tbuckley/cabot-search huggingface dataset:
Practice patterns of platinum chemotherapy use in a population-based cohort of women with nonmetastatic triple-negative breast cancer.
Authors: Tess King, Catherine R. Fedorenko, Li Li, Rachel Lynn Yung
Journal: Journal of Clinical Oncology (2021)

e18590 Background: The use of platinum agents (PT) in neoadjuvant chemotherapy (CTX) for triple negative breast cancer (TNBC) has been debated in research and practice guidelines. In high risk patients, the addition of PT to standard anthracycline and taxane regimens improves pathological complete response without definitive evidence of survival benefit (Korde JCO 2021). Due to PT’s toxicities and unclear benefit in early stage breast cancer, this study aimed to elucidate the real world practice patterns of PT use and overuse in breast cancer patients. Methods: The cohort was defined as women with stage I-III TNBC (ER, PR, and Her2 negative) who received curative intent surgery between 2011-2018. We utilized the Hutchinson Institute for Cancer Outcomes Research (HICOR) database, which links enrollment and claims records from commercial and public health insurance plans with clinical information from Washington state cancer registries (Manohar JACR 2020). We hypothesized there was overuse of PT CTX in this cohort. Overuse was defined as PT use in stage I, in the adjuvant period (NCCN 2020), and in nonstandard CTX regimens (PT use without taxane and anthracycline (NCCN 2020)). Results: Of the 910 women in the cohort, average age was 63, 90% were white, 682 (75%) received CTX, and 36% had commercial insurance, versus 53% with public insurance (Medicare 45%, Medicaid 8%). Of those receiving CTX, 39% received neoadjuvant and 67% adjuvant. Of those receiving CTX, 85 (13%) received PT, and 28 (4%) received PT without anthracycline. Of those receiving PT, 20% had stage I disease, and of those receiving adjuvant CTX, 43 (9%) received PT in the adjuvant period. Conclusions: We found there was overuse and nonstandard use of PT in this real world data. This overuse was demonstrated by the fact that 20% of women receiving PT had low risk stage I disease, and 9% of women receiving adjuvant CTX received PT in the adjuvant period. Additionally, there was nonstandard use, with 4% of women getting CTX receiving PT without anthracycline. Next steps in this research are to evaluate factors influencing overuse and nonstandard use, as well as complication rates with PT use and overuse.[Table: see text]
Identification of factors related to immunotherapy prognosis in patients with advanced head and neck squamous cell carcinoma.
Authors: Lin Zhang, Xuanli Xu, Dandan Ren, Lijia Wu, Xiaoli Gong, Rongrong Li, Guopei Zhu
Journal: Journal of Clinical Oncology (2021)

e18003 Background: Head and neck squamous cell carcinoma (HNSCC) is often diagnosed at an advanced stage and has a dismal prognosis. Anti-PD1/PD-L1 checkpoint inhibitors have shown survival benefit for the treatment on HNSCC, and are better tolerated than chemotherapy. Unfortunately, the response rate of immunotherapy is low for advanced HNSCC. Therefore, the identification of predictive biomarkers of response to anti-PD1/PD-L1 is a key point for better selecting patients that would benefit from immunotherapy. Methods: The present study included 44 patients with advanced HNSCC who received anti-PD-1 immunotherapy. Follow-up was available for them. Primary tumor tissues and matched blood samples were collected. Genome profiles were analyzed using a designed 543-gene panel based on NGS, and were available on 39 of 44 patients. Profiles of infiltrating immune cells were available for 44 patients. The infiltrating intensity of PD-1, PD-L1, CD8, CD68 and CD57 positive cells were assessed by multiplex immunohistochemistry. Results: The most frequently mutated genes were TP53 (79%), CDKN2A (33%), NOTCH1 (21%), CASP8 (13%) and PIK3CA (10%). Patients with mutations in the PI3K pathway showed a trend of longer OS (P = 0.06). Moreover, the TMB-high group showed significant superior OS than the TMB-low group (p = 0.0018). PD-L1 expression was positively correlated with CD8 expression within stroma, and PD-1 expression correlated significantly with PD-L1 and CD8 expression within both tumor and stroma areas. In addition, tumor/stromal PD-L1 and PD-1 expression were both associated with better OS (P &lt; 0.05). Prolonged OS was also observed in patients with more tumor and stromal infiltration of CD8 + cells, CD8 + PD-L1 + cells, CD68 + macrophages, or nature killer (NK, CD57 + ) cells. Conclusions: Higher TMB, PD-L1 expression, as well as the infiltration of immune cells within both tumor and stromal area might serve as favorable prognostic markers in advanced HNSCC patients treated with anti-PD-1 immunotherapy.
