bluuebunny/crossref_metadata_2025_split huggingface dataset:
EMRseq: Registry-based outcome analysis on 1,000 patients with BRAF V600–mutated metastatic melanoma in Europe treated with either immune checkpoint or BRAF-/MEK inhibition.
Authors: Weichenthal Michael , Svane Inge Marie , Kandolf Sekulovic Lidija , Mangana Joanna , Mohr Peter , Marquez-Rodas Ivan , Schmidt Henrik , Ziogas Dimitrios C. , Bender Marc , Ellebaek Eva , Urch Kristina , Shalamanova-Deleva Gergana , Gavrilova Iva , Espinosa Enrique , Dummer Reinhard , Rutkowski Piotr , Ascierto Paolo Antonio , Gogas Helen , Schadendorf Dirk , Bastholt Lars ,   EUMelaReg Consortium
Published: June 2022

9540 Background: In BRAF mutated metastatic melanoma, potential outcome differences for different choices of 1st line treatments including immunotherapy or BRAF-/MEK inhibition are not completely understood. We therefore analyzed the treatment patterns and outcome of systemic therapies for patients BRAF mutated metastatic melanoma. Methods: From the EUMelaReg treatment registry, patients fulfilling the following inclusion criteria were consecutively included until a number of 1,000 evaluable cases was reached. 1) Patients with metastatic melanoma and BRAF V600 mutation 2) First line treatment with either combined BRAF-/MEK or immune checkpoint inhibition (ICI) with PD-1 single agent or combined PD-1/CTLA-4 antibodies. Multivariable cox regression analysis as well as propensity score based weighting were used to control for bias from baseline imbalances. Primary outcomes of interest were overall survival (OS) and 2nd line PFS (PFS-2), stratified for upfront treatment decision of ICI versus targeted therapy. PFS-2 was defined as the interval from start of first line treatment to a progression after a 2nd line treatment or death of any cause. Further endpoints were evaluated including time on treatment (ToT), time to next treatment and 2nd line treatments. Results: In total 529 (52.9 %) patients received BRAF/MEK-i, and 471 (47.1%) ICI. For various co-variates there were significant imbalances between strata, including number of metastatic sites, AJCC substage, serum LDH, and ECOG performance status, with more favorable prognostic variables for patients receiving immunotherapy. The ORR for BRAF/MEK-i was significantly higher than for ICI (53.3% vs. 42.0%; p=0.0004), but for OS and PFS2 the adjusted hazard ratios were significantly in favor for ICI (HR 0.62 and 0.66, respectively; p <0.0001). In 2nd line, patients switching from ICI to BRAF/MEK-i had again markedly higher ORR than patients switching vice versa (57.7% vs. 19.9%; P<0.0001), and also significantly longer unadjusted PFS (8.1 vs. 3.1 months; p <0.0001) and OS (15.7 vs. 10.6 mths; p=0.01) after start of 2nd line treatment. Conclusions: The two cohorts had imbalances on key prognosis variables. After adjustment for these imbalances, upfront ICI still resulted in significantly longer OS as compared to BRAF/MEK-i. Due to the nature of real-world observational data causing inherent imbalances in the treatments cohorts and being unable to account for potential unknown confounders, outcome may still be biased despite adjustment efforts.[Table: see text]
Preferences for adjuvant immunotherapy in patients with resected stage III melanoma: A discrete choice experiment.
Authors: Livingstone Ann , Menzies Alexander M. , Howard Kirsten , Stockler Martin R. , Morton Rachael L. 
