bluuebunny/crossref_metadata_2025_split huggingface dataset:
A site-specific approach to improved antibody-drug conjugates.
Authors: Italia James 
Published: May 2020

e13009 Background: Antibody based therapeutics have emerged as a highly promising treatment option for various forms of cancer. One such class of emergent antibody therapeutics is antibody-drug conjugates (ADCs), which has experienced remarkable success in the past few decades, including many candidates currently undergoing clinical trials. Despite its promise, developing effective ADCs remains a challenge due to extensive optimization with regard to antibody target identification, conjugate specificity, conjugation chemistry compatibility, heterogeneous side product co-purification, all affecting efficacy, PK/PD characteristics, and toxicity. There is a pressing need to develop alternative strategies for precise (site-specific), flexible (offering numerous options for conjugation site and chemistry), efficient, and scalable generation of antibody-drug conjugates to overcome these limitations and realize the full potential of this highly promising class of therapeutics. Methods: In this study, we demonstrate the feasibility of efficiently incorporating an azide-containing UAA into full-length antibody at different site and facilitate its site-specific functionalization, which provides a facile scale-up compatible route to generate precise antibody-drug conjugates with fine-tuned therapeutic properties. Specifically, we have engineered multiple variants of trastuzumab to contain the aforementioned UAA, enabling site-specific attachment of cytotoxic payloads, such as MMAE/MMAF, via click chemistry to generate ADCs with homogeneous DARs. Results: The resulting BrickBio ADCs exhibit high therapeutic efficacy against HER2+ cell lines in vitro as well as in mouse xenograft models. These homogenous ADCs additionally outperform traditional antibody conjugation technologies which lack site-specificity or site-selectivity. Conclusions: The ability to systematically vary the attachment topology between the drug and the antibody is a major strength of this approach and preliminary data suggest that such variation indeed affect ADC performance. BrickBio ADCs are currently in the preclinical stage with further efforts for safety studies underway.
Barriers to accessibility of targeted therapy for breast cancer: A qualitative study in Yerevan, Armenia.
Authors: Shingala Darshan , Arakelyan Jemma , Bardakhchyan Samvel , Tamamyan Gevorg 
Published: May 2020

e13013 Background: The treatment prospects for Human Epidermal Growth Factor Receptor 2 positive (HER2p) breast cancer (BC) patients are continuously evolving, however, BC remains a major public health problem. Multiple therapeutic and biological strategies are already in function, and specifically the anti-HER2 therapy (trastuzumab, pertuzumab, lapatinib, and ado-trastuzumab emtansine) remains a mainstream clinically approved treatment method. Implementation of the anti-HER2 therapy has substantially strengthened the prognosis for HER2p patients. This has remarkably improved the 5-year survival rates upto 80% in high-income countries, 60% in middle-income countries and 40% in low-income countries by establishing anti-HER2 therapy. Barriers to anti-HER2p therapies in low- and middle-income countries (LMICs) can be minimized by further instigation and licensing of the bio-similar drugs as a low-cost alternative treatment. Bio-similar drugs will also potentially result in a considerable savings for patients and eventually lessen the burden on the health care systems of LMICs as the usual cancer treatment regimen includes multiple systemic therapies for an extended time period, which are highly expensive. The aim of the study is to identify the barriers to accessibility of targeted therapy for BC, among patients seeking BC treatment in Yerevan, Armenia. Methods: The qualitative study assessed the out-of-pocket (OOP) payment burden among patients and their opinions about the quality of treatment using an interview guide with probe questions, adapted to the Armenian context. The study participants were patients seeking BC treatment at Hematology Center and Mikhaelyan Medical Center. Results: All the study participants were satisfied with the quality of health care and health care providers, however, majority of the study participants paid OOP for the examination, analysis and therapeutic drugs. Most participants were sponsored by family members and stated being financially vulnerable. Conclusions: The study provides evidence for the development and implementation of biosimilar drugs, implementation of mandatory health insurance to increase the access to targeted therapy, enhance collaboration with international funding agencies and strengthen diaspora support.
Clinical outcomes and prognostic factors in HER-2 positive breast cancer with brain metastasis: A single-center experience.
Authors: Karakaya Serdar , Karadağ İbrahim , Duran Ayse Ocak , Oksuzoglu Omur Berna , Demirci Umut 
Published: May 2020

