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Catecholamines and prostaglandins are secreted abundantly during the perioperative period in response to stress and surgery, and were shown by translational studies to promote tumor metastasis. Here, in a phase-II biomarker clinical trial in breast cancer patients (n = 38), we tested the combined perioperative use of the β-blocker, propranolol, and the COX2-inhibitor, etodolac, scheduled for 11 consecutive perioperative days, starting 5 days before surgery. Blood samples were taken before treatment (T1), on the mornings before and after surgery (T2&T3), and after treatment cessation (T4). Drugs were well tolerated. Results based on a-priori hypotheses indicated that already before surgery (T2), serum levels of pro-inflammatory IL-6, CRP, and IFNγ, and anti-inflammatory, cortisol and IL-10, increased. At T2 and/or T3, drug treatment reduced serum levels of the above pro-inflammatory cytokines and of TRAIL, as well as activity of multiple inflammation-related transcription factors (including NFκB, STAT3, ISRE), but not serum levels of cortisol, IL-10, IL-18, IL-8, VEGF and TNFα. In the excised tumor, treatment reduced the expression of the proliferation marker Ki-67, and positively affected its transcription factors SP1 and AhR. Exploratory analyses of transcriptome modulation in PBMCs revealed treatment-induced improvement at T2/T3 in several transcription factors that in primary tumors indicate poor prognosis (CUX1, THRa, EVI1, RORa, PBX1, and T3R), angiogenesis (YY1), EMT (GATA1 and deltaEF1/ZEB1), proliferation (GATA2), and glucocorticoids response (GRE), while increasing the activity of the oncogenes c-MYB and N-MYC. Overall, the drug treatment may benefit breast cancer patients through reducing systemic inflammation and pro-metastatic/pro-growth biomarkers in the excised tumor and PBMCs.

Background: With approximately 1.6 million annual procedures in the United States and 3 million world-wide, needle biopsy is considered the Gold Standard for breast cancer diagnosis and treatment planning. Overdiagnosis can result in unnecessary treatment, cost, and anxiety, while underdiagnosis can delay treatment and diminish outcomes. A 2015 study published in JAMA1 found nearly 25% discordance between pathology diagnosis and expert review, most pronounced in cases of DCIS, Atypia and in patients with dense breasts. It has been well established that physiologic differences between benign and malignant tissues are reflected in their electrical properties.2,3,4 Access to real-time tissue properties during the biopsy procedure has the potential for increasing accuracy by enabling the most suspicious tissue to be sampled, and by providing the tissue characterization to pathology for comparison with histologic findings. Through research made possible by the European Union’s Horizon 2020 research award, this feasibility study sought to determine if five 0.8mm miniaturized, flexible RF sensors (Dune Medical Devices, Alpharetta, GA) mounted within the sample cavity of a 14-gauge biopsy needle can accurately measure and map the electrical properties of multiple breast tissue types. Methods: Between March, 2018 and March, 2019, 44 patients undergoing mastectomy or lumpectomy at three medical centers in Israel were enrolled in the study. The biopsy needle was applied to freshly excised specimens, with continuous readings by the sensors. An average of 8.1 cores (ranging from 2-10) were obtained from each specimen. Cores were oriented and analyzed by standard histopathology. Based on histology, the dielectric properties of the various tissue types were derived, and the ability of the device to differentiate between malignant and non-malignant tissue was assessed. Results: A total of 357 cores from 44 specimens were analyzed. Ease of use and quality of tissue samples were equivalent to that of a standard biopsy needle. The dielectric properties of three tissue groups: Fat, Healthy non-Fat, and Malignant, in the low radiofrequency range were measured, showing distinct differences between the various types. Feature sizes larger than 0.8 mm were analyzed. The differentiation ability between tissue types was characterized using sensitivity and specificity of 85% and 99% respectively. Conclusions: Miniature, flexible RF sensors can be incorporated onto a biopsy needle. Although this study utilized a 14-gauge core needle, the 0.8mm sensor size allows for configuration within both vacuum-assisted and core biopsy needles of various gauges. The dielectric properties of breast tissue can be assessed in real-time during the biopsy procedure. These results show promise in differentiating between breast tissue types, specifically cancerous and benign, enabling more accurate tissue sampling and subsequent diagnosis. Improving the accuracy of breast biopsies should provide immediate clinical impact by reducing overstaging and subsequent unneeded treatment, procedures and cost, as well as reducing understaging of breast cancer which results in delayed diagnosis and missed cancer. Forward-looking, real-time tissue characterization during biopsy could prove especially beneficial should newer protocols currently under trial, such as active surveillance for low risk DCIS5 and omission of surgery for exceptional responders of neoadjuvant chemotherapy,6 become treatment options. The ability to mount the sensors to minimally invasive treatment devices will lay the foundation for expanding the technology to other cancer types, with the potential for precision delivery of new targeted drugs, radiation and ablation therapies at the site of the cancer. Citation Format: Noemi Weisenberg, Avihai Lachman, Lisa Cadena, Inbal Shimens, Olga Shmain, Ahuva Grubstein, Yael Rapson, Hana Cernik, Debora Kidron, Tania Zehavi, Evgeny Edelstein, Vladimir Kravtsov, Tatiana Kogan, Meirav Wolff Bar, Judith Diment, Ilana Haas, Patricia Malinger, Eran Sharon, Yehudit Birnbaum, Ada Magen, Yael Sobol, Osnat Givon Madhala, Sonya Wadhawker, Tanir M Allweis. Feasibility of incorporating miniaturized, flexible radiofrequency (RF) sensors in a breast biopsy needle for accurate real-time characterization of benign and malignant tissue [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT3-04-01.