Bone-targeted therapy in patients with renal cell carcinoma bone metastases undergoing palliative surgery.
Authors: Benjamin Garmezy, Ava Brozovich, Lei Feng, Lorenzo Deveza, Robert L. Satcher
Journal: Journal of Clinical Oncology (2021)

e16572 Background: RCC bone metastases (RCCBM) are found in 20-39% of patients and are becoming more prevalent. RCCBM cause significant morbidity and often require surgical intervention. Current bone-targeted therapies include bisphosphonates and denosumab. Previous literature has suggested that bisphosphonates do not improve survival or reduce skeletal related events and little has been published about the effect of denosumab. Here we present experience describing outcomes and therapeutic effect in patients with RCCBM following palliative surgery for bone metastasis. Methods: We performed a retrospective analysis of 226 patients with RCCBM who underwent orthopedic surgery at MD Anderson Cancer Center between 11/2005 – 8/2019. The Kaplan-Meier method and log-rank test were used to estimate and evaluate survival differences. Results: Patient characteristics included: median age 58.2, male 66.4%, clear cell histology 93.5%, metastatic at presentation 57.9%, nephrectomy 79.8% (63.9% prior to orthopedic intervention), received radiation to the surgical site (pre-op: 13.0%, post-op: 41.4%). First orthopedic intervention: resection arthroplasty 37.2%, curettage and intramedullary nailing (IMN) 18.6%, IMN 16.4%, open reduction internal fixation 15.0%, amputation 2.7%, 10.2% other. Pre-op therapy: bisphosphonate 12.4%, denosumab 5.8%, both 2.7%, none 79.2%. Post-op therapy: bisphosphonate 18.1%, denosumab 13.7%, both 0.9%, none 67.2%. With a median follow up of 3.1 years after first orthopedic intervention, median overall survival (OS) was 2.7 yr (95% CI 2.1 – 3.6). Progression free survival (PFS) was calculated from time of first surgery to either first progression or death; median PFS was 5.2 months (95% CI 4.6 – 7.5). Pre-op or post-op bone-targeted therapy was not significantly associated with PFS (yes vs no: Pre-op: median 3.4 vs 6.3 mth, p=0.42; Post-op: median 4.3 vs 5.8 mth, p=0.61) or OS (Pre-op: 2.1 vs 2.9 yr, p=0.45; Post-op: 2.4 vs 3.2 yr, p=0.18). Post-op denosumab compared to bisphosphonate was associated with increased PFS (9.6 vs 3.8 mth, p=0.03) and OS (3.3 vs 1.6 yr, p=0.02). However, post-op denosumab vs no bone-targeted therapy was not significantly associated with increased PFS (9.6 vs 5.8 mth, p=0.42) or OS (3.3 vs 3.2 yr, p=0.85). Of note, post-op bisphosphonate vs no bone-targeted therapy was associated with reduced PFS (3.8 vs 5.8 mth, p=0.04) and OS (1.6 vs 3.2 yr, p=0.01). Conclusion: Addition of bone-targeted therapy did not significantly improve PFS or OS in patients with RCCBM undergoing orthopedic intervention. Post-op denosumab was associated with better PFS and OS compared to bisphosphonates and bisphosphonates were associated with worse PFS and OS compared to no bone-targeted therapy. Patient selection for therapy may be an important source of bias. Prospective research is needed to clarify the role and selection of bone-targeted therapy in RCCBM patients.
