Advanced Stage Breast Research Articles

Moderating effects of organizational minority representation on racial and ethnic differences in early palliative care receipt among patients diagnosed with advanced cancers in 2010-2019 in the US.

52 Background: Early palliative care (PC) is recommended for advanced cancers, but differential use has been documented by race and ethnicity. We examined whether racial and ethnic differences in early PC use were moderated by organization-level proportions of minority patients served. Methods: We identified patients aged ≥65.5 years diagnosed with advanced-stage breast, colorectal, non-small cell lung (NSCL), small cell lung (SCL), pancreas, and prostate cancers in 2010-2019 with ≥6 months survival and continuous fee-for-service coverage from the SEER-Medicare data. Early PC was identified by PC encounter diagnosis codes or hospice and palliative medicine (HPM) specialty codes within 90 days post-diagnosis or up to first hospice admission date. Treating physicians and organizations were assigned based on the plurality of visits within 180 days surrounding diagnosis. Using patient race and ethnicity information, organizations were classified based on the percent of racial and ethnic minorities patients (Low<10%, Medium 10-19%, and High Minority-Serving ≥20%). Multivariable logistic models assessed interacting effects of organizations’ minority representation and individual race and ethnicity on early PC receipt, adjusting for patient characteristics. Results: Among 102,060 patients treated at 8,039 organizations, the percent receiving early PC increased from 1.44% in 2010 to 10.30% in 2019. High Minority-Serving organizations were larger size and more likely to employ a HPM specialist and to treat a higher proportion of patients in metropolitan but lower socioeconomic areas, and were dually Medicare-Medicaid eligible. After adjusting for patient characteristics, Hispanic patients were 1.6 percentage points (ppts, 95%CI=-3.1, -0.1) less likely to receive early PC than Non-Hispanic (NH) White patients in Low Minority-Serving organizations. In High Minority-Serving organizations, Hispanic and NH Black patients were 0.8 ppts (95%CI=0.1, 1.6) and 1.6 ppts (95%CI=1.0, 2.3) more likely to receive early PC than NH White patients. (Table). Conclusions: Racial and ethnic minorities were more likely to receive early PC than NH White at High Minority-Serving organizations but not Medium/Low Minority-Serving organizations. System-level factors may be modified to narrow racial and ethnic differences in early PC use. Adjusted difference in early palliative care by race and ethnicity. Organization Minority Representation Individual Adjusted Probability Difference (95% CI) Low NH White Ref Hispanic -1.6 (-3.1, -0.1) NH Black 0.01 (-1.7, 1.7) Other/Unknown 1.1 (-1.2, 3.4) Medium NH White Ref Hispanic -0.6 (-1.7, 0.5) NH Black -0.8 (-1.7, 0.2) Other/Unknown 0.4 (-0.9, 1.7) High Non-Hispanic White Ref Hispanic 0.8 (0.1, 1.6) NH Black 1.6 (1.0, 2.3) Other/Unknown -0.3 (-1.1, 0.4)

Uptake of and factors associated with telemedicine use for palliative care among patients diagnosed with advanced cancers during the onset of COVID-19.

53 Background: The COVID-19 pandemic propelled a rapid shift to telemedicine use, including patients with advanced cancers needing palliative care (PC). Yet, little is known about disparities in telemedicine use for PC. We leveraged population-based data to examine the trend and factors associated with telemedicine use for PC among Medicare beneficiaries diagnosed with advanced cancers during the onset of COVID-19 pandemic. Methods: We identified patients aged ≥65.5 years diagnosed with advanced-stage breast, colorectal, non-small cell lung (NSCL), small cell lung (SCL), pancreas, and prostate cancers in 2015-2019 from the SEER-Medicare data. We included those with continuous fee-for-service coverage and had any PC claims from diagnosis to death, hospice admission, or by 12/31/2020 (whichever came first). Telemedicine was identified using procedure codes, modifiers, and place of service codes on PC claims. We described the percent of PC recipients using telemedicine each quarter in 2019-2020. Multivariable logistic models assessed patient and provider characteristics associated with telemedicine use among PC recipients in 2020. Results: Telemedicine use for PC was 0.24% to 0.48% across 4 quarters in 2019, which increased to 16.3% in Q1 and stabilized at about 30% in Q2-Q4 in 2020. Among 2,945 PC recipients in 2020, 22.5% used telemedicine. Older patients (75-84 years and 85+ years) were 4.4 percentage points (ppts) and 8.6 ppts (p-values<0.05) less likely than patients ages 65-74 years to use telemedicine. Patients who were female (4.4 ppts), residing in higher socioeconomic status areas (Yost Quintile 5 vs 1: 7.7 ppts), treated by female providers (4.1 ppts), in hospital system (3.7 ppts vs. individual physician office) and organizations with hospice and palliative care specialists (8.9 ppts) were more likely to use telemedicine for PC (all p-values<0.05). (Table). Conclusions: Telemedicine use for PC surged during the onset of the COVID-19 pandemic, with considerable disparities by patient sociodemographic and provider characteristics. These disparities suggest potential barriers related to patients’ technology literacy and internet access, provider awareness, and healthcare organization resources. Future mixed-method studies need to elucidate these barriers to design interventions at patient, provider, and system levels to ensure effective PC delivery. Selected factors associated with telemedicine use for palliative care. Absolute Probability Difference (95%CI) Age group (ref: 65-74) 75-84 -4.4 (-7.6, -1.2) 85+ -8.6 (-13.4, -3.7) Female (ref: Male) 4.4 (0.9, 7.9) Yost quintile (ref : Q1-Q2) Q3-Q4 2.2 (-1.7, 6.1) Q5 7.7 (3.3, 12.1) Hospital system (ref: Individual physician office) 3.7 (0.6, 6.7) Provider: Female (ref: Male) 4.1 (0.7, 7.5) Organization with hospice and palliative care specialists 8.9 (5.4, 12.4)

Early palliative care among patients diagnosed with advanced cancers in the US (2010-2019): Trends and contribution of provider variation.

