bluuebunny/crossref_metadata_2025_split huggingface dataset:
HER2 testing: Insights from pathologists’ perspective on challenging HER2 cases.
Authors: Grimm Erin V , Swenson Karen K , Krueger Janet , Hicks David G. , Allison Kimberly H. , Yaziji Hadi , Rendi Mara Hester , Susnik Barbara , Downs-Kelly Erinn , Tsai Michaela L. , Lillemoe Tamera J 
Published: May 2019

e12512 Background: HER2 status dictates treatment decisions in breast cancer making the precision and accuracy of laboratory testing essential. While most HER2 testing is straightforward using ASCO-CAP interpretation guidelines, 5% of cases fall into the less common categories (groups 2-4) and can present unusual diagnostic dilemmas. 6 high volume HER2 FISH laboratories evaluated 10 challenging HER2 cases. The results highlight the challenges and potential for variability in interpreting rare cases with unusual results. Methods: Ten diagnostically challenging HER2 FISH cases were selected from our breast cancer archives (41 months/3863 cases). Unstained slides were evaluated by 6 high volume laboratories. Laboratories performed HER2 FISH testing (along with HER2 IHC as needed) and rendered an interpretation. Participants discussed results during a conference call. Cases included the following situations: low-level amplification (ratio ≥ 2.0, mean HER2 signals/cell between 4.0-5.9), HER2 mean copy number or ratio near a clinically actionable threshold, complex heterogeneity or clones, and a technical challenge (signal clustering). Results: All laboratories elected to perform HER2 IHC in conjunction with FISH in all cases. Only 3/10 cases resulted in 100% agreement between the 6 institutions, all of which were in the category addressing complex heterogeneity. During the study, we identified a problematic subset (low amplified FISH cases) which may have discordant (negative) IHC results. Another problematic scenario is the finding of a small, highly amplified HER2 clone. Lastly, we identified cases with high cell to cell variability, and we saw discordant values resulting in disparate overall HER2 interpretations. Conclusions: Oncologists and pathologists should be aware of these challenges and the potential for variability in interpretation of these rare case scenarios. Evaluation for concordance between IHC and FISH results, correlation with other clinico-pathologic features and additional steps to ensure the accuracy of test results can help resolve unusual results, but grey zones may still remain and should be discussed when making clinical decisions based on HER2 test results.
Efficacy of abemaciclib (abema) after palbociclib (palbo) in patients (pts) with metastatic breast cancer (MBC).
Authors: Mariotti Veronica , Khong Hung T. , Soliman Hatem Hussein , Costa Ricardo L , Fisher Shanel , Boulware David , Han Hyo S. 
Published: May 2019

e12521 Background: CDK 4/6 inhibitors (Abema and Palbo) have shown efficacy in patients with HR+/HER2- MBC. Abema is distinct from other CDK 4/6 inhibitors and was approved after the approval of Palbo. There is limited data on sequential use or cross resistance. The aim of this study was to analyze the response to Abema based therapy in MBC pts with prior exposure to Palbo. Methods: We queried our EMR database for pts who received Abema from 9/2017-9/2018 after having received prior Palbo. Under IRB approved protocol we retrospectively collected demographics, tumor characteristics, disease status, toxicities and survival. Results: 23 female pts were identified. Four patients discontinued Palbo due to toxicities: two of them remained on Abema for 8 months and the other 2 discontinued Abema due to toxicities. The remaining 19 pts (median age 57 years, range 39-76) received a mean of 5.6 prior therapies (range (1-11) including Palbo in combination with endocrine therapy (fulvestrant 9 in pts and Aromatase inhibitors (AI) in 10 pts) at the time of Abema based therapy. 73.6% had visceral involvement including brain metastasis in 26%. The median progression-free survival (PFS) of Palbo in combination with endocrine therapy was 8 months (range 2.3-14.3). Abema was given in combination with endocrine therapy in 15 pts (9 pts fulvestrant and 6 pts AI) and 4 pts received it as a single agent. The median PFS of Abema based therapy was 7.0 months (range 1.8-12.1). Four pts (21%) had a longer PFS on Abema compared to prior Palbo PFS (table). Abema was discontinued due to toxicities in 15.7%. No partial or complete response was observed but 33% had stable disease. Conclusions: Abema showed response in a significant number of pts previously exposed to Palbo and heavily treated with multiple lines of chemotherapy for widespread metastatic disease. Prospective studies are warranted to better assess the response to Abema after exposure to CDK4/6 inhibitors. [Table: see text]
Fulvestrant versus everolimus plus exemestane for patients with metastatic breast cancer resistant to aromatase inhibitors: Clinical experience from real world.
Authors: Li Yi , Xie Yizhao , Zhao Yannan , Hu Xi-Chun , Zhang Jian , Chen Shen , Gong Chengcheng , Zhang Sheng , Wang Leiping , Wang Biyun 
Published: May 2019

e12522 Background: To present treatment patterns and the outcome of pure endocrine therapy fulvestrant (FUL) versus Exemestane (EXE)and target therapy everolimus (EVE) combination among hormone receptor-positive (HR+)/human epidermal growth factor 2 (HER2)-negative metastatic breast cancer (MBC) after progression on aromatase inhibitor (AI) in the real-life setting. Methods: Patients with HR+/HER2- MBC after AI who received FUL or EVE-EXE between June 2013 and June 2016 were identified from electronic database. Outcome measures included progression free survival (PFS), overall survival (OS) and safety profile. Propensity score matching (PSM) was applied to minimize potential confounders. Results: Among the 168 patients included, 124 patients received FUL and 44 patients treated with EVE-EXE. Patients that received EVE-EXE were significantly younger, more likely to have visceral, liver, multiple sites of metastases and had received more prior chemotherapy than FUL group. There was no significant difference in PFS after adjusted for propensity score between two groups (HR,1.173; 95%CI, 0.797-1.727; p = 0.419). In subgroup analysis, treatment effects were consistent across predefined subgroups except for the subgroup of multiple metastatic sites which the median PFS was significantly longer in EVE-EXE group than in FUL group (6.1vs3.2months, respectively; HR = 0.508;95%CI,0.299-0.862; p = 0.012). The toxicity of FUL regimen was more manageable. More patients discontinued the treatment due to intolerable toxicity in EVE-EXE group than FUL group. Conclusions: We observed substantial changes in treatment patterns in patients received EVE-EXE and FUL. Treatment outcomes were comparable between two schedules after adjusted for confounding factors, while FUL has been better tolerated. Clinical trial information: NCT03695341.
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]