bluuebunny/crossref_metadata_2025 huggingface dataset:
Concordance of multispectral immunofluorescence (mIF) with programmed death ligand 1 (PD-L1) and stromal tumor infiltrating lymphocyte (sTILs) clinical assays in early-stage breast cancer (BC).
Authors: Sanchez Katherine , Chang Shu-Ching , Kim Isaac , Martel Maritza , Wu Yaping , Redmond William L , Sun Zhaoyu , Waddell Dottie , Laxague Deborah R. , Bernard Brady , Shah Monil , Urba Walter John , Page David B.
Published: May 2020

e12589

Background: There is growing need for surrogate immune-based biomarkers in BC to enhance prediction accuracy and to facilitate comparisons of therapeutic activity in the context of clinical trials. We report mIF as a high-dimensional biomarker that is highly concordant with both PD-L1 (SP142) and sTIL clinical assays (H&E), but with greater precision to quantify on-treatment pharmacodynamic effects. We also demonstrate how statistical modeling can be employed to improve precision of PD-L1/sTIL estimates, and reduce sample size requirements for biomarkers-driven comparative clinical trials. Methods: Samples were obtained from a recently-reported pre-surgical cytokine-based phase Ib immunotherapy (IRX-2) clinical trial (NCT02950259). Pre-treatment and resection tissues (n = 30) were analyzed for sTIL score, PD-L1 status, and mIF (PerkinElmer Vectra) using antibodies to quantify BC cells (cytokeratin), immune cells (CD3, CD8, CD163, FOXP3), and per-cell PD-L1 expression. Mixed effects regression models were employed to correct for intratumoral heterogeneity and enhance statistical precision. Monte Carlo simulations were employed to evaluate whether regression modeling could reduce sample size required to detect treatment-related increases in sTIL/PD-L1 in pre-surgical clinical trials. Results: Results: mIF sTIL estimates were highly correlated with H&E sTIL score (pre-treatment samples: r = 0.59, p > 0.001; excisional samples: r = 0.63, p > 0. 001). mIF PD-L1 estimates were highly correlated with the PDL1 SP142 assay, with average densities increasing concordantly according to SP142 IC category (IC0 v. IC1, p = 0.04; IC0 v. IC2/3, p = 0.003). Our regression modeling approach dramatically improved power to demonstrate treatment-related changes in sTIL and PD-L1. The estimated sample size requirement to show the observed effect on sTIL score (1.80 fold change, CV 0.83) was n = 25 with conventional t-testing of means, versus n = 13 with regression modeling. Conclusions: mIF is concordant with SP142 and sTIL prognostic assays, but with increased precision to quantify treatment related changes. Regression modeling can dramatically improve the utility of mIF as a surrogate immune-based biomarker. Our approach is being utilized in ongoing phase II studies to compare the activity of pembrolizumab +/- locoregional cytokines (IRX-2) in triple negative BC, and paclitaxel/trastuzumab +/- pembrolizumab +/- pertuzumab in HER2-positive BC.
A systems medicine-based approach for finding metabolic targets applied to primary basal-like breast cancer.
Authors: Cook Daniel , Nielsen Jens , Braun Eduardo
Published: May 2020

e12590

Background: Although metabolic disfunction is one of the hallmarks of cancer and metabolism-based therapies are a key class of chemotherapeutics, there remains no systematic way to identify metabolism-based targets for therapeutic intervention. Because of this deficiency, metabolism-based therapies offer a largely untapped area for therapeutic discovery, especially for difficult to target tumors, like basal-like breast cancer (BLBC). Adding to the challenge of discovering metabolism-based therapeutics for BLBC, however, is the heterogeneity of tumor behavior across patients, both in terms of aggressiveness and molecular regulation. Methods: We addressed these challenges by introducing a systems medicine-based technique integrating metabolic network modeling with single-patient RNA-sequencing (RNA-seq). We then applied this technique to investigate metabolic weaknesses in primary BLBC. We constructed a genome-scale metabolic model of breast cancer (ecBRCA) along with RNA-seq profiles constructed from The Cancer Genome Atlas (TCGA) to predict metabolic targets whose inhibition is lethal to BLBC tumors. We then evaluated the effectiveness of drugging these targets across patients by simulating the effect of a targeted knock-out on primary tumors with published RNA-seq profiles from 534 BLBC patients in TCGA and the Swedish Cancerome Analysis Network for Breast (SCANB). Results: We found multiple metabolic targets that may prove clinically useful for complementary treatment of primary BLBC tumors. Among these, we found UDP-Glucose 6-Dehydrogenase (UGDH) and Heparan Sulfate 2-O-Sulfotransferase 1 (HS2ST1) to be particularly promising protein targets for chemotherapy in BLBC, with 80-100% of simulated BLBC tumors responding to their inhibition. Currently FDA-approved drugs down-regulating these proteins, such as metformin (for UGDH) and surfen (for HS2ST1), are potentially viable complementary treatments for BLBC patients. Additionally, we found several metabolite targets whose inhibition may inhibit BLBC growth, including leukotriene A4, creatinine, vitamin D3, and the oncometabolites 2- and 3-hydroxy-glutarate. Conclusions: Taking a systems medicine-based approach to understanding BLBC metabolism allows for a systematic way to identify metabolic targets for therapeutic intervention. Additionally, certain metabolic weaknesses appear to be conserved in BLBC tumors across patients, including a dependence on UGDH and HS2ST1, which could be treated with currently available drugs like metformin and surfen.
Tolerance of concurrent CDK inhibitor and radiation therapy in metastatic breast cancer patients.
Authors: Beddok Arnaud , Arsene-Henry Alexandre , Porte Baptiste , Cao Kim , Scher Nathaniel , Otz Joelle , Minsat Mathieu , Bidard Francois Clement , Fourquet Alain , Cottu Paul H. , Kirova Youlia
Published: May 2020