e13015 Background: Brain metastasis is common in HER2 positive metastatic breast cancer patients. There is limited data on the prognosis, incidence, treatment, risk factors and complications of brain metastasized breast cancer because most clinical trials excluded these patients. we aimed to determine the characteristics and prognosis of brain metastasized HER2 positive breast cancer in our patient group, retrospectively. Methods: We scanned 3100 patients retrospectively and included 105 patients who met the criteria for inclusion in the study. Patients older 18 years old, had HER2 positive breast cancer and brain metastasis with no secondary malignity participated in the study. Results: In total, 35 (33.3%) patients had de-novo metastasis. Median overall survival (OS) was found to be 50 months in all patients. Median OS was 31 and 66 months for patients with de-novo metastasis (without brain metastasis) and patients with no metastasis at the time of the diagnosis, respectively (p < 0.01). When we compared median OS between 25 patients with one brain metastasis and 80 patients with multiple brain metastasis, it was found to be 90 months in the first-mentioned group whereas it was determined to be 45 in the latter group (p < 0.01). In all patients, the median elapsed time for the occurrence of brain metastasis was 22 months (for de-novo metastasis 15 months, for no metastasis 35 months; p < 0.01). Median OS was determined to be 15 months for all patients with brain metastasis after the occurrence of the metastasis. Patients with ECOG PS score of 0-1 at the time of the brain metastasis had 19 months median OS, while patients with ECOG PS score of 2 at the time of the brain metastasis had 8 months median OS (p < 0.01). Median OS after brain metastasis was 32 and 14 months for patients with one brain metastasis and patients with multiple brain metastasis, respectively (p < 0.01). Multivariate cox regression analyses revealed that elapsed time for the occurrence of brain metastasis was shorter in patients with high-grade tumours compared to patients with low-grade tumours (p = 0.04), and in patients with de-novo metastasis compared to patients without de-novo metastasis (p < 0.01). Conclusions: Our study indicated that tumour grade and de-novo metastasis are independent predictive factors that may cause the earlier occurrence of brain metastasis and affect mortality in breast cancer patients. After the occurrence of brain metastasis, lower ECOG PS score and multiple brain metastasis at the time of the diagnosis affected median overall survival as bad prognostic factors.
Tolerability of neratinib in older adults with HER2 positive or HER2 mutated metastatic breast cancer.
Authors: Lee Jin Sun , Yost Susan Elaine , Stiller Tracey , Blanchard Suzette , Padam Simran , Katheria Vani , Tang Aileen , Martinez Norma , Patel Niki Himat , Sedrak Mina S. , Waisman James Ross , Li Daneng , Sanani Shamel , Presant Cary A. , Mortimer Joanne E. , Yuan Yuan 
Published: May 2020

e13018 Background: The tolerability and efficacy of targeted therapy in older adults with cancer have not been adequately studied. Neratinib is an oral pan-HER1, HER2, and HER4 tyrosine kinase inhibitor that has been FDA approved for early stage HER 2+ breast cancer. This phase II trial is designed to evaluate the safety of neratinib in older adults (≥60 years) who have HER2 amplified or HER2 mutated metastatic breast cancer (MBC). Methods: Older adults with HER2+ or HER2 mutated MBC with any number of previous lines of therapy received neratinib at 240 mg daily in 28-day cycles. Loperamide was used for diarrhea prophylaxis: 4mg tid x 14 days followed by 4mg bid for days 15-28, and as needed after first cycle. Participants completed a pre-treatment geriatric assessment (GA) including measures of function, comorbidity, cognition, nutrition, and psychosocial status at cycle 1, cycle 4, and end of the study. Relationships between tolerability (dose reductions and number of completed courses) and log2 risk score were assessed using t-test and linear regression. Response rate (RR), progression free survival (PFS) and overall survival (OS) were evaluated. Results: Twenty-five patients (mean age 68 [60-79]) were enrolled from 12/2016 to 03/2019, and 36% of patients (pts) were >70 years old. Median number of cycles completed was 3 (0-13): 1/25 (4%) pts had a partial response, 11/25 (44%) had stable disease, 12/25 (48%) had progression of disease, and 1/25 (4%) was not evaluable for response. PFS was 2.6 months (95% CI [2.56-5.26]). The median OS was 17.4 months (95% CI [10.3, NA]). A total of 9/25 pts (36%) had dose modification. Of these, 3/9 had at least one dose hold, and all 9 had at least one dose reduction (diarrhea, n = 6). 20/25 participants (80%, 95% CI [59%, 93%]) had grade ≥2 toxicities, and 9/25 pts (36%, 95% CI [18%, 57%]) had grade 3 toxicities that were attributable to treatment: diarrhea (n = 5), abdominal pain (n = 2), and vomiting (n = 2). There were no grade 4 or 5 toxicities. Two pts (8%) were hospitalized due to neratinib toxicity, and two pts went off treatment due to toxicity attributed to neratinib (diarrhea and nausea). There was a trend in the difference in toxicity risk scores by whether a participant had a dose reduction (t-test: p-value = 0.054) with participants with higher risk scores being more likely to require a dose reduction; however, toxicity risk score did not predict number of cycles completed based on linear regression (slope = -1.29, se = 1.44, p = .39). Conclusions: Neratinib is safe in older adults with HER2 positive or HER2 mutated MBC. Clinical trial information: NCT02673398 .
Real-world study of the treatments following trastuzumab-emtansine for HER2-positive metastatic breast cancer: A multicentral cohort study (WJOG12519B).
Authors: Kurozumi Sasagu , Yokoe Takamichi , Nozawa Kazuki , Ozaki Yukinori , Maeda Tetsuyo , Yazaki Shu , Onishi Mai , Fujimoto Akihiro , Nakayama Sayuka , Tsuboguchi Yuko , Iwasa Tsutomu , Sakai Hitomi , Ogata Misato , Terada Mitsuo , Nishimura Meiko , Onoe Takuma , Masuda Jun , Kurikawa Michiko , Shimokawa Mototsugu , Takano Toshimi 
Published: May 2020