11017 Background: Early integration of palliative care (PC) is recommended for advanced cancers, but evidence of its use and the role of provider practice patterns and organizational characteristics in uptake is limited. This study examined recent trends of early PC among Medicare beneficiaries newly diagnosed with advanced cancers, and provider- and organization-variation in the receipt of early PC. Methods: We identified patients aged ≥65.5 years newly diagnosed with advanced stage breast, colorectal, non-small cell lung (NSCL), small cell lung (SCL), pancreas, and prostate cancers in 2010-2019 with ≥6 months survival and continuous fee-for-service coverage from the linked SEER-Medicare data. Early PC was identified by claims with corresponding diagnosis codes or hospice and palliative medicine provider specialty codes within 90 days post-diagnosis or up to first hospice admission date (whichever came earlier). Treating physicians and corresponding organizations (i.e., Tax Identification Number) were assigned based on the plurality of visits within 180 days after diagnosis. We described the percent of patients receiving early PC each year. Generalized linear models with physician- and organization-fixed effects evaluated variation in early PC receipt between and within physicians/organizations. Results: Among 103,045 patients treated by 25,736 unique providers and 11,163 organizations, the percent receiving early PC increased from 0.98% in 2010 to 10.64% in 2019. Although statistically significant increases were observed across cancer types, receipt in patients with prostate cancer was relatively lower compared to pancreas, SCL, NSCL, and breast cancers (Table). After adjusting for patients’ characteristics, variation in early PC use between treating providers and organizations explained 47.9% and 31.2% of the total variation, respectively. Conclusions: Despite considerable growth in early PC receipt, utilization remained low in 2019. The large variation between providers and organizations suggests important modifiable provider behaviors and organizational characteristics in early PC use, which warrant future research. [Table: see text]

Abstract 5663: Clinical relevance of unfolded protein response (UPR) signaling in breast cancer

Abstract Background: Protein homeostasis as regulated by the Endoplasmic Reticulum (ER) is a recognized process involved in cancer progression. ER stress activates the Unfolded Protein Response (UPR) and has been implicated in a variety of cancers. Due to the exposure of chronic stressors, cancer cells learn to adapt to prolonged ER stress by creating pro-survival alterations in the UPR signaling pathway and subsequently drive carcinogenesis. Given the role of the UPR activation in carcinogenesis, we hypothesized that UPR activation could be recognized with pathological progression, mutational accumulation, clinical stage advancement, and survival in breast cancer. Methods: A total of 5,316 breast cancer patients from multiple independent cohorts were analyzed. We defined the UPR pathway score by the degree of enrichment by Gene Set Variant Analysis (GSVA) and median was used to divide high vs low score groups in each cohort. Results: High UPR breast cancer significantly enriched not only cell proliferation-related gene sets (E2F targets, G2M checkpoint, MYC target v1 and v2, and MITOTIC spindle), but also other pro-cancerous gene sets, including MTORC1 signaling, DNA repair, PI3K/AKT/MTOR signaling, and reactive oxygen species pathway, consistently in both METABIC and GSE96058 cohort (all false discovery rate < 0.25). Majority of UPR pathway score high cells in the bulk tumor were tumor cells compared to other cells, including stromal cells, T cells, B cells, and myeloid cells (p < 0.001). UPR score was significantly associated with advanced stage, high grade, and triple negative breast cancer (TNBC) consistently in both cohort (all p < 0.001). High UPR breast cancer was significantly associated with worse patient survival in both cohort (all p < 0.001). Among breast cancer subtype, ER-positive/HER2-negative breast cancer with high UPR was significantly associated with worse survival, but not in HER-positive nor TNBC. High UPR ER-positive/HER2-negative breast cancer was significantly infiltrated with high level of Th1 and Th2 cells, M1 macrophage, and plasma cells consistently in both cohorts (all p < 0.001). On the other hand, high UPR ER-positive/HER2-negative breast cancer was significantly infiltrated with high level of stromal cells, including fibroblasts, adipocytes, and endothelial cells in tumor microenvironment (all p < 0.001). Finally, high UPR metastatic breast cancer was also significantly associated with worse patient survival (p = 0.041). Conclusion: UPR signaling is associated with cancer aggressiveness, and with worse survival in breast cancer, especially ER-positive/HER2-negative breast cancer subtype. Citation Format: Masanori Oshi, Shipra Gandhi, Rongrong Wu, Akimitsu Yamada, Li Yan, Takashi Ishikawa, Itaru Endo, Kazuaki Takabe. Clinical relevance of unfolded protein response (UPR) signaling in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5663.