e12598

Background: Palbociclib, a small-molecule inhibitor of cyclin-dependent kinases (CDK4 and CDK6), combined with letrozole increases progression-free survival among patients with previously untreated ER-positive, HER2 negative advanced breast cancer. The purpose of our study was to retrospectively evaluate the tolerance of the concomitant association of Palbociclib and radiation therapy (RT) at Curie Institute. Methods: Between April 2017 and August 2019, 30 women with ER-positive, HER2 negative metastatic breast cancer received locoregional (LR) and/or symptomatic irradiation at a metastatic site concurrently with Palbociclib at a daily dose of 125 mg, from d1 to d21 every 28 days. Palbociclib was always associated with endocrine therapy: letrozole (with or without an LHRH analogue) or fulvestrant. Thirty-five sites were irradiated: nine patients received post-operative locoregional RT, including the chest wall or breast and lymph node areas, and 26 sites of metastases were irradiated: 17 at the spine, 7 peripheral skeletal lesions, 1 brain lesion and 1 choroidal lesion. The dose prescribed for locoregional mammary radiotherapy was 50 Gy in 25 fractions and varied for the treatment of metastatic sites: 20 Gy in 5 fractions (n = 13), 30 Gy in 10 fractions (n = 10) and 8 Gy in 1 fraction (n = 2). The brain metastasis was stereotactically treated (1 fraction of 18 Gy). The primary endpoint was toxicity scored according to the common terminology criteria for NCI adverse events, version v5.0. Results: Mean number of days of Palbociclib during RT was 8.8 days (range, 1 to 24 days). The most common acute toxicities were dermatitis (12/35, including 2 grade 2) and neutropenia (12/35, including 9 grade 2). Palbociclib had to be stopped during the RT of two patients (2/30): one patient treated locoregionally (bilateral breast and lymph nodes irradiation) developed a grade 3 dermatitis and febrile neutropenia, another treated locoregionally developed grade 2 dysphagia. After a median follow-up since the end of RT of 17 months (6 – 31 months, SD 8), none of the patients have so far exhibited late toxicity. Conclusions: Concomitant administration of palbociclib with RT was reasonably well tolerated in our series of 30 patients. Given this experience, palbociclib should not be discontinued during radiation therapy. Nevertheless, our findings should be confirmed in prospective registration studies collecting larger number of patients.
Risk factors of ipsilateral breast tumor recurrence in triple-negative or HER2-positive breast cancer patients who achieved pathological complete response after neoadjuvant chemotherapy.
Authors: Tazo Mizuho , Kojima Yasuyuki , Yoshida Atsushi , Nakayama Sayuka , Tokui Ryu , Ogawa Tomoko , Kuwayama Takashi , Nakayama Takahiro , Yamauchi Hideko , Tsugawa Koichiro , Nakamura Seigo , Hayashi Naoki , Ishitobi Makoto
Published: May 2020

e12599

Background: To date, patients undergo breast surgery after neoadjvant chemotherapy (NAC) even though they achieve clinical complete response (cCR). The safety of omitting breast surgery for the patients who are predicted to be pCR has recently investigated in some research, however we still have not reached to a definite consensus yet. We may consider the breast surgery omission on the assumption that the rate of ipsilateral breast tumor recurrence (IBTR)after achieving pCR is acceptably low. The purpose of this study is to examine the rate of and evaluate the clinical features of IBTR in patients achieving pCR after NAC. Methods: In this study, a total of 278 patients with HER2-positive or Triple negative type primary breast cancer were enrolled from4 institutions. They were all diagnosed as ypT0 after breast conserving surgery and received postoperative radiotherapy. Occurrence of IBTR and other clinicopathological factors were collected by retrospective chart review. Results: Of the 278 patients, 49 patients (18%) were ER+/HER2+, 106 patients (38%) were ER-/HER2+ and 123 patients (44%) were ER-/HER2-. We found breast recurrence in 11 patients (4%) as a first recurrence. The 5-year breast recurrence rate was 4.5% in total, 2.2% in ER+/HER2+, 4.0% in ER-/HER2+ and 4.6% in ER-/HER2-, respectively. There was no significantly difference among subtypes. Interestingly, the 5-year breast recurrence rate of patients under 40-year-old was 12.3% which was significantly higher than patients with and above 40-year-old (3.1%, p=0.002). Conclusions: We should be extremely careful when consider omitting breast surgery for patients younger than 40 even if they achieved pCR after NAC.
Accuracy of sentinel lymph node biopsy in invasive lobular carcinoma of the breast.
Authors: Guo Ruby , Brabham Case E. , Fahrner-Scott Kelly , Abel Mary Kathryn , Wong Jasmine , Alvarado Michael , Esserman Laura , Ewing Cheryl Ann , Mukhtar Rita A.
Published: May 2020