Treatment for Relapsed/Refractory Acute Myeloid Leukemia
Authors: Felicitas Thol, Michael Heuser
Journal: HemaSphere (2021)

Patients with relapsed or refractory (r/r) acute myeloid leukemia (AML) have a poor prognosis and treatment remains challenging. For the majority of r/r patients, allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment approach. Salvage therapy is given in order to reduce the leukemia load prior to transplantation. Patients achieving complete remission prior to allogeneic HSCT have a more favorable outcome. Intensive salvage regimens commonly consist of an anthracycline and high-dose cytarabine backbone. Donor lymphocyte infusions have shown efficacy in patients relapsing after allogeneic HSCT. For patients who cannot be intensively treated (eg, elderly AML patients), outcome is generally very poor and combinations with novel agents are currently under investigation. Mutational analysis should be repeated at the time of relapse to identify aberrations that can be targeted with new agents. For r/r AML patients with mutated fms-related tyrosine kinase 3 ( FLT3 ), gilteritinib has shown superior results to intensive salvage regimens. The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) approved gilteritinib for FLT3 mutated r/r AML patients. Ivosidenib and enasidenib, inhibitors for mutated isocitrate dehydrogenase ( IDH ) 1 and 2, respectively, have received approval for IDH1 / IDH2 mutated r/r AML by the FDA (not EMA). APR-246 restores the function of mutated TP53 and early study results are promising. Other agents targeting CD47, menin, neural-precursor-cell-expressed developmentally down-regulated 8, as well as bispecific antibodies or chimeric antigen receptor T cells are under investigation. Further trials are needed to understand how to best combine novel agents with each other or with chemotherapy.
The effect of non-oncology drugs on clinical and genomic risk in early luminal breast cancer.
Authors: Barliz Waissengrin, Ido Wolf, Tamar Zahavi, Mali Salmon‐Divon, Amir Sonnenblick
Journal: Journal of Clinical Oncology (2021)

e12505 Background: In women with ER-positive, HER2-negative early stage breast cancer (BC), treatment decisions for adjuvant chemotherapy are based on genomic risk and clinical risk. Recently, an effect of non-oncology medications on cancer cell lines and cancer outcome have been suggested. In this study we aimed to systematically examine the impact of non- oncology drugs on clinical risk and genomic risk (based on OncotypeDx recurrence score [RS]) in early BC. Methods: We collected data from 1385 files of ER positive HER2 negative breast cancer patients regarding their clinical risk (stage and grade), genomic risk (OncotypeDx RS) as well as data regarding medications the patients received during the month before their surgery. Statistical analysis was applied to identify the influence of various medications on OncotypeDx RS. Results: Out of the various medications we examined, we found that Levothyroxine was significantly associated with high median OncotypeDx RS (RS median = 25 ;p &lt; 0.0001) and Metformin was associated with low median OncotypeDx RS (RS median = 12 p &lt; 0.0011) in comparison to patients not receiving these medications (RS median = 17). By contrast there were no differences in the clinical risk between patients who received Metformin or Levothyroxine. Notably, Levothyroxine and metformin did not impact proliferation marker (Ki67) levels but did impact progesterone-related features, suggesting they influence genomic risk through estrogen dependent modules. Indeed, scores of other genomic tests (PAM50, Mammaprint), which are determined largely by proliferative features, were not influenced by Levothyroxine or Metformin. Finally, by using contemporary guidelines to recommend adjuvant chemotherapy based on clinical risk and genomic risk (OncotypeDx ) we show that patients (Age &gt; 50) who received Metformin treatment had 14.5% chance to be recommended adjuvant chemotherapy while patients who received Levothyroxine had 49% (p = 0.0001). Conclusions: The results of this study indicate significant impact of Metformin and Levothyroxine on clinical decisions with potential impact on early BC patients.