e13019 Background: Since trastuzumab emtansine (T-DM1) was established as a standard treatment option, the treatment strategy of metastatic HER2-positive breast cancer has markedly changed. However, clinical evidence regarding the treatments beyond T-DM1 is insufficient. In this study, we attempted to describe real-world selection and efficacy of treatments following T-DM1 for metastatic HER2-positive breast cancer. Methods: This multi-center retrospective cohort study was conducted in 17 hospitals in Japan. Consecutive patients with metastatic HER2-positive breast cancer who had received T-DM1 and started post-T-DM1 treatments between January 2014 and December 2018 were enrolled. Patients treated with investigational drugs were excluded. The primary endpoint was objective response rate (ORR) of post-T-DM1 treatments. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), time to treatment failure (TTF), and overall survival (OS). Results: In this study, 325 patients were eligible, of which 182 (56.0%) cases were estrogen receptor-positive and 61 (18.8%) had brain metastases. T-DM1 had been used as the first to 11th (median third) line treatment for metastatic disease. The types of post-T-DM1 treatment were as follows: 1) chemotherapy concomitant with trastuzumab and pertuzumab (n = 102; 31.4%), 2) chemotherapy concomitant with trastuzumab only (n = 78; 24.0%), 3) lapatinib with capecitabine (n = 63; 19.4%), and 4) others (n = 82; 25.2%). ORR of post-T-DM1 treatments was 22.8% (95% confidence interval [CI]: 18.1 to 28.0) and DCR was 66.6% (95% CI: 60.8 to 72.0), calculated with 290 eligible cases with the target lesion. Median PFS was 6.1 months (95%CI: 5.3 to 6.7), median TTF was 5.1 months (95%CI: 4.4 to 5.6), and median OS was 23.7 months (95%CI: 20.7 to 27.4). Conclusions: This real-world study showed that post-T-DM1 treatments had modest anti-tumor activity. Development of more effective treatments beyond T-DM1 is needed for metastatic HER2-positive breast cancer. Clinical trial information: UMIN000037747 .
Patient-reported pain and pain medication impact in patients with HR+ Her2-neg advanced breast cancer: A U.S. FDA pooled analysis.
Authors: King-Kallimanis Bellinda , Gao Jennifer J , Hodgdon Christine , Bandaru Pradeep , Girvin Andrew , Osgood Christy , Ison Gwynn , Amiri-Kordestani Laleh , Pazdur Richard , Bhatnagar Vishal , Kluetz Paul Gustav , Beaver Julia A. 
Published: May 2020

