Hannah Hazard

Triple-Negative Breast Cancer and Obesity in a Rural Appalachian Population

Background: Our objective was to determine the clinicopathologic features of triple-negative (estrogen receptor, progesterone receptor, and human epidermal growth factor-2 receptor negative) breast cancer and their relationship to obesity in women drawn from a population with one of the highest obesity rates in the United States. Methods: This retrospective study involved 620 White patients with invasive breast cancer in West Virginia. Hospital tumor registry, charts, and pathology records provided age at diagnosis, tumor histologic type, size, nodal status, and receptor status. Body mass index was calculated and a value of ≥30 was considered indicative of obesity. Results: Triple-negative tumors occurred in 117 (18.9%) of the 620 patients, most often in association with invasive ductal carcinomas. Patients with triple-negative tumors were younger than those with other receptor types, 44.5% and 26.7%, respectively, being diagnosed at age <50 years (P = 0.0004). The triple-negative tumors were larger (P = 0.0003), most notably in the younger women, but small tumors (<2.0 cm) were more often accompanied by lymph node metastases. Obesity was present in 49.6% of those with triple-negative tumors but in only 35.8% of those with non-triple-negative tumors (P = 0.0098). Lymph node metastases were more frequently associated with T2 tumors in obese patients (P = 0.032) regardless of their receptor status. Conclusions: Triple-negative breast cancers within a White, socioeconomically deprived, population occurred in younger women, with later stage at diagnosis, and in association with obesity, which itself has been associated with a poor prognosis in breast cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3319–24)

Initial clinical test of a breast-PET scanner

Introduction: The goal of this initial clinical study was to test a new positron emission/tomography imager and biopsy system (PEM/PET) in a small group of selected subjects to assess its clinical imaging capabilities. Specifically, the main task of this study is to determine whether the new system can successfully be used to produce images of known breast cancer and compare them to those acquired by standard techniques.

Combination of Eribulin and Aurora A Inhibitor MLN8237 Prevents Metastatic Colonization and Induces Cytotoxic Autophagy in Breast Cancer

Recent findings suggest that the inhibition of Aurora A (AURKA) kinase may offer a novel treatment strategy against metastatic cancers. In the current study, we determined the effects of AURKA inhibition by the small molecule inhibitor MLN8237 both as a monotherapy and in combination with the microtubule-targeting drug eribulin on different stages of metastasis in triple-negative breast cancer (TNBC) and defined the potential mechanism of its action. MLN8237 as a single agent and in combination with eribulin affected multiple steps in the metastatic process, including migration, attachment, and proliferation in distant organs, resulting in suppression of metastatic colonization and recurrence of cancer. Eribulin application induces accumulation of active AURKA in TNBC cells, providing foundation for the combination therapy. Mechanistically, AURKA inhibition induces cytotoxic autophagy via activation of the LC3B/p62 axis and inhibition of pAKT, leading to eradication of metastases, but has no effect on growth of mammary tumor. Combination of MLN8237 with eribulin leads to a synergistic increase in apoptosis in mammary tumors, as well as cytotoxic autophagy in metastases. These preclinical data provide a new understanding of the mechanisms by which MLN8237 mediates its antimetastatic effects and advocates for its combination with eribulin in future clinical trials for metastatic breast cancer and early-stage solid tumors. Mol Cancer Ther; 15(8); 1809–22. ©2016 AACR.

Breast Cancer Pathology, Receptor Status, and Patterns of Metastasis in a Rural Appalachian Population

Breast cancer patients in rural Appalachia have a high prevalence of obesity and poverty, together with more triple-negative phenotypes. We reviewed clinical records for tumor receptor status and time to distant metastasis. Body mass index, tumor size, grade, nodal status, and receptor status were related to metastatic patterns. For 687 patients, 13.8% developed metastases to bone (n = 42) or visceral sites (n = 53). Metastases to viscera occurred within five years, a latent period which was shorter than that for bone (P = 0.042). More women with visceral metastasis presented with grade 3 tumors compared with the bone and nonmetastatic groups (P = 0.0002). There were 135/574 women (23.5%) with triple-negative breast cancer, who presented with lymph node involvement and visceral metastases (68.2% versus 24.3%; P = 0.033). Triple-negative tumors that metastasized to visceral sites were larger (P = 0.007). Developing a visceral metastasis within 10 years was higher among women with triple-negative tumors. Across all breast cancer receptor subtypes, the probability of remaining distant metastasis-free was greater for brain and liver than for lung. The excess risk of metastatic spread to visceral organs in triple-negative breast cancers, even in the absence of positive nodes, was combined with the burden of larger and more advanced tumors.