The role of DKK-1 In prostate cancer bone metastases
Authors: Zhi G. Li, Funda Vakar-Lopez, Christopher J. Logothetis, Gerard Karsenty, Sue-Hwa Lin, Patricia Ducy, Nora M. Navone
Journal: Cancer Research (2005)

2913  Prostate cancer (PCa) has a tendency to metastasize nearly exclusively to bone, where induces new bone formation. Secreted Wnt proteins are one of the major families of cell signaling molecules that play important roles in tumor formation and various aspects of skeletal development. The signal-transducing components of the Wnt receptor are members of the low-density lipoprotein receptor-related protein (LRP) and Frizzled protein families. Activation of the canonical Wnt signaling pathway after Wnt proteins bind to its receptors results in translocation of β-catenin to the nucleus, where it heterodimerizes with transcription factors of the lymphoid enhancer-binding factor/T cell factor (Lef/Tcf) family. These heterodimers in turn bind to DNA and activate the expression of specific genes. We compared gene expression between two bone-derived PCa cells lines, PC3 (which is osteolytic) and MDA PCa 2b (which is osteoblastic), and found that both cell lines expressed Wnt proteins; PC3 cells expressed 100-fold more Dickkopf-1 (DKK-1), a Wnt inhibitor, whereas MDA PCa 2b cells expressed more β-catenin and Lef1. RT-PCR and Western blot analysis of DKK-1 in conditioned medium obtained from normal prostatic epithelial cells and the bone-derived PCa cell lines MDA PCa 2a, MDA PCa 2b, and PC3 showed that DKK-1 was expressed in the normal cells and the PC3 cells but not in the MDA PCa 2a or MDA PCa 2b cells. Searching for the expression of Wnt ligands in PCa cells, we found that Wnt7b was expressed in all of the prostate cell lines but not in normal cells. Next, in investigating whether PCa cells activate canonical Wnt signaling in osteoblasts, we found that conditioned medium derived from MDA PCa 2b cells could induce proliferation and activate the Wnt-responsive TOP-FLASH reporter in osteoblasts and that these affects were suppressed in the presence of DKK-1. Conditioned medium derived from PC3 cells was unable to activate the Wnt- responsive TOP-FLASH reporter in osteoblasts. These results suggest that PCa cells activate autocrine and paracrine canonical Wnt signaling pathways, resulting in activation of this pathway in neighboring osteoblasts and induction of osteoblast growth and differentiation. Collectively, these findings suggest that PCa cells can signal to osteoblasts via the canonical Wnt signaling pathway; moreover, inhibition of this signaling pathway may account for prostate metastases that do not display an osteoblastic phenotype.
Survival outcomes associated with fewer combination ipilimumab/nivolumab doses in advanced-stage melanoma.
