bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase II study of osimertinib for patients with radiotherapy-naïve CNS metastasis of non-small cell lung cancer harboring EGFR mutations: The OCEAN study (LOGIK 1603/WJOG 9116L).
Authors: Wakuda Kazushige , Yamaguchi Hiroyuki , Kenmotsu Hirotsugu , Fukuda Minoru , Ebi Noriyuki , Suetsugu Takayuki , Inonue Koji , Tanaka Kentaro , Yokoyama Toshihide , Kirita Keisuke , Hataji Osamu , Miura Satoru , Chibana Kenji , Yoshimura Kenichi , Nakagawa Kazuhiko , Yamamoto Nobuyuki , Sugio Kenji
Published: May 2020

9597

Background: Approximately 15%–30% of patients treated with EGFR-TKIs experience central nervous system (CNS) progression. Although radiotherapy is a standard treatment for CNS metastasis, the efficacy of radiotherapy against CNS is poor. The aim of OCEAN study was to assess the efficacy of osimertinib for patients with radiotherapy-naïve CNS metastasis of NSCLC harboring EGFR mutations. Methods: OCEAN study was two-cohort phase II trial, 65 patients (T790M cohort; 40 patients and first-line cohort; 25 patients) with radiotherapy-naïve CNS metastasis of EGFR mutation-positive NSCLC was included. Patients were treated with osimertinib 80 mg once daily. The primary endpoint was the response rate of brain metastasis (BMRR) assessed by the PAREXEL criteria. We set a threshold value of 50% and an expected value of 70% based on the overall response rate (ORR) of AURA trial. Based on one-sided alpha = 0.05 and power = 0.8, the sample size of T790M cohort was calculated to be 40. Key secondary endpoints were progression-free survival (PFS), and ORR, BMRR assessed by the RECIST criteria. We are exploratorily assessing the blood concentration of osimertinib at day 22, which considered to represent steady state. In this report, we present the results of T790M cohort. Results: Between October 2016 to July 2019, 40 participants were recruited in the T790M cohort. The median age was 66.5 with 30.0% male. Eight patients had symptomatic CNS metastasis and most patient had multiple CNS metastasis (77.5%). BMRR assessed by PAREXEL criteria was 66.7% (95%CI: 54.3 – 79.1%) and BMRR assessed by RECIST was 70.0% (95%CI, 49.9 – 90.1%). Median PFS was 7.1 months (95%CI, 3.4 – 13.6 months) and ORR assessed by RECIST was 40.5% (95%CI, 24.7 – 57.9%). Treatment related pneumonitis was observed in 4 patients (10.0%). There was no grade 3 or higher toxicities that were found in more than 10%. Conclusions: This first study assessed the efficacy of osimertinib for patients with radiotherapy-naïve CNS metastasis of EGFR T790M mutation-positive NSCLC. The OCEAN study met primary endpoint. The results of this study suggested that patients with brain metastasis harboring EGFR T790M mutations had better to receive osimertinib prior to brain radiotherapy. Clinical trial information: 071180017 .
ctDNA resistance landscape of lazertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI).
Authors: Han Ji-Youn , Ahn Myung-Ju , Kim Sang-We , Lee Ki Hyeong , Cho Eun Kyung , Lee Yun-Gyoo , Kim Dong-Wan , Kim Joo-Hang , Lee Jong-Seok , Lee Gyeong-Won , Shim Byoung Yong , Kim Jin-Soo , Chun Sang Hoon , Lee Sung Sook , Min Young Joo , Shin Sang Won , Yablonovitch Arielle , Espenschied Carin R. , Jang Hyunwoo , Cho Byoung Chul
Published: May 2020

9601

Background: While EGFR mutant ( EGFRm) non-small cell lung cancer (NSCLC) patients usually experience improved clinical benefit with EGFR TKIs, most eventually progress. Understanding mechanisms of resistance (MoR) may allow for more personalized treatment. Lazertinib is an irreversible third generation EGFR TKI for which MoR are unknown. Obtaining sufficient tumor tissue for genotyping at progression is often difficult. Therefore, we utilized plasma ctDNA from patients treated with lazertinib to explore MoR. Methods: Plasma samples from 47 NSCLC patients in the phase 2 trial of lazertinib (NCT03046992) were collected at screening and progressive disease (PD) and underwent ctDNA NGS of 74 genes using Guarant360. All patients were positive for an EGFR Ex19del or L858R ( EGFRm) and T790M by tissue testing at screening. Acquired, nonsynonymous, characterized mutations detected in a PD sample but not in the screening sample from the respective patient were considered putative MoR, excluding aneuploidy. Patients with detectable plasma EGFRm and/or T790M at screening were evaluable. Results: ctDNA was detected in 47 (100%) screening samples and 43/45 (96%) PD samples (two failed sequencing). An EGFRm was detected in 85% of patients at screening (n = 40), 38 of which had PD ctDNA results and were included in analysis. T790M was detected in 30 patients at screening and subsequently not detected at PD in 21 of these patients, 55% of all 38 included patients. Among the ten patients with T790M detected at PD, on-target MoR were detected in 7 (18% of all included patients) including EGFR C797S (n = 3, 8%), EGFR amplification (n = 3, 8%), and EGFR T854A (n = 1, 3%). All C797S were in cis with T790M. No on-target MoR were detected in patients without T790M detected at PD. Off-target MoR were seen in 34% of patients (13/38) including mutations in PIK3CA (13%; 2 E545K, 2 E542K, 1 E81K), ERBB2 (5%; 1 D769H, 1 V777L), KRAS (3%; 1 G12C), and BRAF (3%; 1 G469A). Gene amplifications were detected in CCND1 (n = 1, 3%) , CCNE1 (n = 2, 5%) , ERBB2 (n = 1, 3%) , FGFR1 (n = 1, 3%) , MET (n = 4, 11%) , and PIK3CA (n = 1, 3%), with some patients having multiple MoR. Conclusions: The spectrum of MoR identified in this cohort of patients treated with lazertinib is similar to that reported in other third generation EGFR TKIs, but with some differences in frequencies. The most common resistance mechanisms are T790M loss and PIK3CA alterations which may address the mechanism of action. Our findings suggest putative MoR of lazertinib and show that ctDNA NGS is an effective way to identify MoR in patients progressing on targeted therapy. Clinical trial information: NCT03046992 .
Phase II study of TAK228 in patients with advanced non-small cell lung cancer (NSCLC) harboring NFE2L2 and KEAP1 mutations.
Authors: Paik Paul K. , Ahn Linda Su Hyun , Plodkowski Andrew J. , Fan Pang-Dian , Rudin Charles M.
Published: May 2020