Abstract P2-06-01: Parp inhibition sensitizes brca deficient cancer cell lines and tumors to clinical x-ray and proton irradiation

Abstract Purpose Triple negative breast cancers (TNBC) are more often found among BRCA gene mutation carriers; even among non-mutation carriers, TNBCs are thought to carry a phenotype of BRCAness. Inhibitors of Poly(adenosine diphosphate-ribose) polymerase (PARPi) have improved survival outcomes for both advanced and early stage breast cancer associated with a BRCA mutation, as well as BRCA mutated ovarian and prostate cancers. Radiotherapy (RT) is a widely used treatment to locally control cancers, but it is unclear how different types of RT, including clinical x-rays and protons, interact with PARPi and how these affect antitumor immunity. Protons induce more clustered DNA lesions, including clustered double and single strand breaks (DSBs and SSBs) and clustered base damages, than x-rays due to their higher ionization density. If not properly repaired, DSBs can generate micronuclei (MN), which activate the cyclic GMP-AMP synthase (cGAS) and stimulator of interferon (IFN) genes (STING) (cGAS-STING) pathway, leading to antitumor immunity. Residual DNA damage also induces cellular senescence, which is a known tumor suppressor mechanism. In this study we investigated the effects of combining a PARPi with x-rays or protons on clonogenic cell survival, residual DNA damage, senescence, cGAS co-localization with MN and delay in tumor growth in the context of BRCA1 mutation. Methods In vitro, BRCA1 deficient (HCC1937 and MDA-MB-436) and proficient (HCC1937-BRCA and MDA-MB-436-BRCA) breast cancer cell lines were treated with a PARPi (Olaparib, 0.1 - 5.0 μM) and irradiated with 6 MV x-rays or protons (9.9 keV/um) with doses from 0.5 to 5 Gy. HCC1937-BRCA was gifted from Dr. Stecklein (The University of Kansas Cancer Center) and MDA-MB-436-BRCA was gifted from Dr. Johnson (Fox Chase Cancer Center). We then quantified clonogenic cell survival, gH2AX and 53BP1 foci at 24 h after irradiation, MN number and MN-cGAS co-localization (cGAS+ MN) at 24 and 74 h after irradiation, and RT-induced senescence. In vivo, we used a preclinical TNBC mouse model (4T1 tumors on the leg of BALB/c mice) to assess survival and tumor growth delay on animals treated with DMSO, PARPi alone (Olaparib, 100 mg/kg), DMSO+x-rays, and PARPi+x-rays. Experiments with protons are ongoing. PARPi was administrated via oral gavage 2 h prior to irradiation (1 × 11 Gy). Results Survival fraction was lower after protons compared to x-rays (RBED10%>1) in HCC1937-BRCA, HCC1937 and MDA-MB-436 cells. Regardless of the radiation type, survival fraction was lower for HCC1937 compared to HCC1937-BRCA cells. PARPi treatment appears to result in greater radiosensitization of cells exposed to protons than those exposed to x-rays as assessed by clonogenic cell survival. The number of MN per nucleus was higher in HCC1937 than HCC1937-BRCA at 24 and 72 h after protons and x-rays at both 2 and 5 Gy, and this effect that was amplified with PARPi vs. without PARPi. Moreover, the number of cGAS+ MN was greater after protons than x-rays for HCC1937 but not HCC1937-BRCA at 24 and 72 h. The proportion of senescent cells for HCC1937-BRCA was higher (1.4 fold) after PARPi+protons compared to PARPi+x-rays. In vivo, x-rays lead to a delay in tumor growth, which was higher for the PARPi+x-rays group compared to PARPi alone or DMSO+x-rays groups. Conclusion In vitro, a PARPi treatment in BRCA1 mutated cell lines leads to a greater sensitivity to radiation compared to their counterparts with recovered BRCA1 function. This sensitivity is higher after protons compared to x-rays (survival fraction and number of micronuclei). In vivo, PARPi treatment combined with x-rays lead to higher delay in tumor growth compared to x-rays alone. These preliminary data are promising results on the effect of radiation combined with PARPi on BRCA1 mutated models. Citation Format: Mariam Ben Kacem, Scott J. Bright, Broderick X Turner, David B Flint, Mandira Manandhar, David Martinus, Gabriel O Sawakuchi, Simona F Shaitelman. Parp inhibition sensitizes brca deficient cancer cell lines and tumors to clinical x-ray and proton irradiation [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-06-01.

Survival Outcomes among Human Epidermal Growth Factor Receptor 2- (HER2-) Positive Breast Cancer Patients at Kenyatta National Hospital.

