bluuebunny/crossref_metadata_2025 huggingface dataset:
Progression-free survival (PFS) and overall survival (OS) in HER2-ve advanced breast cancer (ABC) patients (pts) according to the molecular subtype in the era of modern agents: Results from the GIM-13 AMBRA study.
Authors: Cazzaniga Marina Elena , Pronzato Paolo , Schettini Francesco , Del Mastro Lucia , Riemma Maria , Alù Massimiliano , Turletti Anna , Giordano Monica , Pugliese Palma , De Angelis Claudia , Garrone Ornella , Marchetti Paolo , Riccardi Ferdinando , Bernardo Antonio , Livi Lorenzo , Fabi Alessandra , Taverniti Cristiana , De Placido Sabino , Mustacchi Giorgio ,   on behalf of GIM-13 AMBRA Study Group
Published: May 2019

e12528

Background: Pts with ABC have a diverse clinical course and OS rates vary significantly among pts. New strategies had potentially changed the natural history of these pts, however data from clinical studies are still lacking and Real-World Studies (RWS) are crucial in clinical outcome evaluation. Methods: AMBRA is a longitudinal cohort study, aiming to describe the choice of first and subsequent lines of treatment in HER2-ve ABC pts receiving at least one CHT (SABCS 2016, P5-15-07 & P5-14-09) in the years 2012-2015. The present analysis is focused on the description of Progression-Free Survival (PFS) and OS according to the biologic subtype in the deceased population. So far, 791/1500 pts have been registered into the study and 255 (32.2%) are evaluable. Time to event analysis between subtypes was evaluated by Cox-Mantel Hazard Ratio and Logrank Test. DFS by Wilcoxon Rank-Sum Test. Results: Pts distribution according to molecular subtype was: Luminal A (86, 33.7%), Luminal B (107 (42.1%), TNBC (62, 24.3%). Median ages at diagnosis were 55.8, 52.9 and 55.1 years for the 3 subgroups, respectively. Mean DFS was significantly different according to the molecular subtypes: 87.28, 61.37 and 23.9 months. The difference between Luminal B and TNBC is statistically significant as well. Mean PFS of first-line therapy was 17.9 11.7 and 7.8 months respectively. Mean OS from first progression was 32.9 24.2 and 15.8 months respectively. Statistical details. Conclusions: Our data confirm in a RWS the different biological behaviour between Lum A and B. Metastatic life span is quite good for Luminal and disappointing for TNBC. Median time from last CHT and Death is quite short and similar.[Table: see text]
Abemaciclib with or without fulvestrant for the treatment of hormone receptor-positive and HER2-negative metastatic breast cancer with disease progression following prior treatment with palbociclib.
Authors: Tamragouri Keerthi , Cobleigh Melody A. , Rao Ruta D.
Published: May 2019

e12533

Background: Abemaciclib is a selective inhibitor of CDK4 and CDK6 kinase activity. It is approved for patients with hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) negative, advanced or metastatic breast cancer (MBC) previously treated: in combination with fulvestrant for patients with disease progression following endocrine therapy (MONARCH 2) and as monotherapy for patients with disease progression after endocrine therapy and chemotherapy for MBC (MONARCH 1). The patients in these trials were CDK 4/6 inhibitor-naïve. It has not yet been studied in patients who previously received a CDK 4/6 inhibitor. Methods: We performed a chart review of patients with HR positive, HER2-negative MBC treated at Rush University Medical Center who progressed on palbociclib, either with an aromatase inhibitor (AI) or fulvestrant, and were subsequently treated with abemaciclib with or without fulvestrant. We documented patient demographics, prior treatment, and response to abemaciclib therapy. Results: 21 female patients, mean age 57.8 (+/- 13.2y), were included. Patients had received 1-5 prior lines of endocrine therapy and 0 – 4 prior lines of chemotherapy for MBC. All patients received prior palbociclib: 14 patients with an AI, 6 patients with fulvestrant, and 1 patient received palbociclib with an AI and then with fulvestrant. Of the 21 patients, 17 were treated with abemaciclib monotherapy and 4 received abemaciclib with fulvestrant. SD was seen in 19% of patients (4/21) and 62% had PD (13/21). The CBR was 29% (6/21) and all of these patients received abemaciclib monotherapy. Due to expected toxicities of the drug (diarrhea, neutropenia, and thrombocytopenia), 19% (4/21) of patients discontinued treatment. 4 patients continued abemaciclib monotherapy for greater than 8.3M. 3 patients were on treatment for less than 35 days; 2 stopped due to expected toxicities and one had progression of disease on physical exam. Median treatment duration was 3.1M. Conclusions: This retrospective chart review of 21 patients demonstrates that abemaciclib has limited activity as a single agent in patients previously treated with palbociclib.
Real-world effectiveness of palbociclib in combination with an aromatase inhibitor as first-line therapy in metastatic breast cancer.
Authors: Liu Xianchen , Mardekian Jack , McRoy Lynn
Published: May 2019

