of 32% and an overall cancer yield of 3.3% (10 of 307 MRI exams). All cancers were stage 0 - II. All pts are currently with no evidence of disease. Conclusion: Breast MRI has a high positive predictive value and cancer yield with an acceptable biopsy rate in a diverse group of high risk women undergoing breast MRI at an academic center outside of a clinical trial. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-02-11.</jats:p

Abstract OT3-02-06: A phase 1 study of BMN 673 in combination with carboplatin and paclitaxel in patients with advanced solid tumors (NCI9782)

Abstract Background: Poly(ADP-ribose) polymerase (PARP) enzymes are involved in DNA repair and are activated by DNA strand breaks. DNA damage from carboplatin has been associated with activation of PARP. Preclinical data indicate that PARP inhibition potentiates the anti-tumor effect of platinum chemotherapy. BMN 673 (Talazoparib) is an oral, selective PARP inhibitor. The phase I single agent maximum tolerated dose (MTD) of BMN 673 given once daily was 1mg po qd. Myelosuppresion was primary dose-limiting toxicity (DLT), including grade 3-4 thrombocytopenia. Carboplatin with paclitaxel is a current standard treatment for many solid tumors, including ovarian, bladder, upper gastrointestinal, breast and non-small cell lung cancer. Myelosuppression, including thrombocytopenia, is also seen with this combination. This phase 1 study is combining BMN 673 with carboplatin once every 3 weeks and weekly paclitaxel. Trial Design: Two dosing schedules are being investigated. In both schedules intravenous carboplatin will be administered on day 1 and paclitaxel on days 1, 8, 15 of a 21-day cycle. BMN 673 will be dosed orally once daily for days 1-7 (schedule A) or days 1-3 (schedule B) starting on day 1 of each cycle. After 4-6 cycles of the combination therapy, subjects may continue the combination, change to carboplatin and intermittent BMN 673 without paclitaxel or change to BMN 673 alone with continuous daily dosing. Each schedule will have a 6 subject dose expansion at the MTD. The starting dose level for schedule B will be the MTD from Schedule A. The MTD for each schedule will be considered the recommended phase 2 dose (RP2D). Pharmacokinetic samples will be collected. Planned exploratory correlative studies include RAD51 and gamma-H2AX changes in peripheral blood mononuclear cells and examination of mechanism of secondary resistance by comparing mutation profiles in tumors from biopsy specimens. Key eligibility criteria include age 18 or older with a measurable or evaluable solid tumor malignancy that is metastatic or unresectable. Subjects must have tumor type for which there is a reasonable expectation of response to carboplatin and paclitaxel or they must have BRCA germline or somatic mutation. Adequate performance status and organ function is required. Stable, treated brain metastases are allowed. No prior carboplatin for metastatic disease is allowed. Objectives: The primary objectives are to determine the MTD and RP2D of BMN 673 given on the 7 and 3 day schedules in combination with carboplatin and paclitaxel. Secondary objectives include evaluation of the anti-tumor activity, pharmacokinetic parameters, and the safety and tolerability of the combination. Statistical Plan: A standard 3+3 phase 1 dose escalation design is used. Assuming 3-6 subjects per dose level with two schedules including 6 subject dose expansion cohorts and assuming 6 inevaluable subjects, the maximum sample size is 66. Study Status: The trial will be activating in summer 2015 at the Cancer Institute of New Jersey and University of Wisconsin. It is anticipated that 2-3 patients will be accrued per month with accrual completed within 28 months. For more information: www.clinicaltrials.gov (NCT02317874). Citation Format: Mullvain JA, Leal T, Eickhoff J, Kolesar JM, Liu G, DiPaola RS, Wisinski KB. A phase 1 study of BMN 673 in combination with carboplatin and paclitaxel in patients with advanced solid tumors (NCI9782). [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 OT3-02-06.</jats:p

Abstract OT3-01-03: A phase I trial of the safety and immunogenicity of a DNA plasmid based vaccine (WOKVAC) encoding epitopes derived from three breast cancer antigens (IGFBP2, HER2, and IGF1R) in patients with breast cancer