Detection of Axillary Lymph Node Metastases and Extra-Axillary Metastases With FDG PET/CT in Breast Cancer Patients Scheduled for Neoadjuvant Chemotherapy

develop procedures that could be used in the treatment of peripheral vascular disease. In each case, we aim to provide quantitative measurements which will aid physicians in the characterization of disease status and the effects of therapeutic measures, so that treatments can be applied with optimal effectiveness by taking into account the oxygen-dependent aspects of the therapy. The overall goal is to enhance clinical outcomes. Results: Tumor oximetry measurements have been performed in tumor tissues of 12 patients during courses of radiation and chemotherapy. Tumor types include melanoma, basal cell, soft tissue sarcoma, and lymphoma, andmeasurement sites have ranged from the feet to the scalp. Very recent results and analyses indicate that using a simple clinically applicable approach with breathing carbogen, tumors can be characterized in regard to whether or not they respond to this hyperoxic treatment which does raise the pO2 in the vascular system. Some tumors did not respond at all and some had only minimal changes while others had robust changes in tumor pO2. Conclusions: These results indicate that it should be feasible to more adequately determine the effectiveness of hyperoxic treatments and, therefore, both individualize therapy and develop more robust strategies for optimizing hyperoxic therapies.

Mean radiation dose to the heart in patients with breast cancer.

56 Background: Breast irradiation may expose a portion of the heart to radiation. Heart irradiation is associated with late risk of ischemic heart disease, proportional to dose. A recent publication of patients treated with 2-D planning prior to 2001 noted average mean heart dose (MHD) of 6.6 Gy for left breast tumors, 2.9 Gy for right breast. Current treatment planning can minimize the MHD, reducing the risk of late heart injury. METHODS We reviewed treatment plans of 78 patients (86 breasts) treated 1/2012-3/2013 to obtain MHD. Treatment plans were CT-based, field-in-field forward planning with heart blocking. Two treatment regimens were used; hypofractionation (HF) (16 x 2.66 Gy, no boost) or standard (SF) (46.8-50.4 Gy +/- 10 Gy boost). Statistics were obtained for MHD based on right (N = 44) or left breast (N = 42); HF (N = 31) vs SF (N = 55), and total dose. RESULTS Average (av) MHD for left breast was 1.45 Gy (range 0.19-3.12), for right breast 0.70 Gy (0.12-1.54). For HF patients av MHD left was 1.16 Gy (0.19-1.90), MHD right was 0.48 Gy (0.12-0.91). For SF av MHD left was 1.60 Gy (0.80-3.12), MHD right was 0.84 Gy (0.39-1.54). There was a significant difference in MHD between left and right breasts (p = 0.002) and significant correlation between breast dose and MHD (p = 0.026). CONCLUSIONS MHD from breast RT with current treatment planning is much lower than published reports from 2-D planning. MHD correlates with total breast dose and is greater for the left than right side. Techniques to reduce MHD should be utilized, especially for left-sided breast cancer.

Fingertip beta imager based on the SiPM technology

We have implemented the low-profile SENSL 16ch SPMArray2 module in a small prototype of a beta/positron imager. The SiPM sensor has a 0.5–1mm thick plastic scintillator optically coupled via thin (1–2mm) glass window for better light spread between the sixteen 3mm SiPM pads to allow center of gravity position calculations of the scintillation light flashes. In the initial studies, aluminized Mylar foil and Teflon tape were used for a top surface reflector, and black Tedlar foil for a light-tight mechanical barrier. Sensitivity of 3–5 counts/sec per nanoCi was measured with one layer of 50 micron Teflon and 50 micron Tedlar each. For two Tedlar layers the sensitivity was lower by about 10 percent with the applied broad energy window. Intrinsic spatial resolution was estimated at approximately 2.5mm, with the un-collimated positron beam distribution limiting the measurement. The position information can be used as a finer indication when the hot spots are located within the ∼10mm×10mm useful FOV of the device. According to the initial plans, the imager will be evaluated as a tool assisting with checking the cancer margin adequacy in breast cancer excision (lumpectomy). Before surgery, the patient will obtain systemic injection of positron biomarker, such as F18-FDG, the same that was used to detect the cancer in the PET procedure. Attached to the surgeons fingertip, the imager will be used to scan the surface of the post-extraction cavity for residual positron activity as an indication of non-sufficient cancer margins, to allow for immediate in-situ correction. The imager is planned as another instrument in the set of complementary imaging and non-imaging tools to assist with breast cancer surgeries, not to replace other tools.

The Lack of Consensus of International Contouring Guidelines for the Dorsal Border of the Chest Wall Clinical Target Volume: What is the Impact on Organs at Risk and Relationships to Patterns of Recurrence in the Modern-Era?