9607

Background: Despite past efforts, no targeted therapies exist for squamous cell lung cancer (LUSC) pts. We identified a heretofore untargeted oncogene (NFE2L2)/tumor suppressor (KEAP1) pair, each mutated in ~15% of LUSCs. NFE2L2 encodes NRF2, a transcription factor involved in the oxidative stress response and targeted for degradation by KEAP1. NFE2L2 mutations (mut) occur only in an exon 2 hotspot (Neh2 domain), which is the binding site for KEAP1. Mutations in this region disrupt KEAP1 binding, leading to NRF2 nuclear translocation and increased mTOR signaling via RagD. We report translational studies and results from a phase 2 trial of the oral TORC1/2 inhibitor TAK228 in biomarker-selected pts. Methods: Cell line and xenograft experiments were performed using LK-2 LUSC (NFE2L2 E79K mut), A549 ADCL (KRAS G12S + KEAP1 loss), and SK-MES-1 LUSC cells (NFE2L2/KEAP1 WT) treated with TAK-228, everolimus, rapamycin, or deforolimus. Pts with stage IV LUSC harboring NFE2L2 or KEAP1 mut and ADCL harboring KRAS + KEAP1 co-mut were treated on an NCI CTEP phase 2 study of TAK228 3mg po qd (NCT02417701). Primary endpoint: ORR. Secondary endpoint: PFS. The study used a Simon 2-stage design for each cohort with H0 = 5% (N≥1/5 responses), HA = 40% (N≥2/10 responses). Results: TAK228 exhibited differential anti-tumor activity over TORC1 rapalogs in LK-2 and A549 cells. TAK228 alone was cytotoxic at sub-[μM] (IC50 68nM) in LK-2 cells; all other rapalogs had IC50s > 10μM. This was associated with marked decrease in TORC1/2 & MAPK signaling (decreased pS6, pAKT, pERK). Anti-tumor response was seen in LK-2 and A549 xenografts treated with TAK228. No anti-tumor/growth inhibitory responses were seen with any other rapalog. N = 21 evaluable pts have been treated (10 NFE2L2, 6 KEAP1, 5 KRAS+NFE2L2/KEAP1). Median age = 70; median prior lines tx = 2, smokers = 100%, median pack yrs = 39. Most common AEs included hyperglycemia (72%), fatigue (32%), diarrhea (32%), decreased appetite (32%). In NFE2L2 mut LUSC pts, ORR = 20% (2/10 confirmed PR), DCR = 100% with median PFS = 8.9mos (95%CI 7-NR). In KEAP1 mut LUSC pts, ORR = 17% (1/6 confirmed PR), DCR = 67% with PFS range = 1.8-8.6 mos. In KRAS + NFE2L2/KEAP1 mut ADCL pts, ORR = 0% and DCR = 0%. Conclusions: TAK228 is tolerable with differential activity in NFE2L2 (primary endpoint met) and KEAP1 mutant LUSC. A randomized phase 2 trial of TAK228 + docetaxel vs. SoC chemotherapy in advanced LUSC pts with NFE2L2/KEAP1 mut is in development (LungMAP S1900D) as is an NCI CTEP phase 1/1b trial of TAK228 + CB-839 in advanced NSCLC patients with NFE2L2/KEAP1 mut (NCI #10327). Clinical trial information: NCT02417701 .
Clinical and genomic analysis of non-small cell lung cancer (NSCLC) patients with MET exon14 skipping (METex14) mutations and responses to anti-MET therapy.
Authors: McKenzie Andrew , Fisher Arielle , Correll Mick , Jones Carissa , Correia Jessica , Thurber James , Misch Amanda , Heritage Jessica , Sturgill Emma , Jones Suzanne Fields , Johnson Melissa Lynne , Spigel David R.
Published: May 2020

9613

Background: MET is a validated oncogene for molecular targeted therapy in non-small-cell lung cancer (NSCLC), and METex14 mutations result in MET overexpression. Studies with MET-targeting therapies have demonstrated high objective response rates and prolonged disease control. There are few clinical and genomic analyses of patients with METex14-positive NSCLC in the community setting. We herein characterize key clinical and genomic findings for patients harboring METex14 mutations. Methods: Sarah Cannon provides clinical research to partnering medical oncology practices who order broad-based NGS, from both tissue and blood, as a part of standard of care. Genospace, a clinico-genomic software tool, was used for identification of patients for clinical trials and analysis of clinical and genomic data. Results: Of 6521 lung cancer patients with NGS results, 66 (1.01%) harbored METex14 mutations (45.5% from blood and 54.5% from in tissue). The mean age at diagnosis was 75.7 and 21.2% developed brain metastases. Of the 66 patients with METex14 mutations, 69.5% are current/former smokers. Nineteen percent of former/current smokers and 7.6% of never smokers had PD-L1 scores of > 50%, respectively. The majority of METex14-positive patients either received standard of care (66.7%) or were unable to take (19.7%) 1st-line therapy. Patients who received chemotherapy (Chemo), immunotherapy (IO), and Chemo/IO in the first and second line settings responded to SOC treatment, and patients receiving anti-MET therapy benefited from therapy even after front-line SOC (table). Genomic analysis revealed the most common co-occurring mutations to be EGFR, MET, NF1, KRAS, and BRCA2 (Freq = 8.7%, 8.7%, 8.7%, and 7.6%, respectively). Conclusions: Genospace enables real-time patient identification of METex14-positive NSCLC cases and analysis of these cases indicates that anti-MET therapy may be effective at any line of treatment. Genospace’s clinico-genomic database was used to analyze treatment history, clinical correlates, and co-occurring mutations that may reveal novel treatment combination strategies or resistance mechanisms. [Table: see text]
Randomized phase I trial to evaluate Concurrent or Sequential Ipilimumab, Nivolumab, and stereotactic body Radiotherapy in patients with stage IV non-small cell lung cancer (COSINR Study).
Authors: Patel Jyoti D. , Bestvina Christine M. , Karrison Theodore , Jelinek Michael J. , Juloori Aditya , Pointer Kelli , Hoffman Philip C. , Pitroda Sean P. , Vokes Everett E. , Chmura Steven J.
Published: May 2020