e12604

Background: The safety of the sentinel lymph node biopsy procedure (SLNB) in the surgical management of breast cancer relies upon a false negative rate (FNR) being less than 10%. The accuracy of SLNB in invasive lobular carcinoma (ILC), the second most common type of breast cancer, has not been evaluated. Because of high rates of false negative imaging and the diffuse growth pattern in ILC, less accurate pre-operative staging and a potentially unreliable lymphatic drainage pattern may impact the accuracy of SLNB in this tumor type. We therefore sought to characterize the accuracy of SLNB in a cohort of patients with ILC. Methods: We queried an institutional database of 707 patients with ILC and identified 196 patients who underwent SLN mapping with excision of both sentinel and non-sentinel nodes. A false negative was defined as having negative sentinel lymph nodes and a positive non-sentinel node. We calculated the FNR and sensitivity of SLNB and evaluated clinicopathologic variables. Results: Of 196 cases, 183 were clinically node-negative, 9 were clinically node-positive, and 4 had unknown clinical node status. Of the 183 clinically node-negative patients, 69 (37.7%) patients had node-positive disease at surgery. Overall, 7 of 196 cases had false negative SLNB, yielding an FNR of 8.97%. The sensitivity of SLNB was 91%. Patients with a false negative SLNB were significantly older than patients without (mean age 63 versus 54.7 years, p = 0.041). Significantly fewer sentinel and non-sentinel nodes were removed in women aged 50 years or older compared to those under 50 (1.9 vs. 2.5 sentinel nodes, p = 0.0158; 4.7 vs. 7.9 non-sentinel nodes, p = 0.0077). There were no differences in tumor receptor subtype, grade, stage, presence of lymphovascular invasion, or receipt of neoadjuvant therapy in those with a false negative SLNB compared to those without. Conclusions: The high rate of nodal positivity in clinically node negative patients highlights the challenges of clinical nodal assessment in ILC. Despite this, the SLNB procedure had a FNR that fell within the acceptable range, supporting its use in ILC. The relationship between number of sentinel nodes removed and FNR deserves further study, particularly in older women where extent of nodal surgery continues to decline.
The impact of exogenous estrogen exposure on the characteristics of estrogen receptor (ER) positive, early-stage breast cancer (EBC).
Authors: Yariv Orly , Yerushalmi Rinat , Moore Assaf , Shohat Tzippy , Rotem Ofer , Yasmin Korzets Ceder , Goldvaser Hadar
Published: May 2020

e12606

Background: Oral contraceptives (OC) and hormone replacement therapy (HRT) are well-established risk factors for ER positive breast cancer. Infertility is associated with an increased breast cancer risk and there is conflicting data on the influence of fertility treatments on breast cancer risk. The impact of exogenous estrogen exposure on breast cancer characteristics is not well described. Methods: A single center retrospective cohort study comprising all women with ER positive, human epidermal growth factor receptor 2 (HER2) negative, EBC whose tumors were sent to OncotypeDX analysis treated in our institute between 2005 and 2012. Data on exogenous estrogen exposure were collected including: OC and HRT use and prior fertility treatments. The impact of these exposures was assessed on pre-specified histopathological features including: tumor size, nodal status, ER and progesterone receptor (PR) staining, grade, Oncotype recurrence score (RS), ki67, lymphovascular and perineural invasion. Results: A total of 620 women were included, 79% were postmenopausal. Prior exposure to OC, HRT and fertility treatments was documented in 19% (103), 30% (136) and 11% (62), respectively. OC use was associated with smaller (≤1cm) tumors (30% vs. 20%, p = 0.023) and were less likely to have grade 3 disease (10% vs. 19%, p = 0.049). No other associations were found between exogenous estrogen exposures and tumor characteristics (Table). Conclusions: Use of OC may be associated with breast cancer with a distinct features compared to women with luminal breast cancer without history of OC use. Large scale studies are needed to better characterize these findings. [Table: see text]
Magseed localisation for loco-regional breast and lymph node recurrences: Placement prior to chemotherapy to allow focused removal of the initially diseased tissue.
Authors: Benn Carol , van Loggerenberg Dominic , Shaw Vernon Adrian robert
Published: May 2020

e12610

Background: Multi-disciplinary meeting decisions may suggest chemotherapy prior to surgery. Prior to chemotherapy, localisation of the diseased tissue is important to ensure accurate retrieval. Magseed is induced to become a magnet when used in conjunction with a detector. The aim of this study was to assess the accuracy of placement, retrieval, and localisation of a Magseed into a radiologically suspicious loco-regional recurrence in patients requiring chemotherapy. Methods: Patients with loco-regional recurrence that had been assessed in the multidisciplinary meeting as requiring chemotherapy, as well as being potential candidates for surgery post-chemotherapy, were referred for placement of a Magseed prior to commencing chemotherapy or during treatment. The seed was placed by a senior radiologist in the unit. Ten patients have currently completed chemotherapy and surgery. Two patients had more than one Magseed placed. Giving a total seed placement number of 14 seeds. Results: Seed localisation with the Sentimag probe was successful in all cases at 100% localisation, however the retrieval rate was less at 93% due to a case where a lymph node underwent fibrosis. The maximum number of days between the seed placement and surgery was 249 days. Conclusions: Magseed is successful and accurate in localising and retrieving loco-regional recurrences in patients requiring surgery post chemotherapy. Retrieval is possible due to high recordings on the sensor in all cases. Magseed thus provides the treating clinician with an alternative to conventional radiological markers with the added benefit of a single placement to retrieval methodology.
Abrrant expression of a subset of epithelial–mesenchymal transition genes in triple-negative breast cancer before and after EC-T neoadjuvant chemotherapy.
Authors: Wei Liyuan , Wang Li , Zhang Xiaojun , Zhang Xu Dong , Gao Jinnan
Published: May 2020