Authors: Vincent T Ma, Yilun Sun, Merna Sitto, Jessica Waninger, Leslie Anne Fecher, Michael Green, Christopher D. Lao
Journal: Journal of Clinical Oncology (2021)

9549 Background: Standard combination ipilimumab/nivolumab (I/N) is given as 4 induction doses for advanced stage melanoma. While many patients receive less than 4 doses due to treatment-related toxicities, it is unclear if fewer doses of I/N may still provide long term clinical benefit. Our aim is to determine if response assessment after 1 or 2 doses of I/N can predict long-term survival and if fewer doses of I/N can achieve similar survival outcomes. Methods: We performed a single-center, retrospective analysis on a cohort of patients with metastatic or unresectable melanoma from 2012 to 2020 who were treated with standard I/N. Cox regression of progression free survival (PFS) and overall survival (OS) models were performed to assess the relationship between response assessment after 1 or 2 doses of I/N and risk of progression and/or death. Clinical benefit response (CBR) was assessed, defined as SD (stable disease) + PR (partial response) + CR (complete response) by imaging or physical examination. Among patients who achieved a CBR after 1 or 2 doses of I/N, a multivariable Cox regression of survival was used to compare 3 or 4 vs 1 or 2 doses of I/N adjusted by age, gender, pre-treatment LDH level, BRAF mutation status, primary melanoma site, time to initial assessment, brain metastasis, and liver metastasis. Results: 199 patients were identified and considered evaluable in our study. Median follow up was 28.8 months. Patients with CBR after 1 dose of I/N had improved PFS (HR: 0.23, 95% CI 0.14-0.39; p&lt;0.001) and OS (HR: 0.19, 95% CI 0.10-0.38; p&lt;0.001) compared to progressive disease (PD) [Table]. Patients with CBR (vs PD) after 2 doses of I/N also had improved PFS (HR: 0.17, 95% CI 0.11-0.26; p&lt;0.001) and OS (HR: 0.13, 95% CI 0.07-0.23; p&lt;0.001) [Table]. The survival risk comparing 3 or 4 vs 1 or 2 doses of I/N were HR 0.82 (95% CI 0.45-1.53; p=0.540) for PFS and HR 0.56 (95% CI 0.24-1.30; p=0.175) for OS. Conclusions: Clinical benefit response (CBR) after 1 or 2 doses of I/N may be predictive of long-term survival in advanced stage melanoma. Patients who have CBR after 1 or 2 doses of I/N may achieve a similar survival benefit with fewer doses of I/N. Longer follow up and prospective studies are warranted to validate our findings.[Table: see text]
Progress Toward Rubella Elimination — World Health Organization European Region, 2005–2019
Authors: Patrick O’Connor, Dragon Yankovic, Laura Zimmerman, Myriam Ben Mamou, Susan Reef
Journal: MMWR Morbidity and Mortality Weekly Report (2021)

In 2005, the Regional Committee of the World Health Organization (WHO) European Region (EUR) passed a resolution calling for the regional elimination of measles, rubella, and congenital rubella syndrome (CRS) (1). In 2010, all 53 countries in EUR* reaffirmed their commitment to eliminating measles, rubella, and CRS (2); this goal was included in the European Vaccine Action Plan 2015-2020 (3,4). Rubella, which typically manifests as a mild febrile rash illness, is the leading vaccine-preventable cause of birth defects. Rubella infection during pregnancy can result in miscarriage, fetal death, or a constellation of malformations known as CRS, which usually includes one or more visual, auditory, or cardiac defects (5). The WHO-recommended measles and rubella elimination strategies in EUR include 1) achieving and maintaining ≥95% coverage with 2 doses of measles- and rubella-containing vaccine (MRCV) through routine immunization services; 2) providing measles and rubella vaccination opportunities, including supplementary immunization activities (SIAs), to populations susceptible to measles or rubella; 3) strengthening surveillance by conducting case investigations and confirming suspected cases and outbreaks with laboratory results; and 4) improving the availability and use of evidence to clearly communicate the benefits and risks of preventing these diseases through vaccination to health professionals and the public (6). This report updates a previous report and describes progress toward rubella and CRS elimination in EUR during 2005-2019 (7). In 2000, estimated coverage with the first dose of a rubella-containing vaccine (RCV1) in EUR was 60%, and 621,039 rubella cases were reported (incidence = 716.9 per 1 million population). During 2005-2019, estimated regional coverage with RCV1 was 93%-95%, and in 2019, 31 (58%) countries achieved ≥95% coverage with the RCV1. During 2005-2019, approximately 38 million persons received an RCV during SIAs in 20 (37%) countries. Rubella incidence declined by >99%, from 234.9 cases per 1 million population (206,359 cases) in 2005 to 0.67 cases per 1 million population (620 cases) by 2019. CRS cases declined by 50%, from 16 cases in 2005 to eight cases in 2019. For rubella and CRS elimination in EUR to be achieved and maintained, measures are needed to strengthen immunization programs by ensuring high coverage with an RCV in every district of each country, offering supplementary rubella vaccination to susceptible adults, maintaining high-quality surveillance for rapid case detection and confirmation, and ensuring effective outbreak preparedness and response.
