bluuebunny/crossref_metadata_2025_split huggingface dataset:
Disparities in the occurrence of late effects following treatment among adolescent and young adult melanoma survivors.
Authors: Gingrich Alicia , Goldfarb Melanie , Sauder Candice , Li Qian , Wun Theodore , Keegan Theresa 
Published: May 2019

9580 Background: Melanoma is the third most common cancer in the adolescent and young adult (AYA) population and the incidence worldwide is increasing. However, no studies have addressed the occurrence of late effect medical conditions following melanoma treatment in these young survivors. Methods: All patients ages 15-39 diagnosed with cutaneous melanoma from the 1996-2012 and surviving ≥ 2 years were obtained from the California Cancer Registry and linked to statewide hospitalization data. The influence of age at diagnosis, sex, race/ethnicity, neighborhood socioeconomic status (SES), and health insurance on the development of late effects by system was evaluated using multivariable Cox proportional hazards regression models. Results: Of 8,524 patients, 35.6% were male, 83.1% non-Hispanic white, 82.1% had private health insurance, 60.3% were considered high SES, and 70.7% had no documented co-morbidities at diagnosis. After controlling for competing factors, males had an increased risk of developing late effects across all systems, including cardiac [HR:2.13, 95%CI 1.87-2.42], neurologic (HR:2.24, CI 1.92-2.63), lymphedema (HR:2.22, CI 1.89-2.62), bleeding events (HR:2.35, CI 2.00-2.77), major infection/sepsis (HR:2.23, CI 1.95-2.56), and second cancers [HR:1.66, CI 1.47-1.89]. In addition, patients with public or no insurance (vs. private) had a greater risk of developing all studied late effects, including lymphedema (HR:2.48, CI 2.04-3.01), respiratory illness (HR:2.21, CI 1.85-2.64) renal dysfunction (HR:2.31, CI 1.90-2.81), and subsequent cancers (HR:1.82, CI 1.54-2.16). AYA patients residing in low SES neighborhoods had a similar increased risk of developing late effects. However, neither age nor race/ethnicity had an impact on the occurrence of late effects. Conclusions: Of AYA melanoma survivors, males, those with public or no health insurance, and those living in low SES neighborhoods had a much greater likelihood of developing of late effects. Strategies to improve surveillance and secondary prevention of these late effects is needed among AYA melanoma survivors, particularly for this demographic.
Circulating tumor DNA (ctDNA) in metastatic melanoma (MM) patients (pts) with brain metastases (mets).
Authors: Lee Jenny HJ , Menzies Alexander M. , Carlino Matteo S. , Kefford Richard , Scolyer Richard A. , Long Georgina V. , Rizos Helen 
Published: May 2019

9581 Background: Brain mets are common in pts with MM, occurring in up 50% of pts. Serial ctDNA levels at baseline and early on therapy predict objective response (OR) and overall survival (OS) in MM pts without brain mets receiving immune checkpoint inhibitors (ICI). The predictive utility in pts with brain mets is unknown. Methods: BRAF/NRAS ctDNA at baseline and early on ICI therapy (week 3-8) was analysed using mutation specific digital droplet PCR (detection threshold 2.5 copies/ml plasma) in MM pts with brain mets. Intracranial (IC) and extracranial (EC) disease volume (sum of product of diameters of ALL mets [SPD]) and OR, progression-free survival (PFS) and OS were analyzed. Results: 48 pts with brain mets were studied, 40 with concurrent EC disease (SPD EC med 892mm2 [25-22417mm2], IC med 200mm2 [9-1487mm2]) and 8 with isolated IC mets (SPD med 150mm2 [66-1035mm2]). At baseline, ctDNA was detectable in 28 (58%) pts, 28/40 (70%) with IC + EC mets and 0/8 with isolated IC mets. Baseline ctDNA reflected EC disease volume (Pearson’s r = 0.4, p = 0.01) but not IC volume (r = 0.1, p = 0.5). Baseline ctDNA did not associate with IC or EC OR or PFS, however, undetectable ctDNA was associated with superior OS (HR 0.4, p = 0.01). Early on therapy, ctDNA predicted EC response but not IC response; EC OR was 65% if ctDNA undetectable and 6% if detectable (p < 0.01), IC OR was 35% if undetectable and 12% if detectable (p = 0.1). Nevertheless, undetectable ctDNA early on therapy was associated with a superior PFS (HR 0.3, p < 0.01) and OS (HR 0.2, p < 0.01), indicating survival is largely determined by extracranial disease activity. In the 8 pts with IC disease only, 7/8 had disease progressive disease as best response. 1/8 subsequently developed detectable ctDNA at week 12, with multiple new EC mets seen at first restaging scan at this time. Conclusions: ctDNA does not appear to be a useful biomarker for detecting brain mets nor monitoring brain response in melanoma pts receiving ICI. This has important implications when using ctDNA in the setting of surveillance in the metastatic and adjuvant setting.
An analysis of nivolumab-mediated adverse events and association with clinical efficacy in resected stage III or IV melanoma (CheckMate 238).
Authors: Mandalà Mario , Larkin James M.G. , Ascierto Paolo Antonio , Del Vecchio Michele , Gogas Helen , Cowey C. Lance , Arance Fernandez ANA