e12541

Background: Palbociclib in combination with an aromatase inhibitor (AI) was approved as initial endocrine therapy for patients with HR+/HER2– metastatic/advanced breast cancer (mBC) in February 2015. Evidence of real world outcomes for the combination to date has been limited by small sample size and short follow-up. This study describes patient characteristics and effectiveness of palbociclib + AI as first-line therapy in a large cohort of mBC patients in US clinical practice. Methods: Utilizing Flatiron Health’s longitudinal database, a retrospective cohort study was conducted to evaluate patients with HR+/HER2– mBC who started palbociclib + AI as first-line therapy between February 3, 2015 and August, 31, 2018. Patients were evaluated retrospectively from start of palbociclib + AI therapy on or after February 3, 2015 to November 30, 2018, death, or last visit in the database, whichever came first. Real-world progression free survival (rwPFS) was defined as months from start of palbociclib + AI therapy to death or disease progression based on clinical assessment or evidence by radiographic scan/tissue biopsy. Kaplan-Meier methods were used to estimate survival proportions in overall survival (OS) and rwPFS. Results: Of 878 who met the criteria, 66.9% were white, mean age was 65.2 years, 50.8% had visceral disease (liver and/or lung involvement), and 94% were treated in community practice. Patients were followed up to 46 months. Median rwPFS was 21.9 months (95% CI = 20.1 – 28.2). At 3 years of follow-up, OS rate was 91.9%. For additional outcomes, see Table. Conclusions: These findings from the largest cohort yet evaluated for real world effectiveness confirm the effectiveness of palbociclib + AI in routine clinical practice as a standard of care for first line treatment of HR+/HER2- mBC. [Table: see text]
Assessing treatment benefits with CDK4/6i+ET for hormone receptor-positive advanced breast cancer: A network meta-analysis.
Authors: De Mello Ramon Andrade , Aguiar Pedro Nazareth , Haaland Benjamin , Tan Pui San , Teodoro Fernandes Mariane , Barbin Spinosa Ana Claudia , Del Giglio Auro , Lopes Gilberto
Published: May 2019

e12543

Background: Previously, the treatment of hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer (aBC) has relied solely on endocrine therapy (ET). Unfortunately, almost all tumors developed resistance to ET. Although cyclin-dependent kinase inhibitors (CDKi)+ET clearly improve several clinical outcomes, many relevant questions remain unanswered: is there a benefit in (i) overall survival (OS) (ii) progression-free survival (PFS), and (iii) which CDKi is the best. Methods: A systematic review was performed to identify trials that compared CDKi+ET versus ET alone for HR+/HER2-aBC. Pooled meta-estimates were generated to assess CDKi+ET OS benefit and PFS benefit. Bayesian network meta-analysis was performed to compare each CDKi in terms of PFS, clinical benefit rate (CBR), response rate (RR) and toxicity. Results: 2,523 studies were screened and 8 studies satisfied the inclusion criteria. There was a trend for OS benefit with CDKi+ET compared to ET alone with 97% posterior probability that CDKi+ET is better than ET alone and HR 0.81 (95% CrI 0.66-1.00). CDKi+ET also showed > 99% probability of better than ET alone in both first and second-line settings in terms of PFS, RR, and CBR with PFS HR 0.56 (0.47-0.66) first line, 0.49 (0.39-0.60) second-line; RR OR 1.61 (1.29-1.97) first-line, 2.58 (1.71-3.80) second-line; CBR OR 1.75 (1.38-2.25) first-line, 2.38 (1.65-3.37) second-line. Ribociclib and abemaciclib showed weak-moderate evidence of better PFS and RR compared to palbociclib (64% to 81% posterior probability of superiority). There was no evidence of differences between ribociclib and abemaciclib. Palbociclib achieved better CBR compared to ribociclib and abemaciclib, although this difference may be related to the poor performance of placebo arm in studies that used palbociclib. In terms of safety, abemaciclib caused less neutropenia, but more diarrhea than ribociclib and palbociclib. Deep vein thrombosis was less frequent with ribociclib. Conclusions: CDKi+ET was 97% superior in terms of OS and > 99% superior in terms of PFS, RR, and CBR compared to ET alone. Further studies are necessary in order to find the best agent and the best sequencing of CDKi for HR+/HER2- aBC treatment.
Triple-negative (TNBC) metastatic breast cancer (MBC) patients (pts): Is chemotherapy (CHT) choice influenced by adjuvant (adj) treatments? Results from the GIM-13 AMBRA study.
Authors: Mustacchi Giorgio , Pronzato Paolo , Arpino Grazia , D'Alonzo Alessia , Piezzo Michela , Natoli Clara , Milani Andrea , Bologna Alessandra , Blasi Livio , De Placido Sabino , Diodati Lucrezia , Beano Alessandra , Romagnoli Emanuela , Cazzaniga Marina Elena ,   on behalf of GIM-13 AMBRA Study Group
Published: May 2019

e12549

Background: TNBC shows a very bad prognosis: median time to relapse is 18 months and median overall survival (OS) is less than 24 months. Methods: AMBRA is a longitudinal cohort study, describing the choice of 1st- and subsequent treatments in HER2-ve MBC pts in the years 2012-2015. The present analysis is focused on TNBC pts (127 out of 879 evaluable; 14.4%) and CHT strategies, overall and according to adj treatment. Kaplan Meyer probability of survival from primary (DFS), 1st (PFS1) and 2nd (PFS2) progression and Time from last CHT and death were calculated for the whole population and according the main adj regimens. Results: Median age at primary diagnosis was 53 years. The most used regimens in the adj setting were anthra/taxane(tax) 50.7%, anthra 22.1% or others (CMF included) 20.6%). Median time to events was: DFS 23.2, PFS16.5 and PFS2 4.3 months, respectively. CHT choices in the metastatic setting according to adj treatment were: Conclusions: Our results show that taxanes play a crucial role in MBC even if used in 50% of Adj. CAPE/VRL, Platinum regimens and Eribuline are also widely used. Time from last CHT administration and Death is very short in 30% of cases[Table: see text]
MYC as a therapeutic target for the treatment of triple-negative breast cancer.
Authors: Foley Sarah A. , Castell Alina , Kavanagh Emma , Synnott Naoise C , Crown John , Larsson Lars-Gunnar , Duffy Michael J.
Published: May 2019

