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Background: Little is known about the role of medical cannabis in the care of breast cancer patients. Cancer is 1 of 17 medical conditions in the 2018 launch of Pennsylvania’s Medical Marijuana Program (PA MMP), requiring physician qualification followed by an evaluation by an HCP (usually a pharmacist) at a medical marijuana dispensary. To help reduce this knowledge gap, we analyzed the symptoms for which breast cancer patients sought medical cannabis. Methods: One breast oncologist at Lankenau Medical Center, a community academic hospital, performed all patient certifications after taking the following steps: history and physical examination; review of all medications, including the Prescription Monitoring Program database, for drug-drug-interactions; and informed consent. The dispensary and cannabis products utilized were chosen by the patient. EMR and PA MMD records of all patients certified in the first 10 months of the PA MMP were analyzed. There was no access to the dispensaries’ database. Results: Of the 54 cancer patients certified, 31 had breast cancer: 22 had non-metastatic disease and 9 had metastatic disease. Median age was 64 (range, 26 - 86). Of the 22 women with non-metastatic disease, 16 (73%) sought cannabis for pain, of whom 4/16 (25%) had chemotherapy-induced peripheral neuropathy (CIPN), 3/16 (19%) had exacerbation of pre-existing muscle/joint pain from hormonal therapy. 11/22 (50%) had insomnia and 10/22 (45%) had anxiety—of whom 8 had both. 1 of 22 had nausea. 3 recreational users wanted to shift to medical grade products. The 9 patients with metastatic breast cancer sought medical cannabis for: cancer pain (8/9, 89%), anxiety (8/9, 89%); insomnia (3/9, 33%), anorexia (3/9, 33%), and nausea (3/9, 33%). Patients had an average of 3 symptoms. About half of patients with pain expressed a fear of opioid use and wanted to avoid, stop, or reduce its use. All patients sought a medical solution for symptom relief; only 2 also admitted a desire to get high. The qualifying physician mainly recommended a CBD-dominant sublingual preparation. Topical products applied to focal areas of pain were also commonly suggested. Except for immediate relief of acute pain, smoking and vaping were strongly discouraged to avoid lung toxicity, especially during radiation and chemotherapy. As the PA MMP physician-facing patient-certification database does not interface with the dispensaries’ database, the product type, dose, source, and method of delivery purchased by each patient are unknown. Conclusion: Women with non-metastatic and metastatic breast cancer sought medical cannabis for symptomatic management of pain (73-89%, resp), anxiety (45-89%, resp), insomnia (50-33%, resp), nausea (4% and 33%, resp), and anorexia (0 and 33%). Patients reported an average of 3 symptoms. Pain was rarely experienced alone. Insomnia and anxiety were frequently combined. Other benefits of medical cannabis included the use of safer products (eg with less fungus and pesticides than recreational sources) and a shift to safer methods of delivery (eg. sublingual preparations vs. smoking or vaping). Fear of opioids motivated patients to avoid, reduce or stop opioids. For optimal continuity of care, the physician and dispensary databases must be integrated. Citation Format: Julianne Hibbs, Marisa Weiss, Zonera Ali, Aarti Shevade, Adam Leitenberger, Melissa Bowman-Jenkins, Paul Gilman. Symptom profile of breast cancer patients seeking medical cannabis in Pennsylvania’s new medical marijuana program [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 P5-09-02.