Published: June 2022

9558 Background: Adjuvant immunotherapy has revolutionized the management of resectable melanoma, substantially reducing the risk of recurrence but at the risk of immune-related adverse events (AE). This study aimed to quantify patients' preferences for adjuvant immunotherapy, the influence of varying levels of key attributes, and baseline characteristics associated with preferences. Methods: We performed a discrete choice experiment (DCE), including patients with resected stage III melanoma considering or having received adjuvant immunotherapy. Patients chose between twelve randomly presented choice tasks of two alternative options (adjuvant immunotherapy versus observation without adjuvant immunotherapy). The two options varied across two-three levels of six attributes: chance of 3-year melanoma recurrence, mild, permanent, or fatal AE, drug regimen, and out-of-pocket costs. We calculated the marginal rate of substitution (MRS, how much an individual was willing to trade one attribute for preferred levels of another) and willingness-to-pay (WTP, maximum price to trade their preferred attributes) per year. Results: One hundred and sixteen patients completed the DCE. Patients chose adjuvant immunotherapy over observation without adjuvant immunotherapy in 70% of choice tasks. Patients preferred adjuvant immunotherapy with reduced probabilities of recurrence (OR 0.76, 95% CI 0.70-0.83, p<0.001), fatal AE (OR 0.60, 95% CI 0.44-0.80, p=0.006), permanent AE (OR 0.94, 95% CI 0.89-0.99, p=0.046), and lowered out-of-pocket costs, for those with lower incomes (OR 0.63, 95% CI 0.47-0.85, p=0.003) and higher incomes (OR 0.84, 95% CI 0.15-4.86, p=0.064). Patients accepted an increase in their chance of mild AE from 1% to 37% (OR 2.06, 95% CI 1.13-3.78, p=0.019) in return for adjuvant immunotherapy. Willingness-to-pay was lower for patients with incomes that were lower rather than higher: US$595 (95% CI US-$555 to 1,305) and US$1,638 (95% CI US$ -1,235 to 3,419) per year for adjuvant immunotherapy with an absolute reduction of 1% in the 3-year risk of recurrence. Conclusions: Almost three-quarters of patients preferred adjuvant immunotherapy over observation without adjuvant immunotherapy. Patients were more likely to select immunotherapy if the risk of melanoma recurrence and the chance of fatal AE were reduced. Understanding patient preferences and acceptable trade-offs for adjuvant immunotherapy may allow better-informed decisions for individuals and assist policymakers in decisions about access and subsidization of effective and expensive treatments.
Safety and efficacy of combined melphalan percutaneous hepatic perfusion (M-PHP) and ipilimumab plus nivolumab (IPI+NIVO) in metastasized uveal melanoma (mUM): First results of the phase Ib part of the CHOPIN trial.
Authors: Tong Thaïs M.L. , Burgmans Mark C. , Speetjens Frank M. , van Erkel Arian R. , van der Meer Rutger W. , van Rijswijk Carla S.P. , Jonker Mare A. , Roozen Inge C.F.M. , Lutjeboer Jacob , van Persijn-van Meerten Els L. , Martini Christian H. , Zoethout Remco W.M. , Tijl Fred G.J. , Blank Christian U. , Kapiteijn Ellen 
Published: June 2022

9560 Background: Uveal melanoma (UM) is the most frequent intraocular malignant tumor in adults. Approximately 50% of all patients (pts) will develop metastatic disease in the liver. Until now, there is no systemic therapy that has been shown to improve overall survival (OS), apart from tebentafusp. M-PHP is frequently applied for liver-only UM. However, the majority of pts eventually develops extrahepatic disease after M-PHP. IPI+NIVO has been shown to induce up to 20% response rates in mUM. Our observations that checkpoint inhibition was most effective on extrahepatic UM disease has led to the CHOPIN trial testing the combination of M-PHP and IPI+NIVO. Here we present the safety and efficacy data of the phase 1b part of CHOPIN. Methods: Adult pts with confirmed measurable hepatic mUM and WHO PS 0-1 were included. Two courses of 6 weekly M-PHPs (melphalan 3mg/kg, max 220mg) were combined with four courses IPI+NIVO three-weekly escalating the dosing from 1mg/kg each IPI+NIVO (cohort 1) to IPI 1mg/kg + NIVO 3mg/kg (cohort 2). Primary endpoint was safety of IPI+NIVO plus M-PHP. Secondary endpoints were best overall response (BOR) according to RECIST 1.1, progression-free survival (PFS), and OS. Results: 7 pts were included (4 male, median age 63.6 years (range 50-74)). Both cohorts were tolerated with no dose-limiting toxicities or deaths. Grade III/IV adverse events (AE) were observed in 2/3 pts in cohort 1 and in 3/4 pts in cohort 2 consisting of SIRS, febrile neutropenia, cholecystitis, neutropenia, thrombopenia, leukopenia, increased transaminases and fever. Grade I/II immune-related AEs occurred in all pts (myositis, hypothyroidism, hepatitis and dermatitis). BOR was 1 complete response, 5 partial responses and 1 stable disease accounting for an objective response rate (ORR) of 85.7%. At a median FU time of 20.2 months, 4 pts have an ongoing response. Currently the median PFS is 22.4 months, and all pts are still alive. Conclusions: Combining M-PHP with IPI+NIVO is safe at a dosing of IPI 1 mg/kg and NIVO 3 mg/kg and very promising ORR, PFS and OS have been observed. The randomized phase II part comparing M-PHP versus M-PHP+IPI+NIVO is currently recruiting. Clinical trial information: NCT04283890.