e12617

Background: Pathological complete response (pCR) to neoadjuvant chemotherapy (NACT) is associated with favorable outcomes of patients with triple-negative breast cancer (TNBC). However, the heterogeneous nature of the disease often results in diverse responses to the same NACT protocol. In particular, a proportion of patients with residual disease (RD) develop metastasis at early stages after treatment. Further stratification of TNBC patients without pCR to NACT is needed for the development of novel strategies in the management of these patients. Methods: A retrospective series of ten TNBC patients with locally residual disease after NACT with the EC-T regimen at Shanxi Bethune Hospital between 2014 and 2018 were included. Total RNA from FFPE pre-NACT core biopsies and paired surgical specimens was subjected to the Affymetrix Human Transcriptome Array. Gene Set Enrichment Analysis (GSEA) was used to identify signal pathways and gene signatures associated with early metastasis after NACT followed by surgery. The Cox proportional hazard model and Kaplan-Meier survival curves on DMFS (distant metastasis-free survival) were employed to assess the prognostic value of the identified signature in TNBC patients from GEO datasets. Results: The epithelial-mesenchymal transition (EMT) pathway was markedly more enriched in pre- (NES = 1.92; p.adjust = 0.019) and post-NACT samples (NES = 2.02; p.adjust = 0.010) from patients who developed metastasis at relatively early stages ( < 18 months) after surgery compared with those who had been disease-free. Noticeably, the EC-T NACT differentially affected the expression of EMT genes resulting in global promotion or inhibition of the pathway in a case-dependent manner. Nevertheless, a subset of 6 EMT genes including LUM, SFRP4, DCN, MMP2, CXCL12, and HTRA1 was expressed constantly at higher levels in samples from patients who progressed to metastasis. The potential of this 6-EMT gene signature to predict TNBC metastasis was validated in the MDACC neoadjuvant series (GSE25066) that contained 113 TNBC patients with RD (55 with metastasis; p = 0.0008; HR = 0.36; 95% CI: 0.200-0.685) and the ICO–UMGC dataset (GSE103091) including 107 TNBC patients (31 with metastasis; p = 0.032, HR = 0.46, 95% CI:0.225-0.937). Conclusions: The expression of the 6-EMT gene signature at diagnosis may be a predictive value of metastasis of TNBC. Moreover, the persistently high expression of the signature may signal early metastasis in TNBC patients with residual disease after EC-T NACT.
Impact of antibiotics on residual cancer burden and pathologic response rates during neoadjuvant pembrolizumab in breast cancer (BC).
Authors: Kulkarni Amit , Jewett Patricia , Blaes Anne Hudson , Yee Douglas
Published: May 2020

e12622

Background: Antibiotic exposure during immunotherapy has been shown to negatively affect clinical outcomes in metastatic melanoma and non-small cell lung cancer. We tested whether antibiotics exposure during neoadjuvant pembrolizumab (NA-P) affects residual cancer burden (RCB) and pathologic complete response rate (pCR) in the pembrolizumab-4 arm of the ISPY-2 trial. Methods: I-SPY2 is an adaptively-randomized, ph-II trial in patients with high-risk, stage II/III breast cancer (BC). In pembrolizumab-4 arm patients with HER2-negative BC received NA-P 200mg every 3 weeks for four cycles concurrently with 80mg/m2 paclitaxel weekly for 12 weeks, followed by four cycles of 60mg/m2 doxorubicin plus 600mg/m2 cyclophosphamide every 2 weeks. Data on antibiotic use during NA-P was reviewed. Patients who received at least one dose of systemic antibiotics were included in the antibiotic exposure group (ATB+). All other patients were included in the no exposure group (ATB-). RCB index was used to evaluate RCB as a continuous variable. A higher RCB index indicated higher RCB. RCB index and pCR rates were compared between ATB+ and ATB- groups. Association of antibiotic use with RCB and pCR rates was evaluated using linear regression and logistic regression respectively. Clinical variables for adjustment were age, stage and hormone receptor (HR) status. Results: 69 patients received NA-P with chemotherapy. All patients had HER2-negative BC. One patient was excluded due to missing data on antibiotics. 68 patients were included in the final analysis. 19/68 (28%) patients were in the ATB+ group. Antibiotic use in HR+ and HR- patients were 9/19 (47%) and 31/49 (63%) respectively ( P=0.23). Compared to ATB- group, patients in the ATB+ group had higher mean RCB index (1.05 vs 1.80, P=0.04) and lower pCR rate (53.1% vs 26.3%, P=0.05). Antibiotic use was associated with higher probability of RCB in univariate analysis (Coefficient estimate CE: 0.75, 95% CI 0.01-1.48, P=0.04) and multivariable analysis (CE: 0.89, 95% CI 0.11-1.65, P=0.02). HR positivity was independently associated with higher probability of RCB (CE: 1.07, 95% CI 0.38-1.77 P=0.002). Antibiotic use was associated with higher probability of not having pCR (Odds ratio 3.17, 95% CI 0.99-10.15, P=0.05). Conclusions: Patients with antibiotic exposure during NA-P in HER2-negative early stage BC were associated with higher RCB and lower pCR rates. Further validation in a larger independent cohort is needed to confirm these findings.
Economic evaluation of neoadjuvant chemotherapy for operable breast cancer.
Authors: Zdenkowski Nicholas , D'Silva Shefi Mary , Lawson Kenny , Reeves Penny , Boyle Frances M.
Published: May 2020

e12637

Background: Neoadjuvant chemotherapy is widely and increasingly used for patients with operable breast cancer that is large or highly proliferative. Advantages include downstaging of the breast and. axilla, post-neoadjuvant salvage treatments for poor responders, surgical and reconstruction planning, prognostication and to give time for genetic testing. After neoadjuvant therapy, treatment options may change. We aimed to determine the financial impact to the health system, of neoadjuvant chemotherapy compared with surgery first. Methods: A literature search identified data on the probability of receiving certain investigations and treatments, and associated outcome probabilities for neoadjuvant and surgery-first patients. Published health utility results were used. These data were incorporated into a decision analytic economic model. A cost-utility analysis was undertaken, with sensitivity analyses to evaluate the impact of uncertainties in the data. Pricing was based on publicly available costings of investigations and treatment in Australian Dollars (AUD). A value of information analysis was undertaken to determine the value of further research to reduce uncertainty in results. Results: Expected costs for neoadjuvant vs surgery first differed by $77. Neoadjuvant therapy showed higher effectiveness that surgery first (QALY 0.708 vs 0.698 respectively. The average cost per QALY of neoadjuvant therapy was $7,232 AUD (ca. $4825 USD), below the threshold of $50,000 per QALY. In a sensitivity analysis, neoadjuvant therapy dominated when axillary dissection rate was lower than 60% and postmastectomy reconstruction rate was more than 27%. These factors had the greatest impact on results, which were otherwise robust. Probabilistic sensitivity analysis found that neoadjuvant therapy was cost-effective 71% of the time at a willingness-to-pay threshold of $50,000 per QALY. Value of information analysis found that primary research into treatment probabilities and outcome utilities is needed to validate these results. Conclusions: Neoadjuvant systemic therapy is a potentially cost-effective treatment. However, primary contemporary data in directly comparable patient populations is needed, including the impact of post-neoadjuvant systemic therapy.
Prognostic biomarker candidates of neoadjuvant chemotherapy for luminal B-positive locally advanced breast cancer.
Authors: Liu Zhaoyun , Wang Jinjin , Yuan Chenxi , Yu Zhiyong , Wu Wendy , Wu Lin , Yu Jinming
Published: May 2020