9616

Background: Stereotactic body radiotherapy (SBRT) provides high rates of treated metastasis control, stimulates innate and adaptive immune pathways, and is safe in patients treated with anti-PD1 monotherapy following SBRT. We hypothesize that SBRT may improve outcomes for patients receiving immunotherapy through both direct cytoreduction and increased immunogenicity. Within this context, we conducted a phase 1 trial designed to evaluate the safety of combination immune checkpoint blockade with nivolumab and ipilimumab(N/Ip) plus sequential (Seq) or concurrent (Con) multisite SBRT (mSBRT) in patients with stage IV NSCLC. Methods: Treatment naïve patients (EGFR/ALK WT) with advanced NSCLC received SBRT to 1 to 4 metastases. Not all metastases were targeted, and metastases > 65 mL were partially irradiated. Brain metastases were allowed on protocol, and those > 3mm were treated prior to enrollment. SBRT dose varied by anatomic site and ranged from 45 to 50 Gy in 3 to 5 fractions with predefined dose de-escalation if excess dose-limiting toxicities were observed. Patients on Seq arm received N/Ip between 1-7 days after completion of SBRT. Patients in Con arm received N/Ip prior to completion of SBRT. N/Ip continued until progression, development of toxicity, or up to 2 years. Patients underwent pre- and post-treatment biopsy of one irradiated lesion. Results: A total of 35 patients (Seq/Con 19/16) were enrolled and evaluable for toxicity analysis (SBRT and at least 1 cycle N/Ip). Brain metastases were present in 27%. PD-L1 expression: 0% (16), 1-49% (10), >50% (9). Median number of metastases treated with SBRT was 3.2. 6 patients experienced DLT (4 pneumonitis), resulting in dose reduction in central lung Seq cohort of the organs at risk (OAR) by 20%. Median PFS by RECIST (total/Seq/Con) was 5.9 mo, 95% CI: 4.9-13.1/ 6.2 mo, 95% CI: 3.5-12.6/ 5.9 mo, 95% CI: 3.1-18.0. RECIST best response was 11% CR, 57% PR, 6% SD, and 26% PD. Treatment past first progression was allowed, and time to second line therapy (chemotherapy) by arm (Seq/Con) was NR/17.5 months. Median OS has not been reached with median follow up of 15mo. PDL1 status did not impact PFS (p = 0.64) nor OS (p = 0.77). Conclusions: Multisite SBRT and concurrent N/Ip was well tolerated. Responses appear durable as median OS was not reached. Multimodality therapy with mSBRT and dual checkpoint inhibitor therapy resulted in impressive tumor control and clinical benefit with promising efficacy. Clinical trial information: NCT03223155 .
FLT3 ligand (CDX-301) and stereotactic radiotherapy for advanced non-small cell lung cancer.
Authors: Ohri Nitin , Halmos Balazs , Garg Madhur , Levsky Jeffrey M , Cheng Haiying , Gucalp Rasim A. , Bodner William Raymond , Kabarriti Rafi , Berkowitz Aviva , Yellin Michael Jay , Keler Tibor , Kalnicki Shalom , Guha Chandan
Published: May 2020

9618

Background: In a murine non-small cell lung cancer (NSCLC) model, we demonstrated synergy between localized radiotherapy and the dendritic cell growth factor fms-like tyrosine kinase 3 (FLT3) ligand. We now present results from a phase II study testing this combination in patients with advanced and treatment-refractory NSCLC. Methods: Advanced NSCLC patients with multifocal active disease after at least one line of systemic therapy and ECOG performance status 0-2 received 5 daily subcutaneous injections of CDX-301 (75 µg/kg) concurrent with stereotactic body radiotherapy (SBRT, 30-54 Gy in 1-5 fractions based on target size and location) directed at a single site of disease. Additional “cycles” of SBRT and CDX-301 could be administered at least four months after the initial study treatment, at the discretion of the treating physicians. The primary endpoint was progression-free survival four months after treatment initiation (PFS4), with a hypothesis that the PFS4 rate would exceed 40%. Secondary endpoints included overall survival (OS) duration, responses on PET (PERCIST criteria) and CT (RECIST criteria), and dose-limiting toxicities (grade ≥3 adverse events within 30 days). Lesions targeted with SBRT were excluded from response assessments. The intended sample size was 29 subjects. Blood samples were obtained for flow cytometry and other analyses of immune activation. Results: Twenty-nine subjects received study therapy between October 2016 and January 2020. Subjects received a median of 3 lines (range: 1-5) of systemic therapy prior to study enrollment, including immune checkpoint inhibitors targeting the PD-1/PD-L1 axis in 26 subjects (90%). At the time of this analysis, the actuarial PFS4 rate is 60%, which exceeds our pre-specified efficacy objective. With a median follow-up duration for living patients of 12 months, the actuarial 12-month OS rate is 55%. Partial response of lesions not targeted with SBRT (“abscopal effect”) was observed in 9 subjects (31%) using PET criteria and in 4 subjects (14%) using CT criteria. Seven subjects (24%) received a second course of SBRT and CDX-301 after initial study therapy. No dose-limiting toxicities have been observed. Only six subjects (21%) have received additional chemotherapy or immunotherapy after study treatment. Conclusions: The combination of CDX-301 and SBRT is well-tolerated and has activity as systemic therapy for advanced NSCLC. Additional studies to maximize the efficacy of this in situ vaccination approach with the addition of an agonist anti-CD40 antibody (CDX-1140) are planned. Clinical trial information: NCT02839265 .
Progression-free survival estimates in non-small cell lung cancer when RECIST is unavailable: Project GENIE’s integration of genomic, therapeutic and phenomic data.
Authors: Lavery Jessica A. , Panageas Katherine , LeNoue-Newton Michele , Sweeney Shawn , Sheffler-Collins Seth , Rudolph Julia E , Rizvi Hira , Schultz Nikolaus , Lepisto Eva M. , Kehl Kenneth L. , Warner Jeremy Lyle , Dang Kristen , Phillip John , Park Ben Ho , Riely Gregory J. , Schrag Deborah
Published: May 2020