Introduction HER2-positive breast cancer is associated with poor outcomes and higher mortality rates than other breast cancer subtypes. The advent of trastuzumab has significantly changed the natural history of HER2-positive breast cancer. However, it is not an affordable treatment option in sub-Saharan African countries. Because of the expense, most patients in our setting do not receive trastuzumab for the optimal control of their disease. Additionally, there is a lack of comprehensive data about the survival outcomes of HER2-positive breast cancer patients in our setting. The present study was aimed at determining the survival outcomes among HER2-positive breast cancer patients at the Oncology Department of Kenyatta National Hospital. Methods A hospital-based retrospective cohort design was used to evaluate the survival outcomes among patients with HER2-positive breast cancer treated from 1st January 2015 to 31st December 2019 at Kenyatta National Hospital. A total of 50 eligible HER2-positive breast cancer patients were included in the study. In the predesigned data abstraction tool, data were collected by reviewing the medical records of the patients. The data were entered and analyzed using the Statistical Package for the Social Sciences version 27 software. The mean survival time was estimated using Kaplan-Meier survival analysis. Results The mean age was 45.44 ± 12.218 years, with a majority (80%) of the patients being below 60 years. Most patients (64%) had advanced-stage disease. The median follow-up time for patients with curative stages of breast cancer was 41 months, while the median follow-up time for those with the advanced incurable disease was 8.5 months. The 4-year survival rate was 62.5% for those curable-stage HER2-positive breast cancer compared to 5.6% for those with metastatic disease at presentation. Conclusion The 4-year survival rate for both early-stage and advanced-stage HER2-positive breast cancer in our setting is suboptimal when compared to existing outcome data from health care systems where trastuzumab is more widely available.

Cholesterol lowering drug use and breast cancer survival: the Multiethnic Cohort Study

PurposePrior studies conducted primarily in white populations have suggested that pre-diagnostic cholesterol lowering drugs (CLDs) improved survival among women with breast cancer (BC). However, this association had not been well characterized in diverse racial/ethnic populations. We investigated whether pre-diagnostic CLD use is associated with all-cause and BC-specific mortality among female BC cases of the Multiethnic Cohort (MEC).MethodsCLD use was ascertained through questionnaires administered in 2003–2008. A total of 1448 incident BC cases were identified by linkage to SEER cancer registries in Hawaii and California from 2003 to 2014. Multivariable Cox regression was conducted to estimate hazard ratios (HR) and 95% confidence intervals (CI) of the associations of pre-diagnostic CLD use with all-cause and BC-specific mortality, adjusting for tumor characteristics, first course of treatment, health behaviors, co-morbidities, and demographics. Subgroup analyses by stage and hormone receptor status were conducted for all-cause mortality.ResultsThere were 224 all-cause and 87 BC-specific deaths among the 1448 BC cases during a median follow-up of 4.5 years after diagnosis. Women with BC who ever used CLDs had a 27% lower hazard of all-cause mortality (HR 0.73, 95% CI 0.54–0.98) and 17% lower hazard of BC-specific mortality (HR 0.83, 95% CI 0.49–1.39) compared to never users. CLD use reduced mortality among women with advanced-stage tumors and hormone receptor-positive breast tumors (HR 0.54 95% CI 0.33–0.90; HR 0.69, 95% CI 0.48–0.99, respectively).ConclusionThese findings demonstrate an improved survival associated with CLD use prior to diagnosis in a multiethnic population of women with BC.

CTIM-02. TWO OUNCES OF PREVENTION: A SYSTEMATIC REVIEW AND META-ANALYSIS OF VEGF AND IMMUNE CHECK POINT INHIBITION FOR PRIMARY AND SECONDARY PREVENTION OF BRAIN METASTASES

Abstract INTRODUCTION As treatments for cancer outside of the central nervous system improve, brain metastases (BMs) are becoming increasingly frequent. Despite novel treatment options, BMs remain a frequent cause of death for many advanced malignancies, and both the metastases and their treatments are associated with profound cognitive, quality of life, and economic costs. METHODS We conducted exhaustive, PRISMA-compliant systematic reviews of the literature from January 2000 to June 2020 for studies comparing the frequency of new BM in patients treated with chemotherapy regimens including and not including bevacizumab (“primary prevention”), and for studies comparing the frequency of new outside-of-treatment-field metastases in patients treated with stereotactic radiosurgery (SRS) with or without immune checkpoint inhibitors (“secondary prevention”). Pre-specified data was extracted and summary statistics were calculated using the inverse variance method and random effects model. RESULTS Seven studies (n=6,212) reported on BMs in breast, lung, and colon cancer patients treated with chemotherapy with or without bevacizumab. The relative risk (RR) and 95% confidence intervals [95% CI] for the development of new brain metastases was 0.71 [0.55–0.91, p=0.001]. A sensitivity analysis performed on the 3 breast cancer trials (n=2,350) showed a RR of 0.57 [0.34–0.94, p=0.027]. Seven studies (n=609) reported on patients with melanoma BM receiving SRS without or without an ICI. The RR for the development of new out-of-treatment field brain metastases was 0.70 [0.51–0.94, p=0.017]. Results were similar in sensitivity analyses examining only class I and class II trials. CONCLUSION This analysis suggests that the addition of bevacizumab to chemotherapy or ICI SRS+/- chemotherapy can reduce the development of first-ever or new BM by 30% in patients with advanced stage breast, lung, or colon cancer. Prospective trials of primary and secondary prevention in patient groups at high risk of developing BMs, and examining additional predictors of response, are currently underway.

Evaluating genomic biomarkers associated with resistance or sensitivity to chemotherapy in patients with advanced breast and colorectal cancer.