e12638

Background: In the last decade, the treatment approach for locally advanced breast cancer (BC) patients has partly shifted from adjuvant treatment to neoadjuvant treatment. Systemic neoadjuvant treatment can downstage the tumor for less extensive surgery and improve cosmetic outcomes. Differential subtypes of BC responded unevenly to neoadjuvant chemotherapy. Luminal B type with the relatively higher prevalence (40% in all 4 subtypes) had better therapeutic effect to neoadjuvant treatment than luminal A type, but worse than HER2-positive patients. Methods: We enrolled 87 BC patients for genotyping with multiple cancer-related genes. Among them, 17 patients were luminal A, 21 were HER2-negative luminal B, 23 were HER2-positive luminal B, 17 were HER2-positive and 9 were triple-negative. According to the RECIST, the patients were divided into 1-4 and 5 grades. Fisher test was used to analyze the difference of SNV and CNV between the two primary tumors, as well as TMB difference between post-neoadjuvant chemotherapy and past-neoadjuvant chemotherapy. Results: Base mutations in all patients showed discrepant preference between 1-4 grades and 5 grade groups, G-to-A in 1-4 grades, while A-to-G, A-to-T and G-to-T in 5 grade. In luminal B group (combine liminal B-negative and luminal B-positive groups), FLT4 gene mutation occurred more frequent in 5 grade than 1-4 grades (4/16 vs 0/28, P = 0.01). CNV analysis in NFKBIA and ZNF217 distinguished the two therapeutic efficiency groups in luminal B-positive group. The amplification of NFKBIA and ZNF217 was higher in 1-4 grades than 5 grade (8/14 vs 1/9, P = 0.036; 9/14 vs 1/9, P = 0.017). TMB difference between post and past neoadjuvant chemotherapy in luminal B-positive group was also significant in 5 grade (4.36 vs 1.99, P = 0.002). Conclusions: NFKBIA and ZNF217 amplification notably differentiated the 1-4 grades and 5 grade groups in luminal B-positive patients, suggesting the potential prognostic biomarkers of neoadjuvant chemotherapy in this locally advanced breast cancer subtype, which would be improved by further large-scale cohort study. The differences of TMB and FLT4 gene mutation were also found between the two therapeutic efficiency groups.
Anti-PD-1 responsive circulating immune cells as biomarkers of response to neoadjuvant chemotherapy in HER2+ breast cancer (BC).
Authors: Gaynor Nicola , O'Donovan Norma , Crown John , Collins Denis
Published: May 2020

e12646

Background: HER2+ BC patients (pts) achieving a pathological complete response (pCR) to neo-adjuvant therapy have better long-term survival outcomes. Alternative treatment strategies may be more beneficial for pts that will not achieve a pCR but there are no predictive biomarkers for stratification of pts to appropriate clinical studies. Antibody-dependent cell-mediated cytotoxicity (ADCC) mediated by immune cells like NK cells can be elicited by therapeutic antibody therapies including the HER2-targeting trastuzumab (T). We hypothesised that the presence of immune checkpoint-inhibited ADCC-mediating immune cells in the blood may identify pts with an immune-suppressed tumour microenvironment who will not achieve a pCR. We used an in vitro functional assay to assess the PD-1-inhibited ADCC response of pre-treatment peripheral blood mononuclear cells (PBMCs) from HER2+ BC pts as a potential biomarker of pCR. Methods: Pre-treatment PBMC samples (n = 21) were obtained from HER2+ BC pts who received neo-adjuvant chemotherapy (docetaxel, carboplatin) with a HER2-targeted therapy (T n = 5, T and lapatinib (L) n = 13, or L alone n = 3), ICORG 10-05 (NCT01485926). Pt response was determined as pCR (n = 7), partial response (PR, n = 10) or non-response (NR, n = 4). The immune function assay used a flow cytometry-based method to determine the T (10µg/µl)-mediated ADCC (T-ADCC) capacity of the PBMCs +/- the anti-PD-1 therapy pembrolizumab (P) (10µg/µl). The HER2+ BC cell line SKBR3 was used as the target cell line. Direct PBMC-mediated cytotoxicity against the non-MHC Class I-restricted leukemic K562 cell line was also determined. Statistical analysis was carried out using the MedCalc program. Results: There was no significant difference in direct cytotoxicity against K562 (pCR vs NR p = 0.13, pCR vs PR p = 0.52, PR vs NR p = 0.40), or in T-ADCC against SKBR3 (pCR vs NR p = 0.71, pCR vs PR p = 0.52, PR vs NR p = 0.32), between response cohorts in the absence of P. When T-ADCC was examined in individual pt samples, the addition of P resulted in significant increases in T-ADCC vs T-ADCC in the absence of P in 3/4 NR (p = 0.03, p = 0.01, p = 0.002) and 4/10 PR (p = 0.003, p = 0.007, p = 0.009, p = 0.01). No significant increase in T-ADCC was observed in the pCR cohort (0/7) as a result of the addition of P. Using pre-treatment PBMCs, the assay detected 7/14 (50%) of HER2+ BC pts who did not achieve a pCR. Conclusions: PD-1-inhibited ADCC-capable immune cells may identify a subset of HER2+ BC pts who will not achieve a pCR. Further investigation is warranted using a larger patient cohort.
A phase II single-arm, multicenter, open-label neoadjuvant study of pembrolizumab in combination with nab-paclitaxel followed by pembrolizumab in combination with epirubicin and cyclophosphamide in patients with triple-negative breast cancer: Neoimmunoboost.
Authors: Fasching Peter A. , Hartkopf Andreas , Kolberg Hans-Christian , Haeberle Lothar , Wetzig Sarah , Mau Christine , Engler Tobias , Rübner Matthias , Hübner Hanna , Theuser Anna-Katharin , Hummel Nadine , Uhrig Sabrina , Beckmann Matthias W. , Hein Alexander , Untch Michael
Published: May 2020