RC48-ADC combined with toripalimab, an anti-PD-1 monoclonal antibody (Ab), in patients with locally advanced or metastatic urothelial carcinoma (UC): Preliminary results of a phase Ib/II study.
Authors: Li Zhou, Huayan Xu, Xieqiao Yan, Zhihong Chi, Chuanliang Cui, Lu Si, Bixia Tang, Lili Mao, Bin Lian, Xuan Wang, Siming Li, Xue Bai, Jun Guo, Xinan Sheng
Journal: Journal of Clinical Oncology (2021)

4534 Background: RC48-ADC is a novel humanized anti-HER2 antibody-drug conjugate (ADC), which showed promising data in HER2-positive and even negative patients (pts). Anti-PD-1 Abs have durable antitumor effect for mUC especially in PD-L1 positive patients. The combination may have synergistic antitumor effect. This phase 1b/II study evaluated the safety and activity of RC48-ADC combined with toripalimab in mUC. Methods: In dose-escalation cohort, pts received 1.5 or 2 mg/kg RC48-ADC + 3mg/kg toripalimab with the traditional 3+3 escalation design. In expansion cohort, patients received the recommended dose of RC48-ADC + toripalimab every 2 weeks. The primary endpoints were safety/tolerability and recommended RC48-ADC dose; secondary endpoints included pharmacokinetics, ORR per RECIST 1.1, PFS, and OS stratified by HER2 and PD-L1 expression. HER2 positivity was determined by IHC and in situ hybridization (ISH). PD-L1 expression was tested with IHC 22C3 pharmDx assay. Results: As of 8 Jan 2021 (data cutoff), 14 mUC pts (9 males, median age 66 y [52-76]) were enrolled. Most pts were systemic treatment naïve (57%) in the locally advanced or metastatic setting. The primary site was in upper tract UC in 50%; 50% had visceral metastases (mets), including 36% with liver mets; HER2 expression was positive (IHC 3+ or 2+ ISH+) in 28%, and 43% PD-L1 CPS≥10. A total of 36 pts is anticipated to be enrolled by Apr 2021. No dose limiting toxicity was reported and the recommended dose for RC48-ADC was 2mg/kg. At data cutoff, 10/14 patients were evaluable for response, with 8 PR, 1 SD (tumor shrinking), and 1 PD. The objective response rate (ORR) was 80%, and disease control rate (DCR) was 90%. All responsive patients have durable efficacy and are still on treatment. Follow-up continues for PFS and OS. Most common treatment-related AEs were grade 1-2, including aminotransferase level increased (7/14, 50%), weight loss (6/14, 43%), alopecia (6/14, 43%), asthenia (4/14, 29%), anemia (3/14, 21%), leukopenia (21%), peripheral sensory neuropathy (21%), hypothyroidism (21%), blood triglycerides increased (21%), and creatine phosphokinase increase (21%). One pt had G3 intestinal obstruction attributed to study drug and went back to treatment after recovery. Conclusions: RC48-ADC in combination with toripalimab had a good tolerance and promising anti-tumor activity in pts with mUC. Further evaluation of safety and efficacy is ongoing. Clinical trial information: NCT04264936.
Reduction in Intravenous Infusion Duration of Enzyme Replacement Therapy to Ten Minutes with Velaglucerase Alfa in Adult Patients with Type 1 Gaucher Disease
Authors: Ari Zimran, Shoshana Revel-Vilk, Deborah Elstein, Naama Arbel, Michal Becker-Cohen, Gaya Chicco, Jeff Szer
Journal: Blood (2017)