e12550

Background: Despite intensive efforts, a validated targeted therapy for triple-negative breast cancer (TNBC) remains elusive. One of the most frequent genetic alterations identified in TNBC is amplification of the MYC gene which is found in > 60% of samples. The aim of this study was therefore to investigate the potential value of targeting MYC activation with the recently identified selective and high-affinity low molecular weight MYC inhibitor MYCMI-6, for the treatment of TNBC. Methods: Cell viability was determined using the MTT assay and apoptosis by flow cytometry using annexin V-propidium iodide staining. Results: Based on a panel of 13 breast cancer cell lines, IC50 values for inhibition of proliferation by MYCMI-6 ranged from 1.2 to 96.7 μM. Significantly lower IC50 values were found for TNBC than for non-TNBC cell lines (p = 0.04), i.e., TN cell lines were more sensitive to MYCMI-6 than non-TN cell lines. IC50 values for MYCMI-6 were compared with 2 older MYC inhibitors, i.e., 10058-F4 and KJ Pyr 9. Of these 3 inhibitors, the lowest IC50 values were found for MYCMI-6, i.e., MYCMI-6 was the most sensitive of the 3 inhibitors investigated (p < 0.0001 for MYCMI-6 versus both 10058-F4 and KJ Pyr 9). In addition to inhibiting cell proliferation, MYCMI-6 was found to induce apoptosis in a time and concentration-dependent manner in multiple breast cancer cell lines. A significant correlation was found between MYCMI-6 IC50 and induction of apoptosis ((p = 0.0499, r 2= 0.9026, n = 4), i.e., the lower the IC50 value, the greater the number of apoptotic cells present. This finding suggests that MYCMI-6 decreases cell proliferation by inducing apoptosis. Conclusions: We conclude that the MYC targeting compound, MYCMI-6 is a potential new treatment for TNBC.
Searching for a link between Ki-67 values and HER2 absence in 297 patients with triple-negative breast cancer.
Authors: Kurbel Sven , Tecic Vuger Ana , Separovic Robert , Dmitrovic Branko , Vrbanec Damir
Published: May 2019

e12551

Background: Based on the report that in ER- invasive breast cancer (IBC) patients, the absence of HER2 might be linked to their Ki-67 values ( Kurbel et al. BMC Cancer 2017;17:231), this relation was searched in 297 consecutive IBC patients with triple negative tumors, treated at two Croatian hospitals. Methods: All 297 patients had ER and PgR negative IBC, The HER2 expression was IHC absent in 211 pts.; IHC 1+ in 62 pts.: IHC 2+ & ISH negative in 24 pts. Based on the cited reference that the Expectation maximization clustering (EM) of the pooled IBC Ki-67 values detects three clusters, regardless of the tumor type, the same approach was used. Differences in the distribution of HER2 values were tested by the χ2 test. Results: Three EM clusters were detected among the pooled Ki67 values: LMA (low mitotic activity) cluster: 109 cases with Ki-67 < 44%; IMA (intermediate mitotic activity) cluster: 96 cases, Ki-67 from 44 to 70% and HMA (high mitotic activity) cluster: 92 cases, Ki-67 > 70%. Beside the Ki-67, distribution of HER2 values was dependent on the age (Chi-square: 25.0309, df = 12, p = 0.014677), as shown here: In patients younger than 46, the HMA cluster was 32% larger than expected. Out of 29 HMA pts, 24 had HER2 absent tumors (53% more than expected). In patients aged 46 to 55, the IMA cluster was 27% larger than expected and out of 30 IMA, 24 had HER2 absent tumors (43% more than expected). In patients older than 55, the LMA cluster was 21% larger than expected, due to more patients with tumors positive for HER2. Out of 68 LMA pts., 22 pts. had tumors with HER2 expression (1+/2+), 40% more than expected. Conclusions: HER2 absent triple negative IBCs might be biologically different from the triple negative and HER2 1+/2+ tumors. The former were linked to pts younger than 55 and Ki-67 values > 43%. The latter showed opposite affinities, age above 55 and Ki-67 < 44%. Based on this, the absence of HER2 in triple negative IBC seems a valid target for future research.[Table: see text]
Ki-67 and Cyclin D1 in subtypes of triple-negative breast cancer with different androgen profiles.
Authors: Vashchenko Larisa N. , Karnaukhov Nikolay S. , Gudtskova Tatiana N. , Kvarchiya Mramza V. , Karnaukhova Elena A. , Luganskaya Roza G. , Bakulina Svetlana M.
Published: May 2019

e12552

Background: The purpose of the study was to analyze Ki-67 and Cyclin D1 expression in subtypes of triple negative breast cancer (TNBC) with different androgen profiles. Methods: Tissues of 60 patients with verified TNBC (T1N1M0/T2N0M0, ER-/PR-/Her2-) were studied. Immunohistochemical staining was performed with antibodies to androgen receptors (AR), CK5/6, Ki-67, Cyclin D1, and EGFR. Basal-like (BL) subtype was identified when > 25% cells were CK5/6+ and/or EGFR+ (any staining). Tumors with ≥10% positively stained cells were considered AR+. Parametric statistical methods were used. Significance of the difference between the two means was assessed by the Student's t-test. Results: BL TNBC showed significantly higher Ki-67 expression (81.9±3.1%), compared to other subtypes (70.8±3.1%), p < 0.05. A number of TNBC samples demonstrated Cyclin D1 overexpression ( > 30% stained cells) with no correlation with Ki-67 expression (r = 0.12). High Cyclin D1 levels were less common in BL TNBC (32.4% tumors), compared to other subtypes (43.5% tumors), but its average values were significantly higher (89.9±4.7% vs. 66.5±6.6%, p < 0.05). AR+ tumors were observed in 11 cases (18.3%). Levels of Ki-67 were similar in TNBC with different AR profiles. The percentage of BL tumors was similar in AR+ and AR- cancers (63.6% and 61.3%, respectively). Expression of Cyclin D1 was more frequent in AR+ TNBC (45.5%), vs. 34.7% in АR-. Average levels of Cyclin D1 were significantly higher in AR+ tumors (51.8±13.7%), vs. AR- (31.6±5.1%). Conclusions: TNBC differs in the Cyclin D1 leves; some tumors show its overexpression. Inhibition of cyclin-dependent kinases blocks the cell cycle, which may be useful in the TNBC treatment, which currently has no targets for therapy.
Targeting serum response factor as a novel therapeutic approach for triple-negative breast cancer.
Authors: Prencipe Maria , Gonzalez Claudia Aura , Russell Niamh , Gallagher William M. , Crown John
Published: May 2019