9622

Background: Molecular tumor profiling has become an integral component of oncology practice but linked genomic-phenomic data remain scarce. Recurrence, treatment response and progression are not structured consistently in medical records and this deficit has been a roadblock to discovery of biomarkers that are associated with favorable outcomes. Methods: The Genomics Evidence Neoplasia Information Exchange (GENIE) consortium is an AACR sponsored project to link and share genomic and phenomic data to promote discovery in precision medicine. 3 cancer centers that routinely perform somatic tumor profiling for advanced cancers agreed to curate anti-neoplastic treatment exposures and outcomes including recurrence, progression, response and survival using a standard method. 6 cancer types (lung, colorectal, breast, prostate, pancreas and bladder) were selected and a REDCAP database captures anti-neoplastic treatments, and specific elements from pathology, radiology and oncology reports. Curators abstract data using data fields that rely on the PRISSMM standard. “Real world” progression free survival (PFS) was identified based on curation of: 1) the text of radiologists’ reports for CT, PET/CT, PET and MRI scans (PFSI) and 2) medical oncologists’ notes (PFSM). PFSI and PFSM were estimated from the start of 1st line anti-neoplastic systemic therapy until progression or death for all patients with molecularly characterized non-small cell lung cancer (NSCLC). Results: Genomic sequencing was performed between 2015 and 2017 for 748 patients with NSCLC treated at three major cancer centers. Median age at diagnosis was 66 years (interquartile range 58, 73) and 43% were male. As shown in the table, when RECIST assessments are unavailable, estimates of PFS vary based on whether they are derived from radiologists’ or oncologists’ interpretations. Conclusions: Radiologists’ reports and oncologists’ reports provide different PFS estimates. Cohort studies should specify the method used to define “real world” endpoints. Project GENIE will have 1800 NSCLC patients with curated endpoints by the ASCO meeting. [Table: see text]
Incidence of diabetes and prediabetes unmasked by dexamethasone in women undergoing (neo) adjuvant taxane therapy.
Authors: Mahinbakht Dana , Lavasani Sayeh Moazami , Yu Wai (Kim) , Samoa Raynald , Ruel Nora , Mortimer Joanne E.
Published: May 2020

e12526

Background: Women with early stage breast cancer receive premedication with dexamethasone prior to administration of paclitaxel and docetaxel. We undertook a retrospective chart review to determine the frequency of steroid-induced hyperglycemia in women receiving steroid premedication with paclitaxel and docetaxel. Methods: Women who were receiving paclitaxel or taxotere chemotherapy as (neo)adjuvant therapy were identified from pharmacy records. Patients were excluded if they were currently receiving insulin or hypoglycemic agents for diabetes. A Comprehensive Metabolic Panel (CMP) was performed prior to chemotherapy and the random glucose level was recorded. The highest random glucose level recorded during all cycles of treatment was used in the analysis. The threshold for diabetes is a random glucose of 200 mg/dL and levels > 150 mg/dL, but less than 200 mg/dL is considered prediabetes. Between August 2017 to December 2019, 131 patients were identified and 100 met the criteria for inclusion. The study was approved by the Institutional Review Board. A single individual abstracted the data which included demographic data, BMI, comorbidities, random glucose levels prior to therapy and whether they received treatment for the elevations in blood glucose. Results: A total of 131 charts were reviewed, but 31 were excluded because 2 were male, 13 had type 2 diabetes at diagnosis, and 16 had metastatic disease. The median age of the 100 patients was 53 years (range 31 to 82 years); 45% were White/Non-Hispanic, 28% Hispanic, 18% Asian, 5% African American, 1% were Native Hawaiian or other Pacific Islander, 2% were unknown, and 1% were of mixed race. Prediabetic random glucose levels were recorded in 30% of patients and 23% had levels consistent with a diagnosis of diabetes. Out of the patients who exhibited a blood glucose above 200, 16 out of the 23 patients were White, 6 of them were Hispanic and 1 was Asian. The average BMI was 27.7. The average BMI of patients who exhibited a blood glucose of over 200 mg/dL was 28.85 and the average of those who had a blood glucose of over 150 mg/dL was 27.56. Conclusions: Diabetes and prediabetes were unmasked by taking the premedication with dexamethasone in 53% of women undergoing (neo)adjuvant docetaxel or paclitaxel. Current guidelines do not recommend additional blood work after completion of active treatment. Given our results, it is important that medical oncologist ensure that patients with elevations in random glucose be referred for appropriate endocrine workup and therapy, including lifestyle modifications.
Assessment of the risk of tumor progression in different subtypes of breast cancer.
Authors: Vladimirova Liubov Yu , Frantsiyants Elena M. , Samaneva Natalia Yu. , Storozhakova Anna E. , Bandovkina Valeria A. , Cheryarina Natalia D. , Sheiko Elena A. , Sergeeva Marina M. , Kit Oleg I. , Lisutin Aleksandr E. , Nepomnyashchaya Evgeniya M.
Published: May 2020