Carcinogenesis is driven by an array of complex genomic patterns; these patterns can render an individual resistant or sensitive to certain chemotherapy agents. The Personalized Oncogenomics (POG) project at BC Cancer has performed integrative genomic analysis of whole tumour genomes and transcriptomes for over 700 patients with advanced cancers, with an aim to predict therapeutic sensitivities. The aim of this study was to utilize the POG genomic data to evaluate a discrete set of biomarkers associated with chemo-sensitivity or-resistance in advanced stage breast and colorectal cancer POG patients. This was a retrospective multi-centre analysis across all BC CANCER sites. All breast and colorectal cancer patients enrolled in the POG program between July 1, 2012 and November 30, 2016 were eligible for inclusion. Within the breast cancer population, those treated with capecitabine, paclitaxel, and everolimus were analyzed, and for the colorectal cancer patients, those treated with capecitabine, bevacizumab, irinotecan, and oxaliplatin were analyzed. The expression levels of the selected biomarkers of interest (EPHB4, FIGF, CD133, DICER1, DPYD, TYMP, TYMS, TAP1, TOP1, CKDN1A, ERCC1, GSTP1, BRCA1, PTEN, ABCB1, TLE3, and TXNDC17) were reported as mRNA percentiles. For the breast cancer population, there were 32 patients in the capecitabine cohort, 15 in the everolimus cohort, and 12 in the paclitaxel cohort. For the colorectal cancer population, there were 29 patients in the bevacizumab cohort, 12 in the oxaliplatin cohort, 29 in the irinotecan cohort, and 6 in the capecitabine cohort. Of the biomarkers evaluated, the strongest associations were found between Bevacizumab-based therapy and DICER1 (P = 0.0445); and between capecitabine therapy and TYMP (P = 0.0553). Among breast cancer patients, higher TYMP expression was associated with sensitivity to capecitabine. Among colorectal cancer patients, higher DICER1 expression was associated with sensitivity to bevacizumab-based therapy. This study supports further assessment of the potential predictive value of mRNA expression of these genomic biomarkers.

Abstract 4908: Exemestane worsens everolimus-associated stomatitis in cancer patients

Abstract Everolimus is an antitumor drug usually indicated for the treatment of breast, kidney and neuroendocrine malignancies that inhibits the activation of the mammalian Target of Rapamycin (mTOR). Despite the efficacy and success of the treatment, side effects are not uncommon, and stomatitis is quite prevalent. mTOR inhibitor associated stomatitis (mIAS) is described as ulcerated aphthous-like lesions associated with mTOR inhibitors use. mIAS may cause severe pain, leading to nutritional deficiency and general health decline, besides drug dose reduction or suspension. Clinical observation suggested mIAS to be more common among breast cancer patients. Thus, we hypothesized that exemestane could contribute to increase everolimus toxicity in the oral mucosa. We prospectivelly collected clinical data from patients who used everolimus, associated or not with exemestane, from March 2016 to September 2017, and correlated them with information regarding mIAS (date of onset, number of lesions in the oral cavity, grading). We also performed in vitro experiments with Dysplastic Oral Keratinocytes (DOK). Cells were treated with vehicle, everolimus, exemestane or the combination of everolimus and exemestane. Drug induced citotoxicity was evaluated by MTT assay and migration inhibition by scratch wound healing assay. All assays were done in triplicate. Frequencies were compared by Fisher's exact or McNemar test. Log-rank and Wilcoxon tests were employed to compare time to mIAS development. Multivariate ANOVA was used to compare results from in vitro experiments. SPSS and Image J were used to make all statistical analysis. One hundred and thirty patients were evaluated. Mostly were females, with mean age of 60 years, and had previously treated advanced stage (IV) breast cancer. 30.3% developed mIAS. Breast cancer patients (treated with exemestane plus everolimus) had 2.29 higher chance to develop mIAS when compared to neuroendocrine tumos patients (treated with everolimus alone). In vitro experiments showed that the association of everolimus and exemestane increased cell death and migration (wound healing) inhibition of DOK in comparison with cells treated with everolimus or exemestane alone. The clinical data suggests that exemestane increases the risk of developing mIAS, and the in vitro experiments reinforces the idea that exemestane may enhance oral mucosa toxicity mediated by everolimus. Citation Format: Vladmir C. de Lima, Matheus H. de Lima, Fabio A. Alves, Gláucia N. Hajj. Exemestane worsens everolimus-associated stomatitis in cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4908.

Breast cancer: T-DM1 - an important agent in the history of breast cancer management.

Updated results from the EMILIA and TH3RESA trials in patients with advanced-stage HER2-positive breast cancer confirm the overall survival benefit and favourable safety profile of T-DM1 after prolonged follow-up durations. The efficacy of T-DM1 as a second or later line of treatment indicates that HER2 is a relevant therapeutic target throughout the course of the disease.

Abstract 2160: Targeting SMC1 in combination therapy for triple negative breast cancer