Plasma methylated DNA markers of cutaneous melanoma: Association with PET/CT-positive disease.
Authors: Meves Alexander , Taylor William R. , Berger Calise K. , Mahoney Douglas W. , Burger Kelli , Quattrocchi Enrica , Doering Karen A. , Gonser Anna M. , Cao Xiaoming , Heilberger Justin , Gysbers Brianna J. , Foote Patrick H. , Katerov Viatcheslav E. , Allawi Hatim T. , Kisiel John B. 
Published: June 2022

9567 Background: Cutaneous melanoma surveillance is important to identify low-volume systemic disease, but imaging is costly and poorly accessible to patients; frequent skin checks lack sensitivity and specificity. We aimed to establish clinical feasibility of a liquid biopsy blood test, which quantifies validated, melanoma-specific, methylated DNA markers (MDMs), previously discovered, and reported by our team, using tissue extracted DNA. Methods: We prospectively collected blood from adult patients with histologically confirmed melanoma metastases and no other internal malignancies (within 5-years) who underwent surveillance by FDG-PET/CT (N = 88). Blood from age- and sex balanced cancer-free controls (N = 100) were compared. From PET/CT, we extracted the number of organs involved, SUV-max, and largest tumor diameter. Unequivocal metastasis was defined as SUV ≥ 4 and largest diameter > 5 mm. Because PET/CT is inadequate for the screening of brain metastases, we excluded the brain from the analysis. MDMs ( chr11.149, HOXA9, chr20.210, FLJ22536, CLIC5, SIX4, chr7.155, chr17.730, chr1.110) were assayed using target enrichment long-probe quantitative-amplified signal assays, normalized to B3GALT6, in blinded fashion. Using a logistic regression approach and nine candidate MDMs, we calculated the sensitivity for detecting patients with metastasis on PET/CT at 100% specificity. Results: 52/88 (59%) of melanoma patients showed evidence of metastasis on PET/CT at the time of blood draw. At 100% specificity, a panel of 4 MDMs ( HOXA9, chr20.210, chr17.730, chr1.110) yielded a sensitivity of 86.5% (45/52 cases) vs. 100 cancer-free controls. When applying this model to the 36 PET/CT-negative patients, specificity was as high as 97.2% (35/36 cases) while maintaining a sensitivity of 86.5% (one patient with a positive test result had a complete metabolic response to binimetinib / encorafenib prior to negative PET/CT). For patients with ≥ 2 organs involved by metastasis, sensitivity was 100% (29/29 cases). False-negative cases had metastasis in single organs and were characterized by minimal tumor burden and oral corticosteroid use. One false-negative patient had localized stage III disease without known primary melanoma. Conclusions: Plasma MDM levels appear highly concordant with FDG-PET/CT in patients with metastatic cutaneous melanoma. A liquid biopsy approach has potential to lower cost and improve patient access to surveillance. Additional prospective studies in larger intended use cohorts are needed to validate our results.
Utility of adjuvant chemotherapy in early-stage, estrogen receptor-positive breast cancer patients under 50 years with a 21-gene recurrence-score of 16-25: A retrospective analysis using the National Cancer Database.
Authors: Ashok Kumar Prashanth , Wang Dongliang , Huang Danning , Sivapiragasam Abirami 
Published: June 2022

e12501 Background: The TAILORx trial showed that addition of adjuvant chemotherapy (AC) to endocrine therapy (ET) had no advantage in estrogen receptor (ER)+, HER2-, node negative (N0) breast cancer (BC) patients with an intermediate (11-25) 21-gene recurrence-score (RS). However, a subgroup analysis revealed that in women ≤ 50 years, AC had a lower rate of distant recurrence if the RS was 16-25. Using a large national database, we studied the utilization of AC in the aforementioned subset. Methods: The 2004-2018 National Cancer Database BC cohort was used to include female patients of 18-50 years. Inclusion criteria were N0, M0 patients with any T stage, RS 16-25, ER+/PR± and HER2-. Patients who received neoadjuvant chemotherapy were excluded. Logistic regression was used to evaluate AC utility trends. Kaplan-Meier (KM) and multivariate (MV) propensity score (PS) weighted Cox model were used to compare survival between patients without and with AC use. Results: Of the 15,792 patients, 4808 (30.45%) received AC. Median RS was 18 and 21 in patients without and with AC. Factors associated with AC use were higher T stage, poor and moderately differentiated tumors, age <40, care at an academic center, Caucasian race, patients undergoing mastectomy, regional lymph node (RLN) surgery, ET and Radiation Therapy (RT). KM survival at 10 years was better with AC [96.2% vs 91.6%]. Patients without AC had worse survival [Hazard Ratio (HR)=1.683, 95% Confidence Interval (CI): 1.392-2.036, p<0.0001] (Table). Conclusions: In this analysis,AC use had a 5% improvement in 10 year overall survival, in contrast to TAILORx trial which only showed a disease free survival benefit. Whether the benefit was due to direct cytotoxicity or ovarian function suppression effect of AC remains to be seen. In clinical practice, AC use is determined based on patient and tumor characteristics. Limitations of our study include non-population-based data and the possibility of cofounding despite the use of PS matching. [Table: see text]
Baseline GP2 immune response as an independent prognostic factor in a phase IIb study evaluating HER2/neu peptide GP2 (GLSI-100) versus. GM-CSF alone after adjuvant trastuzumab in HER2-positive women with breast cancer.