e12551

Background: Breast cancer (BC) is still one of the main causes of death in women due to the tumor recurrence and/or resistance to anticancer therapy. The criteria to assess the risk of tumor progression in breast cancer after 2 chemotherapy cycles are required. The purpose of the study was to analyze blood levels of TGFβ, TGFR2, TNF, TNFα, TNFR1, TNFR2, MMP-9 and CD-44 in patients with various BC subtypes before and after 2 chemotherapy cycles. Methods: The study included 42 patients with various BC subtypes: luminal A, luminal B and triple-negative BC (TNBC). Levels of TGFβ, TGFR2, TNF, TNFR1, TNFR2, CD-44, MMP-9 were measured by ELISA in the blood of all patients prior to anticancer therapy and after 2 chemotherapy cycles. Statistical processing of results was performed using the Statistika 6.0 software by the Student’s t-test. Results: Levels of TGFβ, TGFR2, TNF, TNFα, TNFR1, TNFR2, CD-44, MMP-9 in patients with all BC subtypes were high before the treatment. After 2 chemotherapy cycles, the values decreased statistically significantly in all BC subtypes: CD-44 decreased by 25.2%, 30% and 54.7% in luminal A, luminal B and TNBC, respectively; TNFα – by 26.2%, 48.3% and 50.8%, respectively; TNFα-R1 – by 52.1%, 39.2% and 50.3% respectively; TNFα-R2 – by 31.7%, 32.8% and 41.9% respectively; MMP-9 – 35.3%, 32.6% and 43.3% respectively. The patients remained in remission for 3 years. When the levels were high or did not differ from initial values, the tumor progressed. Conclusions: We identified a set of criteria allowing with high probability to determine the growth and progression of tumors in various subtypes of breast cancer after two cycles of chemotherapy. A decrease in the levels of TGF-β, TNF, MMP-9, and CD-44 demonstrates remission; stabilization or increase of these indicators leads to further early progression of the disease.
Evaluation of prognostic significance of microRNA in tumors of luminal, primary operable breast cancer without Her2 neu overexpression in postmenopausal women.
Authors: Ulianova Elena P. , Tokmakov Vasilij V. , Shatova Iuliana S. , Sagakyants Aleksandr B. , Goncharova Anna S. , Zaikina Ekaterina V. , Chernikova Elena N. , Bakulina Svetlana M. , Pushkareva Tatiana F. , Kit Oleg I. , Lisutin Aleksandr E.
Published: May 2020

e12558

Background: Breast cancer (BC) is associated with miRNAs, the qualitative and quantitative analysis of which shows significant differences between molecular subtypes, as well as between miRNAs circulating in the bloodstream and detected in tumor tissue. Since there is no clear characteristics for markers of luminal B primary operable BC without Her 2 neu overexpression, our purpose was an evaluation of prognostic significance of miRNA-21, 221, 20a, 200a, 196a in such postmenopausal patients in order to create a diagnostic panel. Methods: The study included 120 samples of healthy tissues of patients with luminal A BC (group 1, mean age 76.16±3.14 years) and tumor tissues of patients with luminal B BC (group 2, mean age 69.5±3.2 years); invasive ductal carcinoma in all patients. The expression status was analyzed using 5 mioRNA markers associated, according to the literature, with various molecular subtypes of BC (miRNA-21, 221, 20a, 200a, 196a). The Thermo Scientific PureLink RNA Mini Kit was used for the total RNA isolation. The reverse transcription reaction was performed using the ImProm-II Reverse Transcriptase kit (Promega). The Livak/2 method was used to assess the relative expression of miRNAs. Results: The average relative expression was: miRNA-21 in group 1 – 0.2±0.01, group 2 – 1.5±0.05; miRNA- 221 in group 1 – 0.19±0.02, group 2 – 0.43±0.04; miRNA -20a in group 1 – 0.12±0.01, group 2 – 0.13±0.01, miRNA -200a in group 1 – 0.22±0.02, group 2 – 0.96±0.06; miRNA- 196a in group 1 – 1.06±0.02, group 2 – 1.56±0.04. The differences between the groups were statistically significant (p = 0.0001); the difference was statistically insignificant only for miRNA -20a (p = 0.159955). Conclusions: Results of the study allow considering the overexpression of miR-21, 221, 200a and 196a and the relatively low expression of miR-20a as diagnostic markers for a diagnostic panel for luminal B BC without overexpression of HER2/neu.
Prognostic factors impacting survival in early HER2-positive breast cancer (BC): Results from a 1,142 patients database study.
Authors: Hegg Roberto , Mattar Andre , Rocha Maurício , Oliveira Renato Watanabe , Julian Guilherme Silva , Gebrim Luiz Henrique
Published: May 2020