Abstract Triple negative breast cancer (TNBC) defined primarily by lack of expression of estrogen and progesterone hormone receptors (HR) and lacking HER2 overexpression and/or gene amplification (HER2) is an aggressive subtype with poor prognosis. Presentation is frequently at an advanced stage, and TNBC is particularly prevalent in younger women, African Americans, and/or in women with BRCA1 and less frequently with BRCA2 gene mutations. Over the last several years, although great progress has been made in the treatment of early HR positive and HER2+ (as well as advanced stage) breast cancer, relapse/progression-free and overall survival of patients with TNBC remains a serious problem. Molecular subtyping identified subsets of TNBC, several of which are thought to be DNA-repair deficient (either due to germ-line mutations such as BRCA1 or 2, or somatic mutations affecting DNA-repair), may be amenable to treatment with DNA-damaging agents such as platinum compounds and PARP (poly(ADP-ribose) polymerase-1) inhibitors. This could be particularly useful in BRCA-mutated cancers. As for the other TNBC subtypes, development of novel therapeutic agents, represents a high priority. In response to this clinical need, we tested the efficacy of a novel combinatorial strategy which targets differentiated cells and TNBC cancer stem cell like population (CSCs). Structural maintenance of chromosome-1 (SMC1) was selected as a tumor antigen based on our published studies showing its surface localization and the role in cell proliferation, survival and metastasis in TNBC cells. Bioinformatics analyses using public available patient cohorts with clinicopathological information such as TCGA, NCBI and BRAVO showed statistically higher mRNA overexpression of SMC1 in TNBC compared to HR+ and HER2+ breast cancer. To target SMC1, we developed several monoclonal antibodies against the epitope of SMC1 which showed similarity to cell-adhesion peptides in order to facilitate biochemical and cellular assays. The impact of SMC1 inhibition in combination with veliparib, an inhibitor of PARP-1 was tested in BRCA1-wild-type (MDA-MB-231) vs. mutant (MDA-MB-436) TNBC cells and in CSCs (CD44+/CD24low-) sorted from these cells by MTT and colony forming assays. TUNEL and Annexin-V flipping assays were used to determine cell apoptosis. The role of intrinsic vs. extrinsic pathways of apoptosis was examined by measuring activation of Caspase 8 and 9 as well as measurements of cytochrome-c release from mitochondria. Our results showed that Mab-S15 recognizes SMC1 which is selectively expressed on the surface of cancer cells (including CSC’s) and differentiated TNBC’s, but has a minimal distribution in normal cells. The antibody distinctly inhibits the survival of TNBC in culture, including CSC’s, sorted from TNBC’s. The Mab-S15 and veliparib combination was more effective than the individual agents in inhibiting the growth and survival of TNBC cells including those with a functional BRCA1. Citation Format: Sushma Yadav, David Berz, George Somlo, Kimlin Ashing, Yate-Ching Yuan, Robert J. Hickey, Sailee Yadav, Arthur D. Riggs. Targeting SMC1 in combination therapy for triple negative breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2160.

1225 Potential long-term cost savings due to significant clinical benefit of pertuzumab in combination with trastuzumab for the neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory or early stage breast cancer

1225 Potential long-term cost savings due to significant clinical benefit of pertuzumab in combination with trastuzumab for the neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory or early stage breast cancer

Therapeutic vaccines and cancer: focus on DPX-0907

In an attempt to significantly enhance immunogenicity of peptide cancer vaccines, we developed a novel non-emulsion depot-forming vaccine platform called DepoVax™ (DPX). Human leukocyte antigen (HLA)-A2 restricted peptides naturally presented by cancer cells were used as antigens to create a therapeutic cancer vaccine, DPX-0907. In a phase I clinical study, the safety and immune-activating potential of DPX-0907 in advanced-stage breast, ovarian, and prostate cancer patients were examined, following encouraging results in HLA-A2 transgenic mice. The DPX-0907 vaccine was shown to be safe and well tolerated, with injection-site reactions being the most commonly reported adverse event. Vaccinated cancer patients exhibited a 61% immune response rate, with higher response rates in the breast and ovarian cancer patient cohorts. In keeping with the higher immune efficacy of this vaccine platform, antigen-specific responses were detected in 73% of immune responders after just one vaccination. In 83% of responders, peptide-specific T-cells were detected at two or more time points post-vaccination, with 64% of these patients showing evidence of immune persistence. Immune monitoring also demonstrated the generation of antigen-specific T-cell memory, with the ability to secrete multiple type 1 cytokines. The novel DPX formulation promotes multifunctional effector/memory responses to peptide-based tumor-associated antigens. The data support the capacity of DPX-0907 to elicit type-1 biased immune responses, warranting further clinical development of the vaccine. In this review, we discuss the rationale for developing DPX-based therapeutic cancer vaccine(s), with a focus on DPX-0907, aimed at inducing efficient anti-tumor immunity that may eventually be shown to prolong patient survival.

Impact of body mass lndex on locoregional control in saudi patients with breast cancer after breast conserving surgery and modified radical mastectomy

Abstract Background: Obesity and increased body mass index (BMI) are increasing among Saudi women across the all age groups, with an overall prevalence of 44%. Increased BMI is associated with advanced stage breast

Abstract B89: Understanding changes in the USPSTF mammography screening guidelines: The role of the Avon Breast Health Outreach Program in reaching underserved women.