Authors: Patel Snehal , McWilliams David , Thompson Jaye , Patel Mira , Daugherty F. Joseph 
Published: June 2022

e12519 Background: Delayed type hypersensitivity (DTH) skin tests to GP2 were conducted in the randomized, active-controlled, single-blinded, multicenter Phase IIb trial investigating GLSI-100 (GP2+GM-CSF) administered in the adjuvant setting to node-positive and high-risk node-negative breast cancer patients with tumors expressing HER2. Previously it has been reported that subjects with baseline response to GP2 by DTH were more likely to experience a recurrence sooner than those without a positive baseline response. It was of interest to determine if this response was independent of other known prognostic factors. Methods: Patients were randomized and received GLSI-100 (500 mcg GP2: 125 mcg GM-CSF) or control (GM-CSF only) via 6 intradermal injections every 3-4 weeks as part of the Primary Immunization Series (PIS) for 6 months and 4 booster injections every 6 months thereafter. GP2 DTH skin tests were placed at baseline and after the 6th dose. After 48-72 hours, the largest perpendicular diameters of induration were measured and the orthogonal mean was calculated. Induration of over 5mm was considered a positive response. The relationship between prognostic factors such as demographic and disease characteristics and the baseline DTH response were investigated by logistic regression. Results: The study enrolled 180 patients who were HER2 3+ positive and low HER2 expressors (1-2+). After 5 years of follow-up, the Kaplan-Meier estimated 5-year DFS rate in the 46 HER2 3+ patients treated with GLSI-100, if completing the PIS, was 100% versus 89.4% (95% CI:76.2, 95.5%) in the 50 patients treated with GM-CSF (p = 0.0338). Just under 23% of subjects experienced an immune response to GP2 by DTH at baseline. The incidence was similar in patients who were HER2/neu positive and those considered low expressors and was equally distributed across GLSI-100 and placebo-treated subjects. Known prognostic factors such as hormone receptor status, stage at presentation, node status, etc. were evenly distributed across subjects that experienced a baseline DTH response to GP2 and those who did not. Each prognostic factor was investigated in a logistic model to determine if it predicted baseline DTH immune status. The prognostic factors did not predict baseline DTH immune response in the logistic models. There appears to be no correlation between baseline immune response to GP2 and known prognostic factors. Conclusions: Baseline GP2 immune response as measured by the delayed-type hypersensitivity test may be an independent prognostic factor for recurrence. Knowledge of this GP2 immune response may identify a patient with increased risk of rapid recurrence. Clinical trial information: 00524277.
Adjuvant trastuzumab and vinorelbine (TV) for early-stage HER2+ breast cancer.