e12561

Background: early systemic therapy has reduced recurrence and mortality from BC, especially among HER2+ subtype. Despite these advances, the difficulty of developing countries in incorporating new treatments, as well as the molecular and phenotypic profiles of HER2+ BC, are associated with the heterogeneity of treatment responses, leading to poor prognosis and outcomes. However, real-world data on prognostic factors for early HER2+ BC patients are scarce, especially in the Brazilian context. Therefore, this study aims to evaluate the influence of prognostic factors on disease-free survival (DFS) and overall survival (OS) in early HER2+ BC patients. Methods: this retrospective study identified early HER2+ BC (stage I to III with positive immunohistochemistry and in-situ hybridization) patients from Pérola Byington’s public hospital database (São Paulo, Brazil) diagnosed between January 2010 to March 2018. Patients were excluded if they were less than 18 years old, participated in clinical trials, presented metastatic disease de novo, concurrent malignancy, or inconsistent data. Multivariate Cox regression was used to evaluate prognostic factors for survival, and OS and DFS were estimated by Kaplan-Meier analyses. Results: of the 1,625 patients identified in the database, 1,142 women were included in the study. Of those, 40% were diagnosed with less than 50 years old. Among the included patients, 40.3% were HR-/HER2+ and 59.7% were HR+/HER2+. In addition, 19.4% of patients were diagnosed at stage I, 42.9% at stage II and 37.7% at stage III. A total of 1033 patients were included in the DFS analysis, with a probability of 71.8% DFS in 5-years. For OS analysis, a probability of 75.4% OS in 5-years was observed for 1139 patients included. The multivariate analysis showed that tumor staging, lymph node involvement and pathological complete response (pCR) were independent prognostic factors for both DFS and OS. Conclusions: the study in the Brazilian cohort corroborates the literature, showing that tumor staging, pCR, and lymph node involvement are key markers for DFS and OS and they should be considered when managing the early HER2+ BC patients. [Table: see text]
Loss of Her-2 expression after neo-adjuvant therapy with dual anti-Her-2 agents (Pertuzumab/Herceptin) with chemotherapy in locally advanced Her-2 positive breast cancer.
Authors: Gupta Niraj K. , Giblin Erica , Spivey Tara , Govert Kristen , Leagre Christopher A. , Liebross Robert H. , Schmidt Kristen , Heckman Patrick , Burnett Riessa , Yadav Rina , Tutterrow Rachelle , Beaudrie Nick , Durk Jessic , Tumati Vasu , Dugan Thomas , Paul Robert , Sando Ian , Donnelly Jamie ,   St. Vincent Cancer Care
Published: May 2020

e12562

Background: Conversion of Her-2 positive to negative after neoadjuvant treatments in Her-2 positive breast cancer has been reported. In most of these reports either chemotherapy alone or in combination with a single Her-2 agent (trastuzumab) was utilized. Use of dual anti-Her-2 agents (Pertzummab/Trastuzumab) along with chemotherapy as the neoadjuvant treatment regimen in Her-2 + breast cancer is a standard of care now. We looked at the loss of Her-2 expression after neo-adjuvant regimen consisting of dual anti-Her-2 agents and chemotherapy in locally advanced Her-2 + breast cancer. Methods: We reviewed the records of Her-2 positive patients with T2 or higher or lymph Node+ Her-2 + breast treated at our institution. Patients who had received neo-adjuvant chemotherapy and dual anti-Her-2 agents, pertuzumab and Trastuzumab were identified for this study. Clinical and pathologic data was collected. Her-2 expression was determined by IHC and FISH. Results: Between Dec 2014 and June 2019, 79 patients for identified. Median age was 47 yrs, range 31-83 yrs. All were females except one. Pre-treatment, 74 pts. were 3 + on IHC and 5 pts. were 2+ on IHC, but positive by FISH. Median Her-2/CEP 17 copy number ratio was 6.2, range 3.6-16.7. Sixty patients were ER positive and 19 were ER negative. Pertuzumab+ TCH was the most common regimen used, 91% of the patients. All patients underwent surgery. Forty five out of 79 patients, 56%, had a pCR. Thirty four pts with residual disease were re-assessed for Her-2 expression. 7/32 (20.5%) patients were Her-2 negative. 6/7 pts. were 0/1+ by IHC and 1 pt. was 2+ by IHC but negative by FISH. Five out of seven pts. (71.5%) converting to Her-2 negative were ER negative at diagnosis and 2/7 (28.5%) converting to Her-2 negative were ER + at diagnosis. All patients converting to Her-2 negative had received Pertuzumab+TCH. Conclusions: Loss of Her-2 expression is observed after neoadjuvant treatments with a dual anti-Her-2 regimen along with chemotherapy. Implications of this change on choosing adjuvant treatments in Her-2 + pts who have had neo-adjuvant therapy and effect on recurrence/survival outcomes needs to be explored in larger studies.
Increased favorability of small breast cancers.
Authors: Maeda Shigeto , Yamanouchi Kosho , Hirayama Takanori , Kobayashi Shinichiro , Tokunag Hiroyuki , Takeshita Hiroaki , Miura Shiro , Ito Masahiro , Kuroki Tamotsu
Published: May 2020

e12576

Background: Breast cancer is classified into three prognostic groups based on the following biologic factors: estrogen-receptor (ER) status, progesterone-receptor (PR) status, and nuclear grade (NG). According to this classification, we determined the biological behavior in order to understand if a small breast cancer is biologically more favorable than a large one (T1-2 breast cancers). Methods: The inclusion criteria for this study were (1) presence of T1-2 breast cancer measurable by magnetic resonance imaging (MRI) or ultrasound(US), and (2) availability for determination of ER, PR, and NG histological status. Inflammatory breast cancer, male breast cancer, tumors of unknown size on MRI or US, and complications due to other cancers were excluded from this study. From April 2007 to December 2019, 1173 patients with surgically proven breast cancer presented at National Hospital Organization Nagasaki Medical Center, and 1080 patients were retrospectively analyzed. The favorable (F), intermediate (I), and unfavorable (UF) groups were defined as follows. F: NG1 (ER+PR+, ER+PR-, ER-PR+), UF: NG2 (ER-PR-) or NG3 (ER-PR-, ER+PR-, ER-PR+). IF: all other types of F and UF. Overall survival (OS) was calculated using the Kaplan-Meier method. All statistical analyses were performed using JMP 9.0.2, and probability values of <0.05 were considered statistically significant. Results: Number (%), age (year), size (cm), and 10-year OS (%) in the F, I, and UF groups are presented in the table. The tumor size in F group was significantly smaller than that in the other groups and had better prognoses. The F, I, and UF distribution of tumors less than 1 cm in size were 66%, 29%, and 5%, respectively. On the other hand, the F, I, and UF distribution of tumors 1-2 cm, 2-3 cm, 3-4 cm, 4-5 cm in sizes were (42%, 41%, 17%), (34%, 46%, 20%), (31%, 39%, 30%), and (27%, 45%, 28%), respectively. The 10-year OS of F group stage I, I group stage I, F group stage II, and UF group stage I were 99%, 94%, 93%, and 80%, respectively. Conclusions: Small breast cancers, especially those less than 1 cm in size, were shown to be significantly biologically favorable. Small breast cancers are candidates for de-escalation of treatment. [Table: see text]
A nomogram based on genetic and clinicopathologic features to predict the nonsentinel lymph node metastases in Chinese women breast cancer patients.
Authors: Zhu Liling , Liu Ke , Li Fengyun , Liang Wentao , Shi Wenzhao , Feng Gang , Wang Jiandong
Published: May 2020