e12647

Background: The NeoImmunoboost study (NCT03289819) was designed to evaluate the pathological complete response (pCR) rate and safety of a neoadjuvant combination of the PD-1 antibody pembrolizumab and nab-paclitaxel followed by pembrolizumab with epirubicin and cyclophosphamide in patients with early triple negative breast cancer (TNBC). Methods: This is a prospective, single-arm, multi-center, open-label phase II clinical trial. Female patients with early TNBC were eligible for trial participation. Patients received 12 cycles of weekly nab-paclitaxel intravenous (i.v.) 125 mg/m² body surface area (BSA) in combination with 4 cycles of pembrolizumab i.v. 200 mg q3w; followed by 4 cycles of epirubicin i.v. 90 mg/m² BSA and cyclophosphamide i.v. 600 mg/m² BSA q3w in combination with 4 cycles of pembrolizumab i.v. 200 mg q3w. After 25 patients the protocol was amended, with an initiation boost of 1 cycle of pembrolizumab i.v. 200 mg q3w monotherapy prior to the chemotherapy. Primary trial endpoint was pCR. Secondary endpoints included safety and clinical response rate. Results: Between March 2018 and October 2019, 53 patients were included into the trial. Until now, 47 patients have completed trial treatment and 6 patients are still receiving therapy. 28 patients have received the initiation boost with pembrolizumab, 25 patients did not receive the initiation boost. Up to now, 4 patients terminated the therapy prematurely. Conclusions: pCR data of all patients will be available at the meeting and results of the pCR rates and selected secondary endpoints will be presented at the meeting. Clinical trial information: NCT03289819.
Test measuring signaling activity in live patient tumor cells to identify PI3KCA WT patients who may benefit from PI3K inhibitors.
Authors: Laing Lance G. , Khan Salmaan , MacNeil Ian A. , Kuzmicki Catherine , Rich Benjamin E. , Shukla Abhay , Brass Kelly , Sullivan Brian
Published: May 2020

e13000

Background: Biological factors other than PIK3CA status, such as aberrant GPCR-linked signaling, may be important to measure when identifying patients eligible for PI3K inhibitors. A new assay, the CELx PI3K test, using an impedance biosensor was developed to measure ex vivo live tumor cell response to specific S1P agonists and PI3K antagonists to diagnose breast tumors with PI3K-involved hyperactive signaling. This study set out to: 1) compare CELx PI3K test results and xenograft results using cell lines with PIK3CA mutations; and 2) assess whether PI3K-involved hyperactive S1P signaling is found in PIK3CA WT breast cancer patient tumors. Methods: A panel of 17 fresh HER2-/PIK3CA WT tumor cells from breast cancer patients and three PIK3CA mutated breast tumor cell lines were obtained. Live cell response to an S1P agonist, PI3K-α antagonist (alpelisib), PI3K-γ antagonist (IPI-549), and a pan-PI3K inhibitor (taselisib) were measured using an xCELLigence RTCA impedance biosensor. From these responses, PI3K-involved signaling was quantified and characterized as normal or abnormal using a previously determined cutpoint. For the xenograft study, 16 NSG mice were injected with HCC1954 PIK3CA mutated breast cancer cells and randomly assigned to either the control or taselisib group (10 mg/kg). Results: Four of the 17 PIK3CA WT tumor cells had abnormal levels of combined PI3K-α and PI3K-γ signaling. Only one of the three PIK3CA mutated breast tumor cell lines (BT20) had abnormal levels of PI3K-α and pan-PI3K involved signaling. The HCC1954 cell line had normal PI3K-α and abnormal pan-PI3K signaling. CAL-51 reported normal PI3K-α and pan-PI3K signaling. The normal levels of PI3K-α signaling found in the HCC1954 and CAL-51 cell lines correlated with previously reported xenograft studies that found alpelisib had no anti-tumor effect. The xenograft study reported here using HCC1954 cells found taselisib induces a significant anti-tumor effect (T/C ratio = 0.21; p = 0.009; t-test). Conclusions: A sub-set of PIK3CA WT patient breast cancer tumors had abnormal PI3K-involved signaling comparable to levels found in PI3KCA mutated cell lines. Abnormal pan-PI3K signaling and normal PI3K-α signaling in the HCC1954 cell line correlated with xenograft results. This study thus suggests that measurement of PI3K-involvement in hyperactive S1P signaling in live patient breast cancer cells may provide a means to identify breast cancer patients who may or may not benefit from treatment with PI3K inhibitors.
Comparisons of survival time in BRCA-positive patients with metastatic breast cancer using electronic health records (EHRs).
Authors: Choi Yookyung Christy , Tyczynski Jerzy Edward , Zhang Dongmu
Published: May 2020