Abstract Objective: Given recent changes to mammography screening guidelines from the US Preventive Services Task Force (USPSTF) advising against routine screening of women ages 40-49, we sought to better understand knowledge, attitudes and educational practices of those charged with educating women about breast cancer screening. A major goal of the Avon Breast Health Outreach Program (BHOP) is to educate women about breast cancer early detection and to connect them to screening services. Special emphasis is focused on reaching women in underserved communities where there are disproportionately high rates of advanced-stage disease and breast cancer mortality. BHOP supports breast health Outreach Educators (OE), Case Managers (CM) and Patient Navigators (PN) who assist women from the point of learning about screening, getting screened and following up on results, as needed. The revised USPSTF guidelines have caused controversy and confusion among the lay public, as well as breast health educators and providers. Methods: An online survey of Avon BHOP fiscal year 2011 grantees was conducted to document understanding of USPSTF guideline changes, strategies used to educate BHOP clients and provide decision support, and to identify potential training needs. An electronic mail invitation was sent to a total of 175 Avon BHOP grantee organizations across the US (n=112 community-based organizations and 63 Safety Net Hospitals). Avon BHOP OEs, CM, and PN participated in the self-administered, anonymous survey between December 2011 and January 2012. Results: A total of 164 respondents completed survey. Most were over age 40, had at least a college education, and reported that their role was to reach underserved, underinsured, and uninsured women. Half were White (49%) and about a quarter were Hispanic or African American (25% and 23%, respectively). Despite the USPSTF guideline change, 86% of respondents reported that they continue to tell women ages 40-49 that they should have an annual mammogram. The majority (75%) learned about the guideline change through mass media. Of those who were aware of the guideline change, 73% reported that they did not agree with the change; most did not believe that there were disadvantages to having a mammogram. Few respondents perceived the need to discuss the pros and cons of screening with their clients. Conclusions: In our sample of relatively well-educated BHOP staff, knowledge and awareness regarding USPSTF guidelines for mammography was low. Our findings support the notion that stakeholders, including women, breast cancer educators and outreach workers, remain committed to annual mammography for women over 40. Results indicate a need for additional training for BHOP staff regarding the range of mammography screening guidelines across major medical organizations, and strategies for explaining inconsistencies to their clients. While the need for decision support for women age 40-49 was not recognized as a high priority, helping women to understand that there are pros and cons of screening in this age range are also needed for informed decision-making, especially in underserved communities. Citation Format: Shirley M. Bluethmann, Jennifer D. Allen, Hannah L. Mills, Kelly Morrison Opdyke, Kathryn Gates-Ferris, Marc Hurlbert, Elizabeth Harden. Understanding changes in the USPSTF mammography screening guidelines: The role of the Avon Breast Health Outreach Program in reaching underserved women. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr B89.

First-in-man application of a novel therapeutic cancer vaccine formulation with the capacity to induce multi-functional T cell responses in ovarian, breast and prostate cancer patients

BackgroundDepoVaxTM is a novel non-emulsion depot-forming vaccine platform with the capacity to significantly enhance the immunogenicity of peptide cancer antigens. Naturally processed HLA-A2 restricted peptides presented by breast, ovarian and prostate cancer cells were used as antigens to create a therapeutic cancer vaccine, DPX-0907.MethodsA phase I clinical study was designed to examine the safety and immune activating potential of DPX-0907 in advanced stage breast, ovarian and prostate cancer patients. A total of 23 late stage cancer patients were recruited and were divided into two dose/volume cohorts in a three immunization protocol.ResultsDPX-0907 was shown to be safe with injection site reactions being the most commonly reported adverse event. All breast cancer patients (3/3), most of ovarian (5/6) and one third of prostate (3/9) cancer patients exhibited detectable immune responses, resulting in a 61% immunological response rate. Immune responses were generally observed in patients with better disease control after their last prior treatment. Antigen-specific responses were detected in 73% of immune responders (44% of evaluable patients) after the first vaccination. In 83% of immune responders (50% of evaluable patients), peptide-specific T cell responses were detected at ≥2 time points post vaccination with 64% of the responders (39% of evaluable patients) showing evidence of immune persistence. Immune monitoring also demonstrated the generation of antigen-specific T cell memory with the ability to secrete multiple Type 1 cytokines.ConclusionsThe novel DepoVax formulation promotes multifunctional effector memory responses to peptide-based tumor associated antigens. The data supports the capacity of DPX-0907 to elicit Type-1 biased immune responses, warranting further clinical development of the vaccine. This study underscores the importance of applying vaccines in clinical settings in which patients are more likely to be immune competent.Trial RegistrationClinicalTrials.gov NCT01095848

Effect of the novel therapeutic cancer vaccine formulation DPX-0907 on multifunctional T-cell responses in ovarian, breast, and prostate cancer patients.

2588 Background: To increase the efficacy of peptide cancer vaccines, we developed a novel vaccine platform called DepoVax, an adjuvanted water-free depot formulation with the ability to generate enhanced immune responses. Naturally processed HLA-A2 restricted peptides that are selectively presented by breast, ovarian and prostate cancer cell lines, but not by normal HLA-A2+ cells, were used as antigens with a proprietary adjuvant and a T helper peptide epitope to create a therapeutic cancer vaccine, DPX-0907. Methods: A phase I clinical study was designed to examine the safety and immune activating potential of DPX-0907 in advanced stage breast, ovarian and prostate cancer patients. A total of 23 late stage cancer patients were recruited and were divided into two dose volume cohorts in a three immunization clinical protocol. Results: DPX-0907 proved to be safe with no serious adverse effects related to the vaccine reported. Of those evaluable for immunogenicity, all breast cancer patients (3/3), most of ovarian (5/6) and one third of prostate (3/9) cancer patients demonstrated immune response to one or more of seven antigenic peptides, resulting in a 61% response rate. Immune responses correlated with achievement of CR, PR or SD to last treatment. No difference in immune response rate or magnitude was seen between the two dose groups. DPX-0907 displayed strong immune induction potential, with 73% of immune responders showing responses with just one dose of vaccine. In 83% of responders, immune responses were detected at ≥2 time points post vaccination and 64% had a persistent immune response at one month post last vaccination. Immune monitoring showed peptide-specific CD8 T cells, and these T cells were able to secrete multiple Th1 cytokines indicating their multifunctionality, a feature attributable to cells that mediate protective responses. Conclusions: These data support the ability of DPX-0907 to elicit Th1 dominated, specific immunity and support the rationale for further testing in immunologically competent cancer patients. The novel DepoVax formulation may promote multifunctional memory responses with peptides from other tumor associated antigens.