e12560

Background: Triple negative breast cancer (TNBC) is an aggressive form of breast cancer (BC) which lacks estrogen receptor, progesterone receptor and HER2 amplification. Due to the fact that up to 50% of TNBC express AR and that AR expression has been associated with poor prognosis, targeting AR in TNBC is attracting increasing interest. However, although targeting AR in prostate cancer results in initial response, resistance eventually develops, resulting in treatment failure. We previously identified Serum Response Factor (SRF) as an important transcription factor in a cellular model of castrate-resistant prostate cancer. We showed a relationship between SRF and AR which potentially plays a role in the resistance to AR-targeted therapy. Therefore, we hypothesise that AR resistance mechanisms could be bypassed by targeting SRF, singly or in combination with AR-inhibitors. Methods: In this study three TNBC cell lines with different SRF/ AR levels were selected to investigate the effect of SRF inhibition on cell viability, cell migration and cell invasion. Immunohistochemistry was used to assess SRF expression in 3 BC TMAs: TMA1 (n = 144) and TMA2 (n = 512) with different subtypes of BC and TMA3 with 138 TNBC patients. Results: MTT assays showed response to CCG1423 in the two cell lines positive for SRF (MDA-MB-231 and HS578t) with IC50 values of 20 uM, while MDA-MB-453 (SRF negative) did not respond (IC50 > 80uM). In addition, a synergistic effect on cell viability was demonstrated when CCG1423 was used in combination with MDV3100. Scratch assays to assess cell migration showed a slower gap-closure post- CCG1423 treatment compared to controls. In addition, CCG1423 treatment significantly reduced both cell lines’ ability to invade by approximately 50% at 48 hours post-treatment (p < 0.05). Analysis of SRF expression in clinical samples showed higher SRF protein expression in TNBC vs. non-TNBC patients. In addition, one TMA (n = 144) showed that higher SRF expression was associated with shorter overall survival (HR 1.99 [CI (1.02, 3.87)], P value 0.039) and shorter disease specific survival (HR 2.93 [CI (1.19, 7.21)], P value 0.014). Conclusions: Our data support the rationale for using SRF as an alternative target to AR, alone or in combination with AR-antagonists.
Associations with response to poly (ADP-ribose) polymerase (PARP) inhibitors in metastatic breast cancer: Results of a meta-regression analysis.
Authors: Desnoyers Alexandra , Saleh Ramy , Nadler Michelle , Amir Eitan
Published: May 2019

e12567

Background: PARP inhibitors (PARPi), when given as single agents, have modest antitumor activity in patients with advanced breast cancer and germline mutation in BRCA1 or BRCA2. It is unclear whether some subgroups derive greater benefit from treatment. Methods: Two electronic databases (MEDLINE, CENTRAL) and one registry (Clinicaltrials.gov) were searched from inception to November 2018 to identify trials of PARPi in patients with metastatic breast cancer. The response rates to PARPi were extracted and pooled. Analyses were performed for patients with a germline BRCA mutation. Meta-regression explored the influence of patient and tumor characteristics and previous chemotherapy on the objective response rate (ORR) as reported in individual studies. Analysis comprised of a linear regression weighted by individual study sample size using the weighted least squares (mixed effect) method. Quantitative significance was defined using methods described by Burnand et al. Results: Of 1855 citations, 11 studies comprising 813 patients were included in the analysis. 765 (94%) patients had a germline BRCA mutations; 48% of breast cancers were triple-negative. 76% of patients had received at least 1 previous line of chemotherapy in the metastatic setting and 30% were exposed to platinum-based chemotherapy. Pooled ORR was 47% in patients with a germline BRCA mutation. Meta-regression showed that previous chemotherapy in the metastatic setting ( = -0.94, p = 0.006), especially platinum-based chemotherapy ( = -0.89, p = 0.02) were associated with highly significant negative association with ORR. A highly quantitatively significant negative association was observed for age ( = -0.80, p = 0.10), but this did not meet statistical significance. Performance status ( = 0.44, p = 0.38) and hormone receptor status (hormone receptors positive: = 0.46, p = 0.30) were not associated with response. Conclusions: PARPi therapy is associated with lesser response in patient with prior chemotherapy exposure, especially platinum-based treatment. Younger patients may benefit more from PARPi. There was no association between ORR and hormone receptor status.
Indirect treatment comparison of the efficacy and safety of olaparib 300 mg tablets BID and talazoparib 1 mg once daily in the treatment of patients with germline BRCA-mutated (gBRCA) HER2-negative metastatic breast cancer.
Authors: McCrea Charles , Hettle Robert
Published: May 2019