e13004

Background: BRCA is a hereditary genetic mutation associated with a higher risk of breast cancer at younger age. Generally, BRCA gene testing is done in perceived high-risk individuals, and different management approaches might be considered given the high risk of breast cancer. This study examines treatment outcomes among BRCA-positive, metastatic breast cancer patients with consideration of prophylactic management by using US nationwide EHR data. Methods: This was a retrospective cohort study using Optum EHRs. The study cohort includes female adults who underwent their first systemic chemotherapy for metastatic breast cancer between 2013-2018 with a BRCA positive test result prior to the systemic chemotherapy, with ≥ 6 months baseline period from the chemotherapy. Physicians’ notes captured in Natural Language Processing (NLP) were further used to construct the cohort. Patients were followed from the earliest breast cancer diagnosis date until a censoring event (death or end of observation period). Death information was provided with national death certificate data. Descriptive statistics were used for patient characteristics and a stepwise Cox Proportional Hazard (CPH) regression model was fit to compare survival time. Results: Of 3624 patients included in the cohort, median age at the earliest breast cancer diagnosis is 50 years old (IQR 43-59), and a total of 540 (14.9%) deaths was observed. Prior to systemic chemotherapy, 1430 (39.5%) received mastectomy/lumpsectomy. 571 (15.8%) received hormone therapy prior to systemic chemotherapy. 646 (17.8%) had a clinical record indicating a triple negative breast cancer (TNBC). 2196 (60.6%) received more than 1 line of chemotherapy. Overall median survival days in the study cohort was 3778 days from the earliest breast cancer diagnosis. Median survival days in those with ER/PR positive and with TNBC status were 4150 days and 3124 days, respectively. From the CPH model, age, tumor mutation status, and prior mastectomy/lumpectomy were identified as significant factors; Hazard Ratio (HR) with each 1 year older in age at diagnosis was 1.02 (95% CL 1.01-1.03), that of TNBC vs ER/PR positive status was 2.27 (95% CL 1.87-2.77) and that of those with prior surgery vs without was 0.567 (95% CL 0.457-0.703). Conclusions: This study demonstrated the utility of EHR database for survival analysis. In metastatic breast cancer patients with a known BRCA-positive status, age at the initial diagnosis, tumor mutation status, and prior mastectomy/lumpectomy were significant factors in survival time.
STAT6 expression and trastuzumab resistance in HER2+ breast cancer.
Authors: Cobleigh Melody A. , DiScala Molly , Najor Matthew S. , Yung Timothy , Abukhdeir Abde M.
Published: May 2020

e13006

Background: Approximately 20% of breast cancers are HER2-positive. Trastuzumab has improved patient outcomes significantly for these cancers. However, acquired resistance occurs in almost all patients with metastatic breast cancer. Therefore, identifying molecular changes that are associated with trastuzumab resistance is worthwhile. STAT6 is a transcription factor that regulates a variety of genes involved in cell cycle regulation, growth inhibition, and apoptosis. STAT6 expression is lost in approximately 3% of breast cancers, but little work has been done in the context of trastuzumab resistance in breast cancer. Methods: In isogenic cell line pairs, we observed that trastuzumab-resistant cells expressed significantly lower levels of STAT6 compared to trastuzumab-sensitive cells. Therefore, in order to study the consequences of STAT6 loss in HER2+ breast cancer, we knocked out both alleles of the STAT6 gene using somatic cell gene targeting. Results: We observed that loss of STAT6 resulted in resistance to trastuzumab treatment in HER2-over-expressing cells. Additionally, loss of STAT6 resulted in anchorage-independent growth and changed expression of several genes involved in epithelial to mesenchymal transition. Functional studies revealed that STAT6 loss caused a non-tumorigenic human breast cell line to form tumors in mice. Conclusions: Loss of STAT6 in breast cells results in enhanced growth properties and resistance to trastuzumab. This study suggests that STAT6 may play a role in the pathophysiology of HER2+ human breast cancer. Disclaimer: The work herein was completed while AMA was a faculty member at Rush University. AMA is currently an employee with the U.S. Food and Drug Administration. The views and data in this publication do not reflect the opinions of the U.S. Government or The U.S. Food and Drug Administration.
Extrapolation of indications and drug interchangeability as barriers to use trastuzumab-dkst biosimilar in Brazil.
Authors: Resende Heloisa Magda , Cardoso Paola , Marassi Pedro , Precivale Maristela Seoanes , Alcantara Alexandre , Cardoso Ana Carolina , Facó Lara Lopes , Alves Leandro Ladislau , Castilho Vivienne Carduz
Published: May 2020

e13010

Background: Brazil has a complex health-care system which comprises 76% of population in the public unified health system (SUS) and only 24% in private system. Even with most of the population in the public system low resources has been allocated SUS by the government compared with that in private system. Breast cancer (BC) is the more frequent malignant neoplasm in Brazilian women, including HER2 overexpression, and the most are treated in SUS. Although, the HER2 blockage benefits in overall survival have been demonstrated since 2005, the adjuvant and neoadjuvant HER2 blockage was included in SUS protocols only 2013 while the metastatic only 2018. Brazil and development countries have limited accesses to biological drugs and target therapies due to the high cost. The biosimilar technology would improve the patient access to these drugs, health-care savings with efficacy and safety. In 2017, Brazil has approved the first biosimilar in oncology, the anti-HER2 monoclonal antibody trastuzumab-dkst. Our aim is understanding the reasons that hampered the Brazilian oncologists changing practice about biosimilars. Methods: We submitted an on-line survey with 12 questions to 144 Brazilian oncologists which are registered in Brazilian Clinical Oncology Society from North, Northeast, Center east, Center west and Southeast regions in Brazil. The questions were about the anti-HER2 biosimilars knowledge, the manufacturing process, the costs, the biosimilars-based clinical trial, the drug efficacy and safety. Results: We observed that all responders have 9 years experienced oncologist with mean of care 15 patient with HER2 BC per month. In total, 95% of oncologist knows biosimilar definition and 96% assume prescribe biosimilars without doubts. However, 81% oncologists would prescribe biosimilars to all patients, 82% would interchanges and 63% would extrapolate the indication. Conclusions: This survey was conducted to understand the Brazilian oncologist knowledge about biosimilar. We demonstrated a high knowledge of biosimilar definition, however with high percentage indicated adherence barriers. The pharmacovigilance, clinical trials that support biosimilar approval and extrapolation concepts are the main aspects to be addressed. The opportunity of patient access with biosimilars is real and it is the oncologist’s duty to engage in medical education programs. This study could highlight a crucial need for greater strategies to educate physicians, to disseminate biosimilars and provide more informed decision making.
Safety of a trastuzumab biosimilar, used under routine clinical practice conditions in adult HER2+ breast cancer patients in Morocco.
Authors: Errihani Hassan , Berrada Narjiss , Khouchani Mouna , Acharki Abdelkader , Lahbabi Kamal , Jouhadi Hassan , Glaoui Meryem
Published: May 2020