BACKGROUND: Nausea and vomiting are some of the most common and distressing side effects of chemotherapy according to patients. Chemotherapy-induced nausea and vomiting (CINV) places a substantial burden on patients and their loved ones, which greatly reduces the quality of life, nutritional habits, ability to work and socialize, and adhere to treatment regimens. Therefore, assessment of CINV is an essential component of care for patients receiving chemotherapy. Multiple factors influence the incidence of CINV with the chemotherapy regimen, both type and dosage, being the primary risk factor. It is generally assumed that the strongest patient-related factors are younger age and female sex. However, reports in the literature have demonstrated that using these factors clinicians underestimate the prevalence of CINV, especially delayed nausea. Thus, there is a need for risk assessment tools to accurately identify patients requiring anti-emetic regimens to improve quality of life of patients and their families. Our assay is based on the knowledge that chemotherapeutic agents cause bursts of reactive oxygen species (ROS) resulting in cellular damage and release of substances that activate receptors in the chemoreceptor trigger zone. Glutathione (GSH), a key antioxidant, is responsible for maintaining redox homeostasis by neutralizing ROS. Therefore, we hypothesized that a patient’s risk of CINV may reflect individual variations in the efficiency to scavenge and neutralize ROS after chemotherapy. METHODS: Patients enrolled in our institutional review board approved study (N= 220), were treated in the adjuvant or neoadjuvant setting with highly or moderately emetogenic chemotherapies for their breast cancer diagnosis. Blood samples were drawn from chemotherapy naïve patients and used in the predictive blood assay. The assay is based on the conversion of a bioactive probe, hydroxyethyl disulfide, into mercaptoethanol, which once normalized to red blood cell count, indicates glutathione recycling capacity. Incidence and severity of delayed nausea symptoms were collected from notes in medical records as well as anti-emetic prescription history. RESULTS: A recent second evaluation of patients treated with platinum-based therapies confirmed our previously published data, demonstrating a correlation between low glutathione recycling capacity and risk of delayed nausea for patients with lung and colon cancer (N=111; misclassification rate 0.153; AUC 0.72). In this study, we evaluated age-matched patients treated with anthracycline/cyclophosphamide (AC)(N=42), docetaxel/cyclophosphamide (TC)(N=39), docetaxel/carboplatin/trastuzumab (TCH)(N=27) or docetaxel/carboplatin/trastuzumab/pertuzumab (TCHP)(N=25). The incidence of moderate-to-severe nausea was highest in the AC (38.1%) and TCHP (36.0%) groups. The TCH group had the lowest incidence of patients (11%) reporting delayed nausea. SAS/STAT v.14.1 classification trees demonstrated a weak association between anthracycline-induced delayed nausea and MyNauseaRisk score (misclassification rate 0.333; AUC 0.67). Similarly, patients treated with TC demonstrated a correlation between MyNauseaRisk score and severity of nausea as previously seen for platinum therapies. The algorithm determined that age stratification of patients in the TCHP group prior to applying the MyNauseaRisk score reduced the misclassification rate (0.280) and improved the AUC (0.72). CONCLUSION: The results from this exploratory prospective study suggests that a reduced ability to recycle GSH in the blood may offer an objective prediction of delayed nausea, possibly allowing for optimal anti-emetic regimen to improve the quality-of-life for breast cancer patients. Citation Format: Nicole F Laslett, Dillon D McCourt, Kinjal Parikh, John F Kennedy, Zonera A Ali, Erik L Zeger, Aarti L Shevade, Tracey L Evans, Paul B Gilman, Margaretha Wallon. MyNauseaRisk assay - Predicting chemotherapy-induced delayed nausea using a blood-based assay [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 P2-12-12.

Background: Chemotherapy-induced nausea and vomiting (CINV) is a distressing side effect according to patients. CINV can negatively affect nutritional habits, ability to work and motivation to follow treatment regimens. Assessment of CINV is an essential component of care for patients receiving chemotherapy. Multiple factors influence the incidence of CINV with the chemotherapy regimen, both type and dosage, being the primary risk factor. It is generally assumed that the strongest patient-related factors are younger age and female sex. However, reports in the literature have demonstrated that using these factors clinicians underestimate the prevalence of CINV, especially delayed nausea. Thus, there is a need for risk assessment tools to accurately identify patients requiring anti-emetic regimens to improve quality of life of patients and their families. Most chemotherapeutic agents cause bursts of reactive oxygen species (ROS) resulting in cellular damage and release of substances that can activate receptors in the chemoreceptor trigger zone. Glutathione (GSH), a key antioxidant, is responsible for maintaining redox homeostasis by neutralizing ROS elicited from chemotherapy. Therefore, we hypothesized that a patient's risk of CINV may reflect individual variations in the efficiency to scavenge free radicals after chemotherapy. Methods: In our Institutional Review Board approved study, we have enrolled over 300 patients and completed assessment of 133 patients. These patients were treated with highly or moderately emetogenic chemotherapies for lung, colon, or breast cancer. Blood samples were drawn from chemotherapy naïve patients and used to determine the glutathione recycling capacity. The assay detects the conversion of a bioactive probe, hydroxyethyl disulfide, into mercaptoethanol, which once normalized to red blood cell count, indicates glutathione recycling capacity (ChemoTox). Nausea severity was reported using the Rotterdam Symptom Check-List at each treatment cycle. Self-reported symptoms were compared to notes in medical records and anti-emetic prescription history. Results: We previously published the correlation between low ChemoTox and risk of delayed nausea for patients receiving platinum-based therapy for lung and colon cancer (N=64; correctly classified 88.5%; AUC 0.77). In this second evaluation, using SAS/STAT v.14.1 classification trees, we show the results from testing this prediction tool for breast cancer patients that typically are treated with anthracycline- or taxane-based chemotherapies. An early evaluation of anthracycline-based therapies (N=37) demonstrated a weak association between experienced nausea and ChemoTox (correctly classified 69.2%; AUC 0.64). In contrast, patients treated with taxane-based therapies (N=32) demonstrated a similar correlation between ChemoTox and severity of nausea as previously seen for platinum therapies. Also, a similar accuracy in identifying patients at risk of moderate-severe nausea was identified (correctly classified 77.3%; AUC 0.79). Conclusion: The results from our prospective study suggests that a reduced ability to recycle GSH in the blood may offer an objective prediction of delayed nausea, possibly allowing for optimal anti-emetic regimen to improve the quality-of-life for breast cancer patients. Citation Format: McCourt DD, Parikh K, Dadivas A, Brady AL, Kennedy J, Ali ZA, Zeger EL, Shevade A, Gilman PB, Wallon UM. Assay for personalized prediction of chemotherapy-induced delayed nausea [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-11-08.