Purpose Variation exists in cooperative group recommendations for the dorsal border for the chest wall clinical target volume (CTV). We aimed to quantify the impact of this variation on doses to critical organs and examine patterns of chest wall recurrence relative to the pectoralis muscle. Methods and Materials We retrospectively assessed patterns of chest wall recurrence quantified to the recommended CTV borders for women treated between 2005 and 2017. We compared treatment plans for 5 women who were treated with left postmastectomy radiation therapy, with the chest wall contoured using varying dorsal borders for CTV: (1) Anterior pleural surface (Radiation Therapy Oncology Group), (2) anterior surface of pectoralis major (European Society for Radiotherapy and Oncology), and (3) anterior rib surface (institutional practice). Treatment plans were generated for 50 Gy in 25 fractions. Doses to organs-at-risk were compared using paired-sample t tests. Results Institutional patterns of chest wall recurrence were 64.7% skin and subcutaneous tissue, 23.5% both anterior to and between the pectoralis muscles, and 11.8% isolated to the tissue between the pectoralis major and minor. No chest wall recurrences were noted deep to pectoralis minor. When comparing the plans generated per the Radiation Therapy Oncology Group versus European Society for Radiotherapy and Oncology contouring guidelines, the mean lung V20Gy, heart mean dose, and left anterior descending artery mean dose were 33.5% versus 29.4% (P < .01), 5.2 Gy versus 3.2Gy (P = .02), and 27.3Gy versus 17.8Gy (P = .04), respectively. Conclusions The recommended variations in the dorsal chest wall CTV border have significant impact on doses to the heart and lungs. Although our study was limited by small numbers, our institutional patterns of recurrence would support a more anterior dorsal border for the chest wall CTV consistent with older literature.

Abstract B20: Development of metastatic patient-derived xenografts (PDXs) for accurate assessment of anti-metastatic therapeutics in pre-clinical settings

Background: Although advances in treating early stage breast cancers have increased the overall survival rate, once the disease has metastasized treatment options subside to palliative care. The limited access to metastatic biopsies and disease-relevant pre-clinical models to test new therapeutics targeted against advanced metastatic cancers limits progress and translation of investigational therapeutics to the clinic. Methods: To address this deficiency we developed a collection of metastatic patient derived xenograft models via direct transplantation of metastatic biopsy or residual surgical material in immunocompromised mice. We successfully collected and established triple negative as well as ER/PR positive patient xenografts which are available for collaborative research. We further characterized and utilized the PDXs to assess the efficacy of new combination therapy to treat distant metastases. Results: The efficacy of Aurora A kinase inhibition by small molecule inhibitor MLN8237 (Alisertib) as monotherapy and in combination with microtubule targeting drug, eribulin, on different stages of metastasis and potential mechanisms of its action was defined. Our work using PDX models indicates that Alisertib does not limit growth of the primary tumor. These findings are similar to the results of clinical trials with Alisertib in breast cancer. Importantly, we found that Alisertib dramatically decreases growth of the established metastases and prevents further dissemination via inactivation of AKT and activation of cytotoxic autophagy. Combination of Alisertib with eribulin led to a synergistic decrease in metastases to distant organs and provided additional local control of mammary tumor growth. Conclusion: Metastatic PDX models provide new, accurate assessment of anti-metastatic regiment9s efficacy. MLN8237 plus eribulin combination shows synergistic inhibition of metastatic spread, growth of established metastases and prolongs overall survival. Future clinical trials are needed to further test this regiment in clinic to improve survival of metastatic cancer patients. Citation Format: Ryan Ice, Anna Kiseleva, Yuriy Loskutov, Matthew Smolkin, Adham Salkeni, Hannah Hazard, Ginger Layne, Elena Pugacheva{Authors}. Development of metastatic patient-derived xenografts (PDXs) for accurate assessment of anti-metastatic therapeutics in pre-clinical settings. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr B20.

Operative Management of Metastatic Breast Cancer

Worldwide, breast cancer is the second most common malignancy in women. The World Health Organization estimated 3.78 million new cases of breast cancer in 2008 (GLOBOCAN 2008), with an associated 458,000 deaths from the disease during the same time period. The worldwide incidence of breast cancer is increasing as life expectancy lengthens and as non-western societies adopt the lifestyle practices of western society. In the United States, the American Cancer Society estimates 234,580 new breast cancers will be diagnosed and 40,030 deaths will occur in 2013. For women, a new diagnosis of breast cancer in 2013 will represent 29 % of all malignancies diagnosed. Despite the increase in incidence, breast cancer-related mortality has shown a steady decline over the last decade. The decline in mortality can primarily be attributed to two factors: the first is a better understanding of and adherence to screening guidelines, and the second is the advances made in the systemic treatment of breast cancer patients.