e12577

Background: Sentinel lymph node biopsy (SLNB) is the standard treatment for breast cancer patients with clinically negative axilla. However, axillary lymph node dissection (ALND) is still the standard care for sentinel lymph node (SLN) positive patients. Clinical data reveals 20–60 % of patients without non-sentinel lymph node metastasis (NSLNM) after ALND. Unnecessary ALND increases the risk of lymphedema and detracts from quality of life. In this study, we expect to develop a nomogram based on genetic and clinicopathologic features to predict the risk of NSLN metastasis in SLN-positive Chinese women breast cancer patients. Methods: This retrospective study collected data from 310 women breast cancer patients who underwent SLNB followed by ALND and without any neo-adjuvant therapy in Chinese PLA General Hospital, China, between 2016 and 2017. Genetic features contain 96 single nucleotide polymorphisms (SNPs) associated with breast cancer susceptibility and prognosis based on the GWAS studies and clinical information. SNP genotyping was identified by the quantitative PCR detection platform. The genetic features were divided into two clusters by the gene functions and signaling pathways. The polygenic risk score (PRS) was used to evaluate the combined effect of each SNP cluster. Least absolute shrinkage and selection operator (LASSO) regression model was adopted for feature selection and nomogram construction. Internal validation was performed and the area under ROC curve (AUC) was assessed. Results: 81 patients of 310 patients (26%) had a positive axillary NSLNM. The LASSO regression analysis identified the clinicopathologic characteristics including molecular subtype, cN-stage, number of positive SLNs and number of negative SLNs as significant predictors of NSLNM. Furthermore, two SNP clusters were also showed statistically significant in the prediction of NSLNM. In internal validation, the average AUC of the nomogram was 0.795 and the model was well calibrated. Conclusions: We present a new nomogram by combining genetic and clinicopathologic factors to achieve higher sensitivity and specificity comparing with traditional clinicopathologic factors to predict NSLNM in Chinese women breast cancer. It is recommended that more validations are required in prospective studies among different patient populations.
Association of Th2 high tumors with aggressive features of breast cancer.
Authors: Tokumaru Yoshihisa , Le Lan , Oshi Masanori , Katsuta Eriko , Matsuhashi Nobuhisa , Futamura Manabu , Yoshida Kazuhiro , Takabe Kazuaki
Published: May 2020

e12584

Background: Recent studies have shown that infiltrating T-lymphocytes have been implicated in the promotion of breast cancer progression. Upon activation, these antigen-presenting cells then recruit adaptive immune cells. It has been proposed that polarization of CD4+ effector T-cells towards the immunosuppressive Th2 cells induce cytokine release and T-cell anergy, which lead to polarization of M2 tumor-associated macrophages (TAM’s), providing a protumorigenic microenvironment. We hypothesized that there is a correlation between high levels of Th2 cells and aggressive features of breast cancer and unfavorable tumor immune environment. Methods: Clinicopathological data and overall survival information was obtained on 1069 breast cancer patients from The Cancer Genome Atlas (TCGA) database. We defined Th2 high and low levels with the median cutoff. Results: Analysis of cell composition of the immune cells within tumor immune microenvironment demonstrated that Th2 high tumors did not consistently associated with unfavorable tumor immune microenvironment. Pro-cancer immune cells, such as macrophage M2 cells were increased with Th2 high tumors whereas, regulatory T cells were decreased with Th2 high tumors (p < 0.01 and p < 0.001 respectively). On the contrary, infiltration of anti-cancer cells, such as macrophage M1 was increased whereas CD8 T cells were decreased with Th2 high tumors (p < 0.05 and p < 0.001 respectively). Th2 was not shown to have correlation with IL-4, IL-6, IL-10 and IL-13, all of which has been reported to associate with Th2 cells. Th2 levels were associated with advanced grades. Also, correlation analysis demonstrated that there was a strong correlation between Th2 levels and Ki-67. These results were further validated with gene set enrichment analysis (GSEA). GSEA revealed that in Th2 high tumors enriched the gene sets associated with cell proliferation and cell cycle. Conclusions: High expression of immunosuppressive Th2 cells was associated with highly proliferative features of breast cancer, but not with unfavorable tumor immune microenvironment.
Developing a breast cancer tissue biobank in low and middle income countries (LMICs): A research program-based approach for improving molecular profiling.
Authors: Sharma Avinash , Odujoko Oluwole O. , Alatise Olusegun Isaac , Edelweiss Marcia , Ntiamoah Peter , Ogunleye Gbenga Samson , Kingham T. Peter , Iyengar Neil M. ,   African Research Group for Oncology (ARGO)
Published: May 2020