Introduction: Vinca alkaloids, such as vincristine, are important anticancer agents mainly employed in the treatment of hematological cancers. The principal mechanism for the antineoplastic activity is microtubule disruption. However, these agents also cause damage to mitochondria which leads to oxidative stress and production of reactive oxygen species (ROS). Other chemotherapeutic drugs that are suggested to cause peripheral neuropathy by this mechanism, i.e., increased oxidative stress, include taxanes and platinum compounds. Oxidative damage to peripheral neurons can cause damage to myelin sheath, mitochondrial proteins, and other antioxidant enzymes, resulting in hyperexcitability of peripheral neurons. This nerve damage results in the commonly seen dose-limiting neurological side effect chemotherapy-induced peripheral neuropathy (CIPN). Hence, assessment of biomarkers for peroxidation, myelin repair/maintenance, and red-ox balance (glutathione recycling) can be helpful in monitoring the on-set and course of peripheral neuropathy. We hypothesize that chemotherapeutic agents with similar effects on mitochondria (vinca alkaloids, taxanes and platinum compounds) will produce a specific pattern of glutathione recycling in patients prone to CIPN. Methods: Patients who had given written consent to participate in this exploratory single-centered, prospective IRB approved study contributed a blood sample prior to each treatment cycle. At each visit, the Rotterdam Symptoms Check-List (RSCL) was filled out and reported symptoms confirmed by comparison to notes in medical records. Whole blood was analyzed for glutathione recycling capacity using the bioactive probe hydroxyethyldisulfide (HEDS) and incubated at room temperature for 2 hours with gentle mixing. Prior to spectrophotometric determination, blood cells and proteinaceous thiols will be removed from the sample by acid precipitation and centrifugation. The final spectrophotometric reading will be converted into ME produced using the conversion factor provided in the assay kit Rockland Inc). Recycling capacity was compared to self-reported grade of CIPN. Results: Thus far we have enrolled 276 patients with an average age of 63.69 years (±12.85 STDEV; Range; 25-91). Patients are predominantly of Caucasian heritage (80.8%) along with 18.1 % African American and 1.1% Asian heritage. Females constitute 53.26 % of the cohort. To date we have 150 patients with more than 24 months of follow-up and among these patients, 5.5% had no reported symptoms of CIPN. Of those with severe CIPN (NCCN grade 3) neuropathy, 71% had a reduction in GSH recycling of greater than or equal to 40% from pre-treatment level. The reduced glutathione recycling capacity preceded on-set of symptoms by approximately 4 weeks. The majority of patients demonstrating this pattern of glutathione recycling had persistence CIPN that lasted for 6-18 months before an improvement was noted in medical records. We are currently assessing the value of adding biomarkers for lipid peroxidation and/or myelin formation/maintenance to further improve the likelihood ratio and AUROC values for the test. Conclusions: This data suggests the importance of GSH recycling in the ability to predict risk of CIPIN. Patients whose pre-treatment baseline was less than 1 or progressively dropped by at least 40%, seem to be at most risk for CIPN. Further, this may predict persistence of CIPN even after cessation of chemotherapy. Most patients in this cohort received taxanes or platinum therapy. However, given the similarity in mechanism and results from an early assessment of lymphoma patients treated with vinca alkaloids that resulted in similar outcomes with reduced glutathione recycling capacity suggest the possible use of this test to predict CIPN among lymphoma patients. Disclosures No relevant conflicts of interest to declare.