e13024

Background: Hertraz, the first trastuzumab biosimilar was approved in Morocco in 2017. Real world data on trastuzumab biosimilars are very limited or not available. HERLife is a prospective, non-interventional phase IV study program that investigated the experience of using Hertraz, a biosimilar for trastuzumab (Herceptin), under routine clinical practice conditions in Morocco. The primary aim of this study was to confirm the acceptable safety and tolerability of Hertraz. Methods: Ninety-nine patients with HER2-positive breast cancer treated with Hertraz were enrolled from 8 public and private sector hospitals and followed up for 12 months as part of this non-interventional study. Cardiac events (LVEF) and other unexpected or serious adverse events were monitored. The study arms consisted of patients with early breast cancer (Arm 1, n=70) and metastatic breast cancer (Arm 2, n=29) whose median age was 53 years in both groups. Results: Switching from Herceptin to Hertraz was observed in 45% of 29 MBC patients and 27% of 70 EBC patients. Switching was done at a median of 4th cycle. Pertuzumab was used in combination with Hertraz in 69% and 19% of patients in the metastatic and neoadjuvant settings, respectively. Two patients had a decline in LVEF. One patient treated with Hertraz alone and one patient treated with Hertraz and pertuzumab developed a decrease in LVEF requiring a three-week treatment discontinuation of Hertraz. Treatment of Hertraz was continued after 1 skipped cycle without occurrence of new side effects. No other trastuzumab related adverse events was observed. Four patients in the metastatic group and 2 patients in the early breast cancer arm had a relapse in the 12 months of clinical follow-up. Conclusions: The management of HER2+ breast cancer in Morocco follows the international recommendations. This is the first real world safety data of Hertraz from Morocco. The 12-month follow-up treatment with Hertraz showed an acceptable cardiac safety profile. In cases where there was a switch from Herceptin to Hertraz or Hertraz combined with pertuzumab, the safety profile was similar to that previously reported in other studies.
The effect of everolimus on adipose tissue in patients with metastatic breast cancer.
Authors: Acuna Villaorduna Ana , Ko Heidi , Haken Orli , Deng June , Patel Janki , Podolski Amanda , Munoz-Arcos Laura Sofia , Wang Xiaoyang , Anampa Mesias Jesus Del Santo
Published: May 2020

e13026

Background: Obesity has been associated with negative outcomes in early breast cancer. Addition of everolimus (Eve) to endocrine therapy improves progression-free survival (PFS) in patients with hormone-receptor (HR) positive, HER2-negative metastatic breast cancer (MBC). Eve targets the mTOR signaling pathway which regulates cell growth/metabolism and has been implicated in obesity and diabetes. Changes in weight and body mass composition and its correlation with PFS have not been described in patients with MBC treated with Eve. We aim to compare total adipose tissue (TAT), subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) before and after treatment with Eve in patients with HR+/HER2- MBC. Methods: Patients with metastatic HR+/HER2- MBC treated with Eve and endocrine therapy (Eve/ET) between 2012 and 2018 were identified. Each Eve/ET case was matched to a patient who received endocrine therapy alone (ET) by age at diagnosis (+/- 5 yrs), body mass index [BMI] (+/-5 kg/m2) and visceral metastatic disease. VAT, SAT, TAT, and skeletal muscle index (SMI) were measured by computerized tomography at L3 level using TOMOVISION software prior to treatment initiation (T0) and after 3-6 months of treatment (T3). TAT was defined as SAT + VAT and sarcopenia as SMI < 40. Paired t-test and Wilcoxon paired-test were used to compare body composition parameters at T3 vs T0 in Eve/ET and ET groups. Results: 78 patients (Eve/ET: 41 and ET: 37) with a median age of 65.5 yrs were included. Of these, 16 (21.3%) were Non-Hispanic White, 31 (41.3%) were Non-Hispanic Black and 27 (36%) were Hispanics. Visceral metastases were seen in 57 (73.1%) cases. Mean weight, BMI, VAT and SAT at T0 were 70.8 kg, 27.4 kg/m2, 170.1 cm2 and 196.1 cm2, respectively and did not differ between Eve/ET and ET groups at baseline. At T3, there was a reduction in TAT (348.4 to 289.2 cm2, p < 0.01) and SAT (181.7 to 142.7 cm2, p < 0.01) in the Eve/HT group; while there were no significant changes in TAT (373.1 to 363.9 cm2, p = 0.39) or SAT (212 to 221.8 cm2, p = 0.33) in the ET group. No changes in visceral fat %, VAT/SAT ratio and sarcopenia between T0 and T3 in either treatment group were seen. In patients treated with Eve/ET, there were no differences in PFS between low TAT-loss (TAT loss < 40 cm2) and high TAT-loss (TAT loss > 40 cm2) (3.6 vs 4.8 months, p = 0.97). Conclusions: Eve induces TAT loss in patients with HR+/HER2- MBC, specifically driven by decrease in SAT. The pathophysiology of this association is still to be discerned. Further studies are required to evaluate TAT or SAT as a predictive/prognostic biomarker in patients receiving Eve.