e13027 Background: Despite the ubiquitous prescribing of pain medications (PMs) in cancer clinical trials, the impact of such prescribing patterns and reporting on the experience of pain is not often investigated. We examined patient-reported pain before initiation of PM reporting and at the next available pain assessment. Our aim was to understand change in patient-reported pain. Methods: We pooled data from 7 phase 3 randomized, controlled, registration trials of CDKI with endocrine therapy in patients with hormone receptor positive, human epidermal growth factor receptor-2 negative MBC. We restricted our analyses to patients who started therapy with no PM reported and looked at patients who had NSAID or opioid medication documented. We calculated change between 2 assessments in patient-reported pain before and after PM using the pain occurrence item (Q9) on the EORTC Quality of Life questionnaire (QLQ-C30). Results: Of the 4200 patients who received at least 1 dose of CDKI/placebo, 1488 started with no documented PM, with 48% reporting none at all when asked about pain at baseline. Subsequently, 185 patients had documented NSAID and 43 an opioid and had a pain PRO assessment before and after. NSAIDs documentation occurred on average 11 weeks into trial and opioids 5. Before documentation of NSAIDs, 45% of patients reported no pain compared to 23% of patients with an opioid. Patients who had documented NSAIDs, 29% experienced an improvement in their self-reported pain, whereas 32% of patients with documented opioids improved. On average the time between the 2 pain assessments was around 58 days for both PMs. Conclusions: In this analysis in patients who had a pain assessment before and after documentation of a PM, there is a small group whose pain improved. It is important to note that patients’ response to the pain item was not provided to the clinical care team, which may explain why there may have been suboptimal pain control. Further study is needed to examine how pain management can be achieved in patients with advanced breast cancer. Future analysis should be performed with patients whose PRO pain results are communicated with the clinical care team in real-time. [Table: see text]
CDK 4/6 drug target activation mapping of HR+/HER2- metastatic breast cancer for treatment selection and response prediction.
Authors: Abu-Khalaf Maysa M. , Hatzis Christos , Hodge K. Alex , Valdes Frances , Sikov William M. , Mita Monica M. , Denduluri Neelima , Awerkamp Kris , Murphy Rita , Zelterman Daniel , Dunetz Bryant , Petricoin Emanuel , Pierobon Mariaelena 
Published: May 2020

e13029 Background: Despite the fact that a number of CDK 4/6 inhibitors have become FDA approved as the main frontline therapy for HR+/HER2- metastatic breast cancer (MBC), there are no validated predictive markers of response to this class of drugs. Additionally, approximately 30-40% of patients (pts) have little to no response to these agents, with disease progression occurring in weeks to a few months after therapy initiation. We have initiated a clinical trial (NCT03195192) to utilize cutting edge proteomic technologies to map the functional activation of the signaling architecture of tumors taken from HR+/HER2- MBC pts at diagnosis. We plan to correlate these functional phosphoprotein-based signaling patterns with PFS intervals to identify candidate markers associated with response to CDK 4/6 inhibitor therapy. Methods: Pre-treatment diagnostic FFPE biopsy material from 26 individuals enrolled on study were analyzed by an LCM- reverse phase protein array workflow. Quantitative measurements of a focused set of 8 qualifying (pre-hypothesized) protein/phosphoprotein CDK 4/6 kinase pathway biomarkers, total Rb, Rb (S780), total Cyclin D1, Cyclin D1 (S286), total pI6INK, total p27, p27 (T187), FoxM1 (T600) were measured. Results: Baseline tumor tissue was successfully analyzed for 26 pts, 17 (65%) White, 8 (31%) African American, and 1 (4%) Asian; average age 62 (range 36-79); 4 pts (15%) had prior endocrine therapy and 4 (15 %) had chemotherapy in the adjuvant setting. Seven pts remain on study treatment. Unsupervised analysis revealed substantial concordance between a number of the total-phosphoprotein paired biomarkers, with 8/26 (31%) patients having relatively low activation/expression pattern (within the bottom quartile of the data range of the 8 markers) and 6/26 (23%) having relatively high activation/expression pattern within the top quartile of the data range of the 8 markers). Conclusions: Functional CDK 4/6 drug target pathway mapping analysis is possible from the pre-treatment diagnostic FFPE material and revealed sub-populations of patients who had systematically low and high levels of CDK 4/6 kinase substrate proteins and phosphoproteins that indicate overall drug target activity. Correlations of those patterns with PFS outcome data is ongoing with final analysis planned for Summer 2020. Clinical trial information: NCT03195192 .
Metastatic-free intervals and risk of breast cancer-specific mortality among patients with hormone receptor-positive breast cancer: A population-based analysis from the Surveillance, Epidemiology, and End Results registries.
Authors: Calip Gregory Sampang , Law Ernest H , Hubbard Colin , Nabulsi Nadia Azmi , Asfaw Alemseged Ayele , Lee Inyoung , Zhou Jifang , Cueto Jenilee , Mitra Debanjali 
Published: May 2020