e18210 Background: We have previously reported on glutathione recycling capacity (GRC) in red blood cells as a predictor of delayed nausea in cancer patients treated with platinum-based chemotherapies [1]. The test identifies individual variations in the efficiency to scavenge reactive oxygen species, produced by chemotherapy-induced cell-damage, which triggers release of serotonin – a know inducer of chemotherapy-induced nausea and vomiting. In this current study, we have examined if the GRC assay and/or changes in substance P (SP), another inducer of nausea, can predict delayed nausea among breast cancer patients receiving doxorubicin- or taxane-based therapies and thereby provide better guidance to individualized antiemetic therapies. Methods: Chemotherapy naïve breast cancer patients were asked to participate in this IRB-approved study. Consented patients donated a tube of blood prior to each treatment cycle. Commercial kits were used to measure GRC (OxPhos, Rockland Inc.) and Substance P (Parameter, R&D Systems). On-set, duration and severity of nausea, and anti-emetics prescribed were documented by the medical staff. Results: Obtained GRC and SP values were compared to documented incidences of nausea. We found that 26.8% of taxane treated patients [N = 42] had moderate/severe nausea and demonstrated a similar GRC pattern to platinum-based induced nausea, i.e. low GRC results in more severe nausea. Among doxorubicin treated [N = 31] patients, 41.9% had moderate/severe nausea but showed no correlation with GRC. However, preliminary evaluation of these patients showed a continuous increase in SP levels (average 1.74 fold increase after one cycle). Conclusions: In this initial evaluation of our on-going study, we found that fewer patients had nausea in the taxane treated group with a similar GRC predictive pattern as previously reported. However, patients in the doxorubicin treated group were more likely to experience nausea with no correlation to GRC but with a steadily rising level of SP during the early part of their regimen. Using SP testing could help identify patients that might have a medical benefit from additional NK1 antagonist therapy. 1. Kutner, T., et al. Supprot Care Cancer (2017) 25:581-587.

Background: Though genetic alterations initiates' tumor formation, extracellular signals from the tumor microenvironment can modify the growth and spread of cancer cells. We are studying a small modifier protein, tissue inhibitor of metalloproteinase-4 (TIMP-4) that can accelerate tumor growth and metastatic potential as seen in both cell culture, animal experiments and prospective studies of clinical subjects. TIMP-4 is synthesized by stromal cells and secreted into the tumor microenviroment. It binds to the membrane-bound tetraspanin CD63 on tumor epithelial cells and induces the activation of the tumor promoting PI3K/AKT pathway. This modifier has its strongest effect on the so-called triple-negative breast cancers (TNBC) and breast cancers with HER2 gene amplification. Methods: Cell culture experiments using the human MDA-MB-468 (TNBC) and SK-BR-3 (HER2 amplified) cell-lines were used to assess the effects of elevated levels of TIMP-4 on downstream targets. Cells with or without human recombinant TIMP-4 added to the growth medium were used to determine the effects on growth, AKT activation, apoptosis and response to anti-TIMP-4 treatment. Tumor growth in nude mice with or without TIMP-4 containing slow-release pellets implanted into the mammary fatpad was followed for six-week period to assess response to anti-TIMP-4 therapy. Lungs, liver, spleen and mammary fatpads were collected and analyzed. Prospectively collected patient samples, in accordance with the IRB approved protocol, were tested for circulating levels of TIMP-4 and the cancer marker CA15-3, using commercially available ELISA kits, in samples collected prior to chemotherapy and at each treatment cycle. Results: Augmentation of TIMP-4 levels in the cell culture medium of TNBC and HER2-amplified cells resulted in accelerated growth and increased activation of AKT as determined by Western blotting for pAKTSer 473 and pAKTThr 308. Adding an anti-TIMP4 therapeutic antibody to TNBC cells grown in the presence of TIMP-4 resulted in reduced growth. HER2-positive cells grown under identical condition and treated with either an anti-TIMP-4 or a neutralizing ErbB2 antibody demonstrated no effects on growth. Only dual blockade of HER2 and TIMP-4 resulted in reduced growth. Using the anti-TIMP-4 therapy in animals resulted in stable disease with no signs of metastatic growths. Patients undergoing treatment for TNBC or HER2-positive breast cancer that had continuous elevated TIMP-4 levels while on treatment had a higher recurrence rate than patients with diminishing TIMP-4 levels in response to therapy. The TIMP-4 levels preceded and correlated better with disease progression than the traditional CA15-3 marker. Conclusion: Together these clinical and laboratory data suggests that TIMP-4 could be a prognostic as well as a predictive marker. Our preliminary clinical data indicates that TIMP-4 might be a more reliable marker for recurrence/progression than CA15-3. Also, our cell and animal studies indicate that TIMP-4 could be therapeutic target for TNBC and HER2-positive breast cancer patients that test positive for this marker. Thus providing a targeted therapy for TNBC patients and HER2-positive patients that do not have full clinical benefit of HER2-targeted therapies alone. Citation Format: Wallon UM, Brady AL, Isaac KM, Ali ZA, Gilman PB, Shevade A. Prognostic and predictive marker in the tumor microenvironment of breast cancers [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 P4-03-10.