Abstract 165: The anticarcinogenic effects of melatonin on inhibition of fatty acid transport and 13-HODE production in HT29 human colorectal cancer occurs via receptor-mediated signal transduction

Abstract Over 620,000 people in the U.S. alone this year will be diagnosed with either breast, prostate, or colorectal cancers, which represent nearly 50% of all reported malignancies. Patients with advanced stage breast, prostate, or colorectal cancer have only a 35% survival rate at 5 years. Epidemiological studies have indicated that the risk of these cancers is increased in persons exposed to excessive sunlight or, interestingly, ocular light at night, as experienced by night-shift workers. This latter finding was shown to be associated with a suppression of the nighttime production of the circadian neurohormone melatonin. Previous work from this laboratory using perfused, tissue-isolated human breast and prostate tumors showed that tumor growth and metabolism in vivo is dependent upon uptake of linoleic acid (LA), the most prominent fatty acid in our western diet, and its conversion to 13-hydroxyoctadecadienoic acid (13-HODE). In tissue-isolated human MCF-7 (steroid responsive and non-responsive) and PC3 prostate tumors perfused in situ with arterial blood, melatonin inhibits LA-uptake and conversion to 13-HODE, a lipoxygenase product that stimulates EGF mitogenesis. The present study explores the effects in vivo of melatonin (500 pM) on perfused, tissue isolated HT29 colorectal carcinomas in nude rats. HT29 colorectal carcinoma latency-to-onset and growth rates, respectively, of 12 days and 0.12 ± 0.01 g/day; mean tumor weights were 5.6 ± 0.2 g (n = 20). Colorectal carcinomas perfused in situ with donor rodent blood for 2 hours (Controls) revealed a tumor LA uptake and 13-HODE release of 0.86 ± 0.08 μg/min/g (20.0 ± 1.6% of arterial supply) and 3.23 ± 0.81 ng/min/g, respectively. Incorporation of 3H-thymidine into tumor DNA and DNA content, respectively were 25.9 ± 1.6 dpms/μg DNA and 2.7 ± 0.1 μg/g tumor. Carcinomas perfused with arterial donor blood augmented with physiological nocturnal levels of 500 pM melatonin showed a complete inhibition of LA uptake, 13-HODE release, ERK 1/2, MEK, Akt, and GSK3β activities, and over a 90% reduction in tumor cAMP levels and [3H]thymidine incorporation into tumor DNA. Addition of the non-selective MT1/MT2 melatonin antagonist S20928, forskolin, 8-Bromo-cyclic-AMP, or pertussis toxin completely reversed the tumor growth inhibitory response. Also, addition of 13-HODE reversed the inhibition of 3H-thymidine incorporation into tumor DNA, while having no effect on LA uptake. These results are the first to demonstrate in HT29 colorectal carcinoma that nocturnal melatonin levels suppress tumor growth via a melatonin receptor-mediated signal transduction mechanism. An understanding of this signaling pathway for the control of LA uptake in cancer could lead to new approaches for therapeutic intervention and/or chemoprevention. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 165. doi:1538-7445.AM2012-165

A Pilot Study Evaluating the Effect of Mindfulness-Based Stress Reduction on Psychological Status, Physical Status, Salivary Cortisol, and Interleukin-6 Among Advanced-Stage Cancer Patients and Their Caregivers

To investigate whether a mindfulness-based stress reduction program for cancer (MBSR-C) improved psychological and physical symptoms, quality of life (QOL), and stress markers among advanced-stage cancer patients and caregivers. A pilot within-subject design was used. Patients previously diagnosed with advanced-stage breast, colon, lung, or prostate cancer and on treatment were recruited from the Moffitt Cancer Center and Research Institute. Twenty-six patient-caregiver dyads completed a modified 6-week, self-study MBSR-C program based on the Kabat-Zinn model. Psychological and physical symptoms and QOL were compared pre- and post-MBSR-C sessions. Salivary cortisol and interleukin-6 were assessed pre- and post-MBSR-C session at 1, 3, and 6 weeks. Following the 6-week MBSR program, patients showed improvements in stress and anxiety (p < .05); caregivers' psychological and QOL also improved but were not statistically significant. Both patients and caregivers had decreases in cortisol at Weeks 1 and 3 (p < .05) but not at Week 6. Similar to cortisol levels at Week 6, salivary interleukin-6 levels were lower overall (before/after an MBSR-C session), compared with Week 1 for patients and caregivers. MBSR-C may be a beneficial intervention for reducing stress, anxiety, cortisol levels, and symptoms in advanced-stage cancer patients and may also benefit caregivers.