Abstract Background: Three proteins insulin like growth factor binding protein 2 (IGFBP2), human epidermal growth factor receptor 2 (HER2), and insulin like growth factor receptor-1 (IGF1R) are overexpressed in in pre-invasive and high risk breast lesions and are associated with progression to invasive breast cancer. These proteins are immunogenic and elicit both humoral and cellular immunity in breast cancer patients. It is hypothesized that immunization with a plasmid vaccine (WOKVAC) targeting antigens from these proteins will be safe and immunogenic. WOKVAC has been designed to include extended sequences of the immunizing antigens that are predominantly associated with eliciting Type I immune responses. Type I immunity results in immune cells called T-cells secreting high levels of inflammatory cytokines (called Th1) that stimulate tumor destruction as well as the generation of cytotoxic T-cells that can directly kill the tumors. Trial design: Phase I dose escalation study of 3 doses of WOKVAC admixed with 100mcg of GM-CSF. Patients will be assigned sequentially to one of three arms (10 patients/arm): Arm 1=150mcg, Arm 2=300mcg, Arm 3=600mcg. Each dose arm will have a staggered enrollment to assess toxicity. If the Arm 1 dose is determined to be safe, Arm 2 patients can be enrolled. If the Arm 2 dose is safe and immunologically more efficacious than Arm 1 then Arm 3 patients can be enrolled. Study treatment includes 3 monthly vaccines, two evaluations at 1 and 6 months post vaccine and a 5 year follow-up to collect reports from the patient's primary oncologist. Toxicity is assessed at baseline through the end of the study. Serial blood draws for immunologic monitoring is done. Eligibility criteria: Patients with non-metastatic, node positive, HER2 negative breast cancer that is in remission and defined as no evidence of disease. Patients must have a good performance status, be at least 28 days from last cytotoxic chemotherapy and/or radiotherapy and 28 days from any use of systemic steroids. Specific aims: (1) Determine safety of 3 escalating doses of WOKVAC, (2) Determine the most immunogenic dose, (3) Determine whether a WOKVAC Th1 polyepitope plasmid based vaccine elicits a persistent memory T-cell and (4) Determine whether WOKVAC vaccination modulates T regulatory cells and myeloid derived suppressor cells. Statistical methods: (1) Safety will be assessed per NCI CTCAE v. 4.0, (2) Immunogenicity will be defined by the magnitude of the Th1 IFN-gamma antigen specific immune response. Successful immunization is a protein specific IFN-g precursor frequency greater than 1:20,000 PBMC for each antigen or 2 fold increase if baseline immune response (3) The IGFBP2, HER2, and IGF1R specific IFN-g/IL-10 ratios by ELISPOT will be evaluated to determine that a predominantly Th1 immune response is stimulated, and (4) Humoral immune response will be measured by ELISA and serum antibody avidity for IGFBP2, HER2, and IGF1R to determine an avidity index (AI) before and after vaccination. Targeted Accrual: 30 patients Contact information: University of Washington: 866-392-8588/[email protected] University of Wisconsin: 608-265-2493/[email protected]. Citation Format: Childs JS, Higgins DM, DeShong K, Heckman-Stoddard BM, Wojtowicz ME, Stanton SE, Bailey HH, Wisinski KB, Disis ML. A phase I trial of the safety and immunogenicity of a DNA plasmid based vaccine (WOKVAC) encoding epitopes derived from three breast cancer antigens (IGFBP2, HER2, and IGF1R) in patients with breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT3-01-03.</jats:p

P4-11-21: A Retrospective Analysis of Women at Increased Lifetime Risk for Breast Cancer: Referral Patterns to Subspecialty Providers, Recommendations and Outcomes.