e12570

Background: PARP inhibitor treatment with olaparib or talazoparib has been shown to improve progression-free survival (PFS) versus chemotherapy treatment of physician’s choice in patients with germline BRCA-mutated (gBRCA) HER2-negative metastatic breast cancer. In the absence of head-to-head evidence, an indirect treatment comparison (ITC) analysis was performed to simulate the comparative efficacy and safety of alternative PARP treatment in this setting. Methods: Bayesian fixed effects ITCs of data published for OlympiAD (NCT02000622) and EMBRACA (NCT01945775) was conducted using the gemtc package in R. Efficacy analyses were performed on the primary endpoint of PFS by blinded independent central review. Safety analyses included the odds ratio (OR) of adverse event (AE)-related discontinuations, and common AEs of any grade reported in each study. All analyses compared olaparib with talazoparib. Results: Efficacy analyses show no significant difference in PFS across treatments (PFS hazard ratio of 1.09, 95% credible interval [0.72; 1.65]). Safety analyses predict differences in AEs across PARP treatment, including hematological events, alopecia, nausea and vomiting (Table). No difference in AE-related discontinuations was observed (0.93 [0.25–3.42]). Conclusions: Results of the ITC suggest that olaparib and talazoparib are equally efficacious on PFS, and differ in AE risk profile, with olaparib predicted to have fewer common hematological and alopecia events, but an increased risk of nausea and vomiting versus talazoparib. Observed differences require confirmation in comparative studies. Limitations of the analysis include heterogeneity in study design, reporting of AEs, and mix of chemotherapies used in the control arm of the studies. [Table: see text]
Satellite alpha transcript levels to predict risk of bilateral breast cancer and multiple primary cancer in patients with breast cancer who lack BRCA-related clinical features.
Authors: Kakizawa Nao , Suzuki Koichi , Tamaki Sawako , Ishikawa Hideki , Ichida Kosuke , Futsuhara Kazushige , Rikiyama Toshiki , Watanabe Fumiaki
Published: May 2019

e12575

Background: Patients with breast cancer who undergo surgery have a risk of developing multiple cancers in the contralateral breast and other organs. We have reported that the overexpression of satellite alpha transcripts (SAT) facilitates chromosomal instability, which is involved in the development of multiple tumors in patients with colorectal and gastric cancer. Methods: In this study, we elucidated the significance of SAT in the development of multiple tumors in patients with breast cancer. Relative expression SAT (rSAT) level was calculated in normal and tumor tissues from 167 patients. Twenty-seven patients developed bilateral breast cancer (BBC) and 27 patients showed multiple primary cancer (MPC). We detected that 71 patients had factors associated with inherited breast cancer; age under 50yo, harboring family history of breast cancer, pathological diagnosis of TNBC, and history of ovarian cancer and we determined these factors as BRCA-related clinical factors. Results: We excluded 71 patients with BRCA-related clinical features, rSAT levels were higher in patients with BBC and MPC than in patients with SBC in tumor tissues ( P = 0.0121) and normal tissues ( P = 0.00586). A univariate analysis indicated significant predictors including rSAT > 1.5 in tumor tissues, rSAT > 2.4 in normal tissues. In a multivariate analysis, rSAT > 2.4 in normal tissues was a significant predictor of BBC (HR, 22.7; P = 0.00120) and MPC (HR, 11.1; P = 0.00885). Conclusions: Our data indicated that patients with breast cancer with high rSAT levels in their breast tissues have a 10- to 20-fold increased risk for the development of multiple cancers when they harbored no BRCA-related clinical features. These patients had been excluded from the high-risk group for BBC, however, our results shed light on these patients and we detected another risk factor which could predict multiple cancers.
Sarcoidosis as a paraneoplastic syndrome for breast cancer.
Authors: Barletta Pamela , Murthi Mukunthan , Salguero Douglas , Mirsaeidi Mehdi
Published: May 2019

e12587

Background: Sarcoidosis is a multisystem granulomatous disease of unknown etiology. The pathogenesis of sarcoidosis is believed to be a result from a cellular immune reaction from exposure to occupational, environmental, or infectious elements that lead to the formation of noncaseating granulomas. Non-caseating granulomas are also present in cancer , and it is well known that the cancer cells carry neo-antigens, leading to a possible association between cancer and sarcoidosis. Several studies have shown an increased risk of breast cancer , in particular, in patients with sarcoidosis, but only a few studies have analyzed the incidence of sarcoidosis following breast cancer diagnosis. The present study aimed to identify patients with sarcoidosis following a diagnosis of breast cancer in our cohort of sarcoidosis. Methods: This is a retrospective case-series study between 2008-2018 of patients with sarcoidosis in the University of Miami Sarcoidosis Program. Sarcoidosis was defined per the World Association for Sarcoidosis and other Granulomatous Disorders guidelines. Breast cancer diagnosis was confirmed through pathology. We collected demographic data of age, gender, ethnicity and the time between diagnosis of breast cancer and sarcoidosis by chart review. Clincial data including clinical manifestations, laboratories, staging, and treatment were also collected. Results: Among 125 patients in our registry, 26 patients had a diagnosis of both cancer and sarcoidosis. In this, 12 (46%) developed sarcoidosis after the diagnosis of breast cancer and are the study population. Among them, 12(100%) were female. The most common ethnic group in the study population was European American with 8(67%) followed by African Americans 2(16.7%) and Hispanic 2(16.7%). Eight (67%) patients were treated with chemotherapy, 7(58%) with radiotherapy, of this, 6 (50%) received both. Mean (SD) age of onset of sarcoidosis was 61.9 ( 10.8) years . The mean time interval between breast cancer diagnosis and the onset of sarcoidosis was 5.58 ( 5.24) years ( (see Figure 1). Nine (75%) had pulmonary sarcoidosis and 3(25%) cardiac sarcoidosis. Among the subjects with pulmonary sarcoidosis 1(11.1%) had Stage 4, 4(44.4%) had Stage 2 and 4(44.4%) had stage 1. Conclusions: Our findings suggest sarcoidosis may be a paraneoplastic characteristic of breast cancer. The mechanism of granuloma development remains unclear. Cancer mediated immune dysregulation could be a potential contributing factor. Further studies are warranted to establish a definitive association.
Incidence of FGFR-TACC gene fusions in Chinese non-small cell lung cancer (NSCLC): A multicenter study.
Authors: Cai Xiuyu , Xu Chunwei , Wang Wen xian , Zhang Quxia , Chen Yu , Fang Yong , Wang Hong , Zhu You-cai , Zhuang Wu , Huang Yun-jian , Zhang Yinbin , Wang Liping , Wang Yafei , Chen Meifang , Yang Dongyong , Cai Shangli , Fang Meiyu , Chen Gang , Lv Tangfeng , Song Yong
Published: May 2019