Authors: McLaughlin Shannon , Nakajima Erika , Isakoff Steven J. , Shin Jennifer , Moy Beverly , Bardia Aditya , Kuter Irene , Spring Laura 
Published: June 2022

e12521 Background: The anti-HER2 antibody trastuzumab has vastly improved outcomes for women with early stage and advanced HER2+ breast cancer (BC) when used in combination with chemotherapy. Anthracycline and taxane-based regimens have historically made up the chemotherapy backbone for patients with localized HER2+ BC, though recent evidence suggests anthracyclines can be safely omitted. The single arm phase II APT trial established trastuzumab and paclitaxel as the standard adjuvant regimen for small HER2+ tumors. However, paclitaxel requires weekly treatment, causes alopecia, and has high rates of neuropathy and hypersensitivity reactions. In patients with metastatic HER2+ BC, the combination of trastuzumab and vinorelbine (TV) is effective and well tolerated. There is a need for alternative regimens for patients with HER2+ early-stage BC, especially for those with contraindications to anthracycline and taxane-based regimens. We conducted a retrospective study of patients with early stage HER2+ BC treated with adjuvant TV to evaluate a non-anthracycline/taxane-based, alopecia-sparing regimen. Methods: Clinicopathological characteristics, treatment details, and outcomes of patients with localized HER2+ BC treated with adjuvant TV for from 2007 to 2021 at a large academic medical institution were collected. Study endpoints included invasive disease-free survival (IDFS), overall survival (OS), and safety/tolerability. IDFS and OS were measured from start date of TV treatment to date of event or last follow-up, respectively. 5-year survival rates were generated in GraphPad Prism. Results: A total of 25 patients were treated with TV. All patients received trastuzumab at standard dosing and vinorelbine at a starting dose of 25 mg/m2 on days 1/8 of a 21-day cycle with 4 planned cycles. Median age at diagnosis was 61 years (range: 36-81). 88% of patients had anatomic pathologic Stage IA BC and 12% Stage IIA BC. Of the 25 patients, 24 of them opted to pursue TV due to concerns over alopecia, neuropathy, and other toxicities while 1 patient had received prior adriamycin and therefore opted for TV. With a median follow-up time of 68 months (5.7 years), the 5-year rate of survival from invasive disease was 90.9%, with 1 local and 1 distant recurrence. The 5-year overall survival was 100%. 76% of patients completed 4 cycles of TV without dose holds or delays and 92% completed 4 cycles without dose reductions. 2 patients required hospitalization during treatment with TV due to toxicity (diarrhea attributed to V, rigors/fever attributed to T). No patients experienced alopecia or long-term neuropathy. Conclusions: Trastuzumab in combination with vinorelbine in the adjuvant, early-stage setting for HER2+ BC is effective and well-tolerated and warrants further exploration as an alternative to taxane-based regimen.
Impacts of subtypes on clinical feature and outcome of male breast cancer.
Authors: Lee Jieun , Lee Keun Seok , Sohn Joohyuk , Lee Kyung-Hee , Jung Kyung Hae , Byun Jae Ho , Koh Su-Jin , Lee Kyoung Eun , Lim Seungtaek , Kim Hee Jun , Won Hye Sung , Park Hyung Soon , Lee Guk Jin , Hong Soojung , Baek Sun Kyung , Lee Soon Il , Choi Moon Young , Woo In Sook 
Published: June 2022

e12528 Background: The treatment of male breast cancer (MBC) has been extrapolated from female breast cancer (FBC) because of its rarity despite their different clinicopathologic characteristics. We aimed to investigate the distribution of intrinsic subtypes based on immunohistochemistry (IHC), their clinical impact, and treatment pattern in clinical practice through a multicenter study in Korea. Methods: We retrospectively analyzed clinical data of 248 MBC patients 18 institutions across the country from January 1995 to July 2016. Results: The median age of MBC patients was 63 years (range: 25–102 years). Among the 148 patients that underwent intrinsic subtype classification, 61 (41.2%), 44 (29.7%), 29 (19.5%), and 14 (9.5%) were luminal A, luminal B, HER2, and triple-negative breast cancer (TNBC), respectively. TNBC patients showed inferior survival compared with those with other subtypes. Of the 221 patients with operable breast cancer, 108 (48.6%) received adjuvant chemotherapy and 52 (23.5%) received adjuvant radiation therapy. Most hormone receptor-positive patients (166 patients, 82.6%) received adjuvant endocrine treatment. Five-year completion of adjuvant endocrine treatment was associated with superior disease-free survival (DFS) in patients classified with an intrinsic subtype (hazard ratio [HR] = 0.19, 95% confidence interval [CI] 0.005–0.65, P = 0.008) and in all patients (HR = 0.16, 95% CI 0.05–0.54, P = 0.003). Conclusions: Distribution of subtypes of MBC was similar to FBC and luminal type A was most common. Overall survival tended to be improved for luminal A subtype although there was no statistical significance. Completion of adjuvant endocrine treatment was associated with prolonged DFS in intrinsic subtype classified patients. MBC patients have tended to receive les treatment. MBC patients should be treated with standard guideline as FBC patients receive.