e13034 Background: Patients successfully treated for hormone receptor (HR)-positive early breast cancer remain at risk of recurrence and metastatic disease even after extended periods of disease-free years. Whether prolonged metastatic-free intervals ultimately confer a benefit to breast cancer-specific survival is not well understood. This study aimed to investigate metastatic-free intervals and risk of breast cancer-specific mortality among patients with HR-positive breast cancer after adjuvant therapy. Methods: We conducted a retrospective cohort study of women aged 18 years and older diagnosed with recurrent metastatic HR-positive breast cancer between 1990 and 2016 in the Surveillance, Epidemiology, and End Results registries. Patients with longitudinal information on primary stage I-III HR-positive breast cancer through the occurrence of metastatic disease and survival were included. Risks of breast cancer-specific mortality associated with metastatic-free intervals (defined as time from primary breast cancer diagnosis to metastasis) of ≥5 years compared to < 5 years were estimated. Fine and Gray competing risks regression models were used to calculate subdistribution hazard ratios (SHR) and 95% confidence intervals (CI). Results: Among 1,057 women with HR-positive breast cancer with a median age of 54 years at primary breast cancer diagnosis and 62 years at metastatic progression, 65% of women had a metastatic-free disease interval ≥5 years, whereas 35% had an interval of < 5 years. Overall, patients with metastatic-free intervals < 5 years had a five-year breast cancer-specific survival rate of 31% compared to 52% in women with intervals of ≥5 years. In multivariable analyses adjusted for age, race, diagnosis year, grade, treatment and sites of metastasis, patients with intervals of ≥5 years had decreased risk of breast cancer-specific mortality (SHR = 0.72, 95% CI 0.58-0.89, P = 0.002) compared to women with metastatic-free intervals of < 5 years. Conclusions: In this population-based study, rates of cancer-specific mortality among patients who experienced metastatic recurrence of HR-positive breast cancer were lower in women with metastatic-free intervals of 5 years or more. The results of this study may inform patient-clinician discussions surrounding prognosis and treatment selection among HR-positive patients.
Integrative assessment of the effect of renal function on ribociclib treatment and dose recommendation in advanced breast cancer patients.
Authors: Ji Yan , Yartsev Vitaly , Wang Yingbo , Quinlan Michelle , Serra Paolo , Samant Tanay , Rodriguez-Lorenc Karen 
Published: May 2020

e13037 Background: Ribociclib is an orally administered CDK4/6 inhibitor used in combination with endocrine therapy (ET) to treat women with hormone receptor-positive (HR+), human epidermal growth factor receptor-2–negative advanced breast cancer (ABC). An integrative assessment was conducted to evaluate the effect of renal function on the pharmacokinetics (PK), efficacy and safety of ribociclib. Methods: To assess the effect of mild and moderate renal impairment, a subgroup analysis was performed to evaluate PK parameters of ribociclib following oral administration of 600 mg QD 3 weeks on/1 week off in two Phase 1/2 and one Phase 3 clinical trials. Steady-state PK exposures in ABC patients at the 600 mg dose was estimated by a population PK model developed based on a pooled dataset from five Phase 1 to 3 trials and were compared by renal function. Efficacy and safety were also analyzed by renal function in a Phase 2 and three Phase 3 trials in ABC patients. The effect of severe renal impairment on ribociclib PK was assessed in a Phase I study in non-cancer subjects following a single oral 400 mg dose. Results: PK analyses in cancer patients showed that both single-dose and steady-state exposure of ribociclib at the 600 mg dose in patients with mild or moderate renal impairment were comparable to patients with normal renal function. Estimated steady-state PK exposure in patients with mild or moderate renal impairment is also comparable to patients with normal renal function. The primary efficacy results of progression free survival (PFS) and the safety profiles were comparable across renal-function cohorts in ABC patients. In non-cancer subjects administered a single oral dose of 400 mg, ribociclib AUCinf and Cmax increased 2.67- and 2.30-fold in subjects with severe renal impairment, respectively, compared to subjects with normal renal function. Conclusions: PK, efficacy and safety of ribociclib are consistent across patients with normal renal function, mild or moderate renal impairment. Hence, no dose adjustment is required in mild or moderate renal impaired patients. Severe renal impaired patients are recommended to have a reduced dose based on PK data in non-cancer subjects.