e13001

Background: Fibroblast growth factor receptors (FGFR) are transmembrane kinase proteins with growing importance in non-small cell lung cancer (NSCLC) biology given the frequency of molecular alterations and vast interface with multiple other signaling pathways. Furthermore, numerous FGFR inhibitors in clinical development demonstrate the expanding therapeutic relevance of this pathway. The aim of this study was to evaluate the prevalence of FGFR-TACC fusions in Chinese NSCLC populations, which had not been reported earlier, and to describe targeting potential in Chinese NSCLC populations. Methods: A multicenter study in China was initiated from February 2014, and NSCLC patients have been enrolled as of December 2018. Capture-based comprehensive genomic profiling was performed on 2743 NSCLC FFPE samples sequenced to a mean coverage depth of > 650X for up to 381 cancer-related genes. Genomic alterations (GA) included short variant (SV) base subs and insertions/deletions, copy number alterations, and rearrangements/fusions. Tumor mutational burden (TMB; mut/Mb) was calculated on up to 1.2 Mb of sequenced DNA. Results: Of this entire cohort, just 16 (0.58%) patients were identified with FGFR-TACC fusions, including FGFR1-TACC 1 fusion (1), FGFR2-TACC2 fusion (3) and FGFR3-TACC3 fusion (12). Median patient age was 57 (range 36-84 years). Of the FGFR-TACC fusion NSCLC patients, 56.25% were detected in female patients. Biopsies were obtained from primary lung tumor (31.25%) and metastatic sites (68.75%). Overall TMB in the FGFR-TACC fusion was low (median 3.6 mut/Mb), although two cases (12.50%) had > 20 mut/Mb. Of the FGFR-TACC fusion NSCLC patients, two cases (12.50%) featured EGFR SV alterations. Conclusions: FGFR-TACC fusions occur in a subset of patients with NSCLC. Such patients should be considered for clinical trials featuring FGFR inhibitors (AZD4547). Moreover, NGS can provide information for targeted therapy. For NSCLC patients to benefit from more personalized cancer treatment, clinical therapy should improve with clinical diagnostics through multi-gene assays to determine the actual clinical benefits.
Pathogenic germline mutation profile in Chinese lung cancers and related-driver mutation pattern.
Authors: Peng Wenying , Wu Lin , Chang Lianpeng , Li Jin , Bai Jing , Zhang Yanyan , Guan Yanfang , Jiang Meilin , Pu Xingxiang , Xu Li , Wang Qianzhi , Xu Fang , Chen Bolin , Cao Jun , Yi Xin , Yang Ling , Xia Xuefeng , Zhang Jianjun
Published: May 2019

e13003

Background: Many cancers could be driven by germline mutation exampled as BRCA1/2 in breast or ovarian cancer. However, the candidate predisposition variants for Chinese lung cancer are largely unknown. Methods: We reviewed 1797 Chinese lung cancer patients with paired tumor-normal samples sequenced by a 1021 gene panel. The annotation of germline variants within 95 selected susceptible genes was based on ACMG 2015 version guideline. Results: The frequency of patients identified with pathogenic or likely pathogenic (P/LP) germline variants were 5.95% (107 in 1797), which elevated to 10.1% (9 in 89) in patients younger than 40. Totally, 112 mutations from 35 genes were screened out. Recurrent pathogenic germline genes were BRCA2 (n = 14), FANCA (n = 9), RAD51D (n = 7), MUTYH (n = 7), ATM (n = 7) and TP53 (n = 5). The average age at diagnosis was numerically 2 years earlier in patients with P/LP (mean, 58.2 vs. 60.0, p = 0.22) than other patients without significance, but different genes contribute to discordant effects. Significantly early onset age was found in germline BRCA1/ 2 mutation (median, 52.5 versus 60.0 yrs in patients without P/LP, p = 0.0080) while later onset age was associated with germline PMS2 mutation (median, 74 versus 60.0 yrs, p = 0.0214 ). In terms of clinical actionable somatic mutation, the frequency of KRAS (15/89, 16.85% versus 121/1429, 8.47%, p = 0.012) and c-MET (6/89, 6.74% versus 31/1429, 2.17%, p = 0.018) in germline mutant patients were significantly higher, while TP53 (41/89, 46.07% versus 847/1429, 59.27%, p = 0.019) was apparently less mutated in P/LP lung cancer. As for frequency of EGFR, ALK, ROS-1, RET and BRAF, mutation frequency were not significantly different in lung cancer with germline mutation. Conclusions: Our study delineated the pathogenic germline mutation landscape in Chinese lung cancers for the first time. Predisposition genes demonstrated clinical actionable roles in onset age and therapeutic interventions. Further follow up may clarify the contribution of germline mutation to somatic mutation driven targeted therapy response and prognosis.
Evaluation of next generation sequencing for detecting HER2 copy number in breast and gastric cancers.
Authors: Lin Dongmei , Ji Jiafu , Niu Dongfeng , Li Lei , Yu Yang , Gao Yun , Zhang Wanchun , Li Zhongwu , Rao Guanhua , Gao Lianju , Cheng Gang
Published: May 2019