Abstract Background: Inheritance of an abnormal BRCA 1/2 gene, a family history of breast cancer (BrCa), or a personal history of lobular carcinoma in situ (LCIS), atypical hyperplasia, or chest wall radiation can significantly increase an individual's lifetime risk for developing BrCa. In 2007, the American Cancer Society (ACS) released updated guidelines for screening in women with a lifetime risk of BrCa ≥20-25%. These guidelines added MRI screening to annual mammography. The objective of our analysis is to characterize patients referred after the release of the 2007 ACS guidelines to subspecialty providers specifically for evaluation of BrCa risk and analyze subsequent screening and risk reduction recommendations in the cohort of patients (pts) with a predicted increased lifetime risk for BrCa. Methods: Pts seen at a single center (University of Wisconsin [UW]) between 1/2007-3/2011 by medical, surgical and/or gynecology-oncology for an increased lifetime risk of BrCa were identified by billing codes or evaluation in the UW Breast Cancer Prevention, Assessment and Tailored Health Screening (PATHS) Clinic. Pts with a personal history of BrCa prior to 1/2007 are excluded. Patients with a known genetic predisposition to BrCa, family history of breast cancer, or a personal history of LCIS, atypical hyperplasia or chest wall radiation are included in this analysis. All charts will be evaluated for documentation of the individual's lifetime risk of BrCa and method used for risk-assessment, recommended and performed screening tests, concordance with ACS screening guidelines, patient adherence to initial and subsequent screening recommendations, and uptake of risk reduction strategies. Call-back rates for additional or follow-up imaging and/or biopsy following BrCa screening and characteristics of all new BrCa diagnoses will be collected. Results: 240 eligible pts were seen during the study period. 15% of pts referred had a known genetic predisposition to BrCa. Most pts (75%) were referred for a family history of BrCa. The majority of these pts had a predicted lifetime risk of BrCa in excess of 20%, with less than 10% of patients being referred having a lifetime risk &amp;lt;20%. The remaining pts were referred for a personal history of LCIS, atypical hyperplasia or previous radiation to the chest wall. Results including subspecialty provider BrCa risk assessment, screening and risk-reduction recommendations, patient uptake and adherence, outcomes of screening and characteristics of diagnosed BrCa cases will be presented. Conclusion: Pts with a predicted increased lifetime risk for BrCa are often evaluated by oncology subspecialty providers. The primary factor related to referral is family history of BrCa. The majority of patients referred to a subspecialty provider have a calculated lifetime risk for BrCa in excess of 20%. This study evaluates provider assessment of BrCa risk and subsequent recommendations for screening and discussion of risk reduction strategies. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-11-21.</jats:p

Abstract P2-11-15: Development of a web-based survey tool to assess change in breast cancer (BrCa) survivor knowledge after receipt of cancer treatment summary and survivorship care plan (SCP).

Abstract Intro: The Institute of Medicine advocates survivorship care plans (SCPs) as tools to improve coordination of care by improving survivor knowledge of follow-up recommendations and future risks. No evidence exists to demonstrate that SCPs impact survivor knowledge of diagnosis, treatment, or future/chronic side effects. Furthermore, there is a lack of information on existing surveys and their ability to assess survivor knowledge regarding these issues, without change over time. The purpose of this research is to report on the development of a survey assessing knowledge of diagnosis, treatment, and side effects in BrCa survivors. Methods: Using existing literature, two oncologists created 24 questions addressing knowledge of diagnosis, treatment, and side effects. Content experts including breast oncology providers (representing multiple subspecialties), Survey Research Shared Service (SRSS) and patient advocates reviewed and revised the questions. Next, potential questions were administered in a group setting to BrCa survivors to evaluate clarity of instructions and survey wording. The Breast Cancer Knowledge (BreaCK) survey was further revised based on survivor feedback. For pilot testing, BrCa survivors were recruited from clinic to test BreaCK survey content and clarity. Survey 1 was administered in clinic online. SRSS conducted verbal assessments regarding content after Survey 1. Four weeks later, survivors received Survey 2 via email and answered online. Correct answers were abstracted from the medical record. Results: Nine subjects completed both surveys. Qualitatively, little intra-subject variation was seen between surveys. Subjects did not feel that the survey was burdensome or intrusive. No subject was able to correctly answer all questions. Final survey adjustments were made based on subject feedback and common incorrect answers encountered when grading the surveys. Specifically, subjects had difficulty understanding “endocrine or hormone therapy.” Furthermore, subjects reported guessing in response to some questions – additional answer categories were added, including “I don't know.” Conclusion: Survivor knowledge did not change significantly between surveys. This suggests survivor knowledge was not impacted by the survey over the four-week interval. The revised BreaCK survey may be a useful tool for assessing survivor knowledge of diagnosis, treatment and side effects. A larger cohort of BrCa survivors is being recruited, starting Summer 2012, and will be evaluated using the survey. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-11-15.</jats:p

Abstract P6-12-02: Use of cytochrome P450 interacting medications in the setting of adjuvant therapy for breast cancer.

Abstract Background: In the current era of personalized medicine, oral targeted therapies are increasingly used in cancer treatment. In breast cancer, oral anti-estrogen agents have historically been part of standard treatment for hormone receptor positive disease. More recently, other targeted agents have been introduced in the metastatic setting, and are being evaluated as adjuvant therapies. Many oral medications, including anticancer therapies, are metabolized by cytochrome P450 (CYP450) enzymes raising possibility of drug-drug interactions that may affect toxicities or breast cancer outcomes. We sought to evaluate concomitant CYP450 medication use among women seeing a medical oncologist to discuss adjuvant systemic therapy for breast cancer. Methods: We performed an electronic medical record database extraction. Adult women diagnosed with breast cancer from 1/2008-7/2011 were identified from the University of Wisconsin Hospital and Clinics Cancer Registry. Medication lists were extracted from the first encounter with a medical oncologist after the initial breast cancer diagnosis. Non-systemic medications were excluded. Cytochrome P450 (CYP450) enzyme-interacting medications were categorized as inhibitors, inducers, and/or substrates of specific enzymes including CYP1A2, CYP2A6, CYP2B6, CYP2C19, CYP2C8, CYP2C9, CYP2D6, CYP2E1, and CYP3A4. CYP450 inhibitors and inducers were further characterized as strong, moderate or weak acting. Results: A total of 455 women with non-metastatic breast cancer were identified. Mean age was 56.6 years (range of 23–90) and 413 (91%) were Caucasian. Polypharmacy, defined as use of 3–5 medications, was seen in 123 (27.0%) women. A total of 236 (51.9%) women were on 0–4; 109 (24.0%) on 5–10; and 13 (2.9%) on &amp;gt; 10 medications at the time of first encounter with a medical oncologist after a breast cancer diagnosis. 23 (5.05%) women were on strong CYP450 enzyme inhibitors while 72 (15.8%) were on strong inducers. CYP450 enzymes most commonly affected were CYP3A4, CYP2C9, and CYP2D6. Among medications taken on a fixed schedule, levothyroxine and simvastatin were the most commonly used, while simvastatin and ranitidine were the most common CYP450 interacting medications. Further classification of potential CYP450 interactions is ongoing. Conclusions: A significant proportion of patients were on one or more CYP450 interacting medications in the setting of adjuvant therapy for breast cancer. Given the number of new oral cancer agents that are also CYP450 interacting, the potential for drug interactions should be recognized and appropriate management strategies implemented. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-12-02.</jats:p

P5-18-12: Perception, Practice and Toxicity of Adjuvant Treatment of HER2+ Breast Cancer in Wisconsin.

Abstract INTRODUCTION: Multiple trastuzumab-containing (neo)adjuvant regimens are used for HER2+ BrCa, but the experience with these regimens in routine practice is not reported. Some oncologists select TCH based on BCIRG 006, whereas others prefer anthracycline-based therapy. We evaluated whether oncologists’ perceptions of these regimens match clinical experience. METHODS: We surveyed 151 Wisconsin (WI) oncologists regarding factors impacting selection of TCH versus AC-TH; 65 (42%) responded. At the same time, we reviewed 200 cases of HER2+ BrCa treated with adjuvant trastuzumab from 2003 to 2010 at the University of Wisconsin Carbone Cancer Center (UW) and the Marshfield Clinic. We collected baseline patient and tumor characteristics, regimen administered, and toxicities as assessed by lab values, cardiac ejection fraction (EF), hospitalizations, dose reductions/delays, and ability to complete therapy. RESULTS: Two-thirds of surveyed oncologists prefer anthracycline-based therapy over TCH. Of oncologists preferring TCH, 20 of 23 had been in practice for &amp;gt;10 years. Oncologists perceived that AC-TH and TCH were equally likely to be completed. The majority of physicians select therapy based on patient age and stage, with a preference for AC-TH for node-positive disease and TCH for early stage (T1a-bN0) tumors. Despite BCIRG 006 remaining unpublished at the time of the survey, peer-review publication was cited as the most important factor in selecting this regimen. Although use of granulocyte colony stimulating factor (GCSF) in BCIRG 006 has not reported, 50% of oncologists indicated routine use with cycle 1 of TCH. Of the 200 cases reviewed, 114 women received AC-TH, 48 women received TCH, and 38 had other regimens. The median age was 53 years old, 52% had node positive disease. Acute toxicity trended higher with TCH. For example, there were fewer dose modifications/delays for AC-TH than TCH (31% vs. 46%, p=0.07). This may have been due to common use of GCSF with AC-TH (77% vs. 33% use with TCH). Neutropenic fever (NF) was higher with TCH, reaching 25% incidence when administered without GCSF. However, NF did not occur in the 8 TCH patients who received cycle 1 GCSF. There was no correlation between NF and patient age. The incidence of left ventricular EF decline leading to cessation of trastuzumab was similar for both regimens (19.4% AC-TH vs. 14.6% TCH; p = 0.64). Trastuzumab was completed as planned in 70% of patients. Although EF decline was most common explanation, 13% of early trastuzumab discontinuations occurred for other reasons. CONCLUSION: TCH and AC-TH are the most commonly administered adjuvant regimens for WI women with HER2+ BrCa. Amongst WI oncologists, TCH is perceived as safer, but is less likely to be recommended for node-positive BrCa. This retrospective analysis suggests that acute myelosuppression is greater for TCH, with a significant rate of NF. Per ASCO guidelines, these data suggest GCSF should be used routinely with TCH due to high rate of FN. We were intrigued that oncologists who have been in practice longer are more likely to choose TCH. The reasons for this are unclear, but are perhaps related to prior experience with long-term cardiotoxicity with AC-TH. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-18-12.</jats:p

Abstract P3-12-10: Feasibility of four cycles of docetaxel and cyclophosphamide every 14 days as an adjuvant regimen for breast cancer: A Wisconsin oncology network study

Abstract Background: Dose-dense therapies have had a major impact on reducing toxicity and improving outcomes in breast cancer. A combination of docetaxel plus cyclophosphamide (TC) every 3 weeks has emerged as a common chemotherapy regimen used for treatment of node-negative or lower-risk node-positive breast cancer. We tested whether it is feasible to deliver TC on a dose-dense schedule. Patients and Methods: We enrolled women with early stage breast cancer on a single-arm phase II study of adjuvant dose-dense TC (ddTC) through a regional oncology network (WON). All women completed primary surgery; subsequent therapy with TC was deemed appropriate by the treating physician. Planned treatment was docetaxel 75 mg/m2 plus cyclophosphamide 600 mg/m2 every 2 weeks for 4 cycles with subcutaneous pegfilgrastim 6 mg administered 24-48 hours after the administration of each chemotherapy cycle. The primary endpoint was feasibility of administering therapy within 10 weeks. A Simon Optimal 2-Stage design was employed for the study design. Results: Of 42 women enrolled, 41 were evaluable by prespecified criteria. Median age was 54 (28-73). Most subjects had node negative (73%) or hormone receptor positive (71%) tumors. Of the 41 subjects, 37 (90.2%) completed therapy within 10 weeks and 34 (83%) completed therapy at 8 weeks without dose modification. Rates of grade 2 neuropathy were similar to that reported previously (15%) and there were no cases of grade 3 or higher neuropathy. The rate of neutropenic fever was low (2.5%). Rash and plantar/palmar erythrodythesia were common and reached grade 3 in four subjects (9.8%). Conclusion: Dose-dense TC is feasible with tolerability profiles similar to standard TC and a low likelihood of neutropenic fever. This study supports further clinical development of this 8-week adjuvant chemotherapy regimen. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-12-10.</jats:p

Abstract P5-13-03: Prospective study of work limitations in breast cancer patients (pts) undergoing curative chemotherapy (CTx)

Abstract This abstract was withdrawn by the authors.</jats:p