Lisa Klepczyk

Abstract B37: Increased expression of poly (ADP-ribose) polymerase (PARP) and phospho-p65 in human HER2+ breast cancer

Background: Despite the efficacy of targeted agents against the HER2 receptor, many patients with HER2+ breast cancer will develop resistance, thus necessitating novel treatment strategies. Poly (ADP-ribose) polymerase inhibitors (PARPi) are a well-tolerated class of drugs that target tumors with defective DNA repair pathways. Interestingly, we previously reported that HER2+ breast cancer cells are sensitive to PARPi alone both in vitro and in vivo independent of a basal or induced DNA repair defect (Nowsheen et al., Cancer Research 2012). Further, we found that attenuation of NF-κB signaling may account for this intriguing susceptibility. To further substantiate the potential utility of PARPi in HER2+ breast cancer, we investigated the expression and cellular location of PARP and phospho-p65, indicators of activity of the PARP and NF-κB pathways, respectively, in human HER2+ breast cancer specimens and compared to HER2- breast tumors. Methods: Breast cancer patients treated at UAB with available stored tissue blocks between the years 1999 and 2012 were identified. Formalin-fixed, paraffin-embedded tissue blocks were stained for PARP and phospho-p65 and evaluated independently by two blinded physicians, including a board-certified pathologist. An H-score was calculated by multiplying the percent of tumor cells with staining intensity of 0, 1, 2, and 3+ and subsequently adding these together for a final score of 0-300. Nuclear and cystosolic staining were scored separately for both proteins. The number of samples with 2 or 3+ staining of PARP or phospho-p65 in each group was also assessed. Results: Forty-one HER2+ and 32 HER2- cases were examined. PARP and phospho-p65 were found to be almost exclusively nuclear in both groups. The mean H-score for nuclear PARP was 122.3 in HER2+ cases compared to 61.6 in HER2- cases (p value Conclusions: Our study suggests that HER2+ breast cancers have elevated markers for PARP and NF-κB activity compared to HER2- cancers. A direct correlation between PARP and phospho-p65 levels was also found. Furthermore, staining of ≥2+ for either protein was significantly different between the two groups suggesting this as a potential biomarker for clinical application. When combined with our previously published preclinical findings, the current research supports the potential clinical utility of PARPi in patients with this aggressive form of breast cancer. Citation Format: Lisa Klepczyk, Shi Wei, Jason Brazelton, Kimberly Keene, Yufeng Li, James Bonner, Andres Forero, Albert LoBuglio, William Grizzle, Eddy Yang. Increased expression of poly (ADP-ribose) polymerase (PARP) and phospho-p65 in human HER2+ breast cancer. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Synthetic Lethal Approaches to Cancer Vulnerabilities; May 17-20, 2013; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(5 Suppl):Abstract nr B37.

Abstract P6-07-37: Impact of body mass index on recurrence risk in patients with ductal carcinoma in situ.

Background: Body mass index (BMI) has been correlated with risk of recurrence in invasive breast cancer, but the association between BMI and recurrence in ductal carcinoma in situ (DCIS) is less clear. Recent retrospective data indicates that local recurrence is not related to BMI at initial diagnosis. Here we examine the relationship between initial BMI and recurrence in a separate cohort of patients with DCIS. Methods: One hundred eighty-nine patients with DCIS treated between the years of 1999 and 2005 at the University of Alabama at Birmingham were analyzed. BMI was divided into 4 categories as follows: underweight (BMI Results: There were 199 cases of DCIS identified in our cohort of 189 patients (10 patients had bilateral disease). Of these 189 patients, 1.1% (2/189) were underweight, 31.2% (59/189) were normal weight, 22.7% (43/189) were overweight, and 21.7% (41/189) were obese. BMI could not be obtained for 23.3% (44/189) of patients. With a median follow-up of 87.2 months, there were 28 total recurrences identified in the 199 cases (14.1%) with 85.7% of these including a local recurrence. No significant associations were found between the likelihood of overall or local recurrence and any of the four BMI categories. Further, analysis of recurrence-free survival did not show any significant associations between BMI and recurrence. Conclusions: Our data supports recently reported evidence that BMI at diagnosis does not affect the risk of overall or local recurrence in patients with DCIS. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-37.

An update on the dosimetric analysis of concurrent radiation therapy and trastuzumab on early cardiac events.

121 Background: The impact of radiation therapy (RT) with concurrent trastuzumab on early cardiac morbidity is relatively unknown. Trastuzumabs radiosensitizing properties may augment both early and late effects of RT. This retrospective review update provides an analysis of cardiac event (CE) development in patients treated with concurrent RT and trastuzumab with a focus on RT heart dose. METHODS Sixty-five patients treated with concurrent RT (30 left, 33 right, 2 bilateral) and trastuzumab at the University of Alabama at Birmingham were identified. Patient data for pre-existing heart disease, cardiac risk factors, drug regimen, and CEs were recorded. Dosimetric parameters of maximum heart dose, mean heart dose, heart volume receiving 5, 10, 15, 20 and 30Gy (V5, V10, V15, V20, V30) were also analyzed. Endpoints include the occurrence of CEs at any time in relation to RT and those specifically after the start of RT. RESULTS In addition to receiving trastuzumab, 80% of patients received doxorubicin. 15.4% had preexisting heart disease. The mean heart dose for all patients was 248cGy. With a median follow-up of 24.5 months, six patients developed CEs (9.2%), and three of these cases occurred after RT initiation (4, 4, and 0.5 months post-RT). All six CEs occurred during treatment with trastuzumab and consisted of congestive heart failure. Analysis of the heart dose maximum, mean, V5, V10, V15, and V20, V30 were similar in patients with and without CEs, and small differences between groups did not reach statistical significance. CE incidence was significantly associated with smoking (p=0.0037) but not hypertension, diabetes or pre-existing heart disease. CONCLUSIONS This updated retrospective dosimetric analysis did not find a correlation between concurrent trastuzumab and RT on the development of early cardiac events. Modern era RT with 3D conformal planning, the use of heart blocks, and breath hold techniques will continue to decrease the dose to the heart. Longer follow-up will be needed for analysis of the impact of modern technologic advances and late cardiac morbidity.