e13004

Background: Amplicon-based next generation sequencing (NGS) approaches have been preferentially adopted by the clinical laboratories on the basis of a short turnaround time (TAT) and small DNA input needs. However, little work has been done to assess the amplicon-based NGS methods for copy number variation (CNV) detection in comparison with current standard methods like immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). The correlation between NGS based CNV detection and the later standard methods has remained unexplored. Methods: We developed an amplicon-based panel to detect human epidermal receptor growth factor (HER2) amplification in formalin-fixed paraffin-embedded (FFPE) tumor tissue samples from 280 breast cancer and 50 gastric cancer patients. Assessment by IHC and FISH was conducted in parallel, and descriptive statistics were used to assess the concordance. Results: The copy number detected by NGS was correlated with either the average HER2 copy number (signals/cell) (r = 0.844; p < 0.001) or the HER2/CEP17 ratio (r = 0.815; p < 0.001). We determined a cut-off value for NGS to categorize HER2 amplification status by using 131 HER2 non-amplified FFPE samples. In breast cancer patients, the cut-off value was 2.910, with 95.28%, 99.23% and 97.29% sensitivity, specificity and concordance, respectively. However, this cut-off value displayed low sensitivity in gastric cancer patients (64.71%), and the following macro-dissection procedure was not effective for increasing sensitivity (57.14%). Thus indicated that HER2 copy number correlation between NGS and FISH in gastric cancer was different from breast cancer. Conclusions: Evaluation of HER2 copy number with NGS in our study was comparable with IHC and FISH in breast cancer patients, but concordance in gastric cancer was only moderate. NGS-based HER2 assessment may decrease the equivocal HER2 determinations in breast cancer patients assessed by FISH/IHC. The greater discordance in gastric cancer may reflect the underlying biological mechanisms, and further study is warranted.
Screening of differentially expressed genes of esophageal squamous cell carcinoma with cDNA microarray.
Authors: Fuchun Si , Jingyu Yue , Gao Si
Published: May 2019

e13005

Background: Esophageal Carcinoma (EC) is one of the most common malignant tumors in digestive system and is the sixth leading cause of cancer-related mortality worldwide. To find out the genes related with the occurrence and development of EC can help to elucidate the pathogenesis and molecular mechanism of it. The aim of the present study was to find out differentially expressed genes of EC in different stages(cancerous tissue, paraneoplastic tissue, normal mucosa tissue) by cDNA microarray technique, so that to provide new molecular biomarker and approach for the treatment and diagnosis of EC, and contribute to comprehensively knowing the mechanism of EC occurrence and development. Methods: The whole RNA of 21 cases of EC cancerous tissue, paraneoplastic tissue and normal mucosa tissue were extracted, then using agarose gel electrophoresis to make quality control, Agilent human genome 4*44K gene chip was applied to screen differentially expressed genes. Results: 2659 differential expression genes between cancerous tissue and normal mucosa tissue were screened, included 1328 up-regulated genes and 1331 down-regulated genes; 2505 differential expression genes between cancerous tissue and paraneoplastic tissue were screened, included 1286 up-regulated genes and 1218 down-regulated genes. 48 significant up-regulation genes and 11 significant down-regulation genes were reported in association with EC for the first time. Through GO classification, screened differentially expressed genes mainly were involved in the following function and process: catalytic activity, signal transduction, molecular transport and combination, enzymatic activity regulation, transcription activity regulation, protein transportation function, cell growth and apoptosis, and so on. Conclusions: The screened differential expression genes of EC in different stages may provide experimental basis for further illuminating the occurrence mechanism of esophageal squamous carcinoma.
Comparative gene expression analysis in gliomas with different IDH1/2 status.
Authors: Timoshkina Natalya N. , Kit Oleg I. , Pushkin Anton , Antonets Anna V. , Rostorguev Eduard Evgenevich , Porksheyan David H. , Kavitskiy Sergey E. , Kuznetsova Natalya S.
Published: May 2019

e13008

Background: The new 2016 WHO classification of tumors of the central nervous system takes into consideration mutational status of IDH genes. Research of molecular changes in gliomas remain to be an actual issue. We analyzed the gene expression of some significant pathways in gliomas. Methods: 27 patients (12 females, 15 males) aged from 27 to 76 years with verified brain tumors (glioblastomas (G4) – 67%, anaplastic astrocytomas and oligoastrocytomas (G3) – 11%, astrocytomas (G2) – 22%) were investigated. 7 mutations in the IDH1 gene and 5 ones in IDH2 in fresh frozen tumor tissues were detected by RT-qPCR with Therascreen IDH1/2 RGQPCR kit (Qiagen). The expressions of EGFR, SMAD4, SMAD7, SMO, NOTCH1, NOTCH2, HBP1, HIF1A, EGLN1, EGLIN3, KDM1B, KDM1A, MSI1, MSI2, TET1 genes in tumor and normal brain tissue obtained while surgical access were assessed with RT-qPCR. PSMC, TBP and RPLO were used as reference genes. Results: Analysis of IDH1/2 status revealed only R132H mutation of IDH1 in 6 patients. The ratio of the relative expression of genes in tumor tissue with mutation and wild-type and the significance of the differences in the Mann-Whitney test are presented in the table below . Conclusions: Expression of SMAD7, EGLN1, EGLN3 as an activating factor of TGF-b-signaling pathway potentially may be used as an additional prognostic marker of gliomas progression.[Table: see text]
A multi-institutional investigation assessing prevalence of germline genetic alterations in Chinese patients with gastric carcinoma.
Authors: Zhang Yinjie , Wang Xicheng , Zhu Changbin , Zhang Xiaotian , Wei Qing , Ren Lvzhi , Shao Di , Gao Jing , Li Yan Yan , Zhang Jingdong , Chen Xiao-Bing , Wang Chaojie , Meng Qiu , Wang Xin , Liu Baorui , Shen Lin
Published: May 2019

e13020

Background: Gastric carcinoma is one of the most common malignancies in east asian. Previous studies demonstrated around 10% of patients with gastric cancer were found to have pathogenic germline variants. While, predisposition genes of gastric cancer in Chinese patients are still largely unknown. Thus, we aim to delineate prevalence of deleterious germline mutations in Chinese gastric patients with hereditary high-risk familial cancer history. We also aim to analyze clinical relevance of deleterious germline mutations. Methods: Forty index cases were recruited from 7 institutions in China. DNA samples extracted from blood specimens were captured using a 171-cancer predisposition gene panel and then sequenced by MGI-SEQ 2000 platform. Germline variants were determined to be deleterious according to the ACMG 2015 guidelines. Pathogenic and Likely pathogenic germline variants were further validated by Sanger sequencing. Results: 12 of 40 (30%) probands had 13 pathogenic/likely pathogenic germline variants involving 11 different genes: CHEK2 (n = 2), SPINK1 (n = 2), BLM (n = 1), CDH1(n = 1), EXT2 (n = 1), MLH1 (n = 1), MSH2(n = 1), MUTYH (n = 1), PALB2 (n = 1), NF1 (n = 1), ERCC2 (n = 1). For patients with multiple primary cancers, pathogenic germline alterations were exclusively presented (5 out of 12) (P=0.003). Besides,27 germline variants (like EPCAM, RAD54B, FANCD2, FANCA) with uncertain significance in 15 patients were predicated to be deleterious via in silico predictors. Conclusions: This multi-institutional study identified 30% (12/40) of Chinese gastric cancer patients with family history to have deleterious germline alterations. And potential deleterious variants were also identified. Our data illustrates a significantly distinguished spectrum of germline variants compared with Caucasian ones. This may indicate unique carcinogenesis of gastric cancer in Chinese patients. Since patients with pathogenic or likely pathogenic germline variants have dismal clinical outcome and higher rate of multi-cancer occurrence, genetic counseling of gastric cancer should be considered for individuals with family history at their early age.
MUC16 germline mutations may predispose inherited cancer family members to lung adenocarcinomas.
Authors: Wang Tao , Liu Hong , Xiao Shanshan , Mao Ruifang , Lin Rui
Published: May 2019

e13039

Background: Familial lung cancer is rare. Previous studies have identified random EGFR mutations associated with the inherited lung cancer. Reports also show that TP53 and CDKN2A mutations may predispose individuals to lung cancer, and MUC16 plays important roles in tumorigenesis and metastasis of lung cancer cells through regulating TP53. However, the molecular findings of familial lung cancer are still few. Methods: We have identified an extremely rare family, four siblings diagnosed with lung adenocarcinomas and one with bladder cancer; all lung cancer patients had multiple synchronous nodules. Their father was also lung cancer patient and deceased. We extracted tumor tissue DNA, genomic DNA (gDNA) and circulating cell-free DNA (ctDNA) from the 5 patients and analyzed the DNA samples using a 500-gene next generation sequencing (NGS) panel. Results: TP53 P72R and other 3 CDKN2B-AS1 germline mutations were identified in all the 5 patients. Although the 3 CDKN2B-AS1 mutations are commonly occurred in population according to dbSNP, these observations are consistent with a hypothesis that TP53 P72R and the CDKN2B-AS1 germline mutants may synergize in predisposing the family members to cancer. Interestingly, 3 MUC16 mutations ((rs754254000, rs754856910, and rs746152510) were all identified in the four lung cancer patients, but none were identified in the bladder cancer patient. All of the 3 MUC16 mutants had very low population allele frequency (all below 0.1%,) suggesting that the MUC16 germline mutations may play roles in the familial lung cancer, which is consistent with previous reports demonstrating the involvement of MUC16 in lung cancer cell growth. Moreover, all the four lung cancer patients had somatic mutations of EGFR L858R/exon 19 deletion prior to treatment with EGFR tyrosine kinase inhibitor (TKI), including one patient with L858R and exon 19 deletion in different tumor nodules, which is consistent with molecular characteristics in synchronous primary lung cancer. Conclusions: We have demonstrated in this study that germline MUC16 mutations may predispose the inherited cancer family members to lung adenocarcinomas. This study provides a clue of the cause of familial lung cancer and also warrants further mechanistic study of MUC16 gene in lung cancer.
Procancerous immune cells in primary tumor is associated with breast cancer recurrence.
Authors: Takeshita Takashi , Yan Li , Takabe Kazuaki
Published: May 2019

e13042

Background: Breast cancer (BC) recurrence is largely determined by cancer factors as well as host factors. It has been implicated that infiltrating immune cells play critical roles in long term survival. We hypothesize that immune cell infiltration profile rather than clinical characteristics or gene expression signatures of the primary tumors associate with the timing of cancer recurrence. Methods: 308 primary BCs in TCGA with cancer recurrence data was divided into; recurrence < 2 years (Early, n = 103), 2-5 years (Late, n = 20), and no recurrence > 5 years (Control, n = 185). 1410 primary BCs in METABRIC with BC specific death data was divided into; death < 10 years (Early Death, n = 499), death > 10 years (Late Death, n = 123), and survived > 10 years (Survivors, n = 788). Results: We found that Early tumors demonstrated more aggressive clinical characteristics such as larger tumor, more lymph node metastases, higher pathological grades, higher Stages, and negative estrogen and progesterone receptors, compared with Control tumors. On the other hand, no clinical characteristics of Late tumors were significantly different from Control tumors, which implicate that clinical characteristics cannot distinguish late recurrence from Control. Gene set enrichment analyses revealed that there was no significant gene sets that enriched with Early nor Late recurrence compared with Control, which implicate that gene expression signatures cannot distinguish recurrent tumor from Control. Utilizing CIBERSORT algorithm, we found that M1 was low and M2 was high macrophages in Early compared from Control. Further, anti-cancer lymphocytes, memory CD4 T cells and gamma delta T cells, were significantly lower, and pro-cancerous regulatory T cells were significantly higher in Early and Late compared from Control. In agreement, cytolytic activity score that assess immune cell killing were significantly lower in Early and Late compared from Control. Interestingly, only elevation of regulatory T cells was similar in METABRIC cohort when Early Death and Late Death were compared with Survivors. Conclusions: We found that not clinical characteristics or gene expression signatures, but pro-cancerous immune cells in primary BC associate with cancer recurrence and breast specific death.