e12585

Background: Breast cancer incidence and mortality is increasing in LMICs especially in sub-Saharan Africa, attributed to changes in lifestyle and possible biological differences. To study putative relationships among lifestyle factors, tumor biology, and the microenvironment, we aimed to develop a breast cancer tissue biobank linked with clinicopathologic and patient reported data in this resource constrained setting. Methods: We prospectively enrolled patients undergoing mastectomy at Obafemi Awolowo University Teaching hospital in Ile-Ife, Nigeria. Pre-operatively, a locally validated survey tool assessed lifestyle factors (diet and exercise); BMI and body composition (by bioimpedence) were measured. Fresh breast tissue was frozen or preserved in 10% neutral buffered formalin, or RNA later for future metabolomic work. Immunohistochemistry (IHC) for ER/PR and HER2 status was performed and read in Nigeria by a locally-trained pathologist, and Memorial Sloan Kettering. The primary outcome was feasibility assessed by successful collection of tissue, clinicopathologic data, and survey completion. Secondary outcomes were completion rate of tumor receptor IHC compared to historic rates and concordance of local vs MSK IHC. Results: From April 2018 to June 2019, 50 patients were enrolled (49 treatment and 1 risk reduction mastectomy). Clinicopathologic, body composition, and survey data, along with breast tissue were collected from all 50 patients. Patient characteristics in table below. Receptor IHC was complete in all patients (100%) compared to a historic rate of 29% (83/286) between 2010-17. Concordance of IHC between sites was 86%, 81% and 84% for subtypes (ER/PR/HER2). Conclusions: Establishing a tissue biobank with clinicopathologic and lifestyle data using locally-adapted protocols is feasible in Nigeria. Patient enrolment is ongoing and updated data will be presented. This initiative also increased local capacity for breast tumor phenotyping, which has critical implications for improving patient care. [Table: see text]
Breast cancer pathology patterns in Armenia.
Authors: Zohrabyan Davit , Bardakhchyan Samvel , Mkhitaryan Sergo , Safaryan Liana , Arakelyan Jemma , Tamamyan Gevorg , Harutyunyan Lilit , Avagyan Armen , Mkhitaryan Armen , Mkrtchyan Gohar , Rushanyan Marine , Harutyunyan Martin
Published: May 2020

e12586

Background: Breast cancer (BC) is the most common malignancy among the women in Armenia (AM). Currently there is a knowledge gap regarding the morphology distribution of the BC in AM. Methods: The data on patients with BC diagnosed in 2015-2016 in the pathology lab “Davidyants Labs” in AM were retrospectively reviewed. Pts with Her2+ results by IHC were excluded from the study, due to unavailability to perform FISH or CISH analyses. Overall 361 pathology reports were evaluated. Results: The median age was 54 years; range [19-82]. Histopathological subtypes were defined for 305 pts, from which lobular carcinoma 57.4% of cases (175/305), ductal carcinoma 26.9% (82/305), mucinous carcinoma 2.6% (8/305), mixed type carcinoma (lobular and ductal) 2.6% (8/305), DCIS 2% (n = 6/305), non specified carcinoma 2% (6/305), medullary carcinoma 1% (n = 3/305) and others 5.6% (17/305). Within the cohort 8.5% (23/270) were grade 1, 65.9% grade 2 (178/270); 25.6% grade 3 (n = 69/270). Vascular or lymphatic invasion was present in 59.5% (50/84) and 64.7% (55/85), respectively. Staging distribution, based on pT pN data for 92 pts who went to primary surgery, was: 0 stage 7.6% (7/92), I stage 22.8% (21/92), II stage 41.3% (38/92), III stage 28.3% (26/92). Staging distribution based on ypT ypN data for 27 pts who went to surgery after neoadjuvant chemo was 0 stage 25.9% (7/27), I stage 18.5% (5/27), II stage 29.6% (8/27), III stage 25.9% (7/27). ER and PR were defined for 244 patients. ER positive 89.8% (219/244) of cases, PR pos. 73% (178/244), ER/PR pos. 72.5% (177/244) cases. Her receptor was defined for 237 patients. Her3+ 16.9% (40/237); Her2+ 12.7% (30/237); Her1+ 38% (90/237); Her0 32.5% (n = 77/237). We could not evaluate Her2+ status by FISH or CISH, so these results were excluded from the analysis. Ki67 was low (≤20) in 42.1% (101/240) of cases and high ( > 20) in 57.9% (139/240). Within the group Luminal A type was 41.4% (84/203); Luminal B 32.5% (66/203); Her positive 19.7% (40/203) and triple negative 6.4% (13/203). p53 and perineural invasion (Pn) was present in 32% (16/50) and 52% (26/50), respectively. Tumor leukocyte infiltration was determined for 16 patients. Leukocyte infiltration was positive in 43.7% (7/16) cases, negative in 25% (4/16) cases, minimal in 31.3% cases (5/16). Conclusions: BC in Armenian women presents with different epidemiological characteristics in comparison with other ethnicities. Lobular type BC is the most frequent type among Armenian women, however, differential diagnosis between lobular/ductal carcinomas was done without IHC (E-Cadherin), which rises the need for further studies on that regard.
Phenotype variants of invasive breast cancer differ in associations between the primary tumor size and its Ki-67 value.
Authors: Kurbel Sven , Dmitrovic Branko , Vrbanec Damir , Separovic Robert
Published: May 2020

e12588

Background: Epidemiological studies report that Ki-67 values are higher in larger invasive breast cancers (IBC). This relation was investigated in 1040 consecutive IBC patients with various immunohistological phenotypes (ER+/-; HER2 0, 1+ to 3+), all treated at a single Croatian hospital. Methods: A scatter plot of 1040 Ki-67 values with their cancer diameter (in cms) have produced an LOWESS nonparametric curve that almost overlapped with the logarithmic function of the same data set (Ki-67% = 18.39+20.63*log(D), where D is a tumor diameter in cm). The next step in using this logarithmic function as a model, was to convert D values into log(D) for linear correlations, amenable to tests of significance. Results: Among all 1040 pts, only ER positive phenotype variants Ki-67% correlated with log(D): Among ER positive tumors, the HER2 expression has decreased the correlation significance and the slope of regression lines, suggesting that the HER2 presence increases Ki67% in small tumors, while larger tumors have Ki67% less augmented than among HER2 absent tumors. Thus the highest slope of the line was found among HER2 absent ER+ patients. Conclusions: Since only ER positive tumors have shown correlation of Ki67% with the log of their tumor size, tumor biology (estimated by Ki67%) of the ER negative IBCs seems unrelated with their size. This possibly suggests that the clinical course of ER negative IBC patients is less predictable due to some etiological distinction the ER positive and ER negative breast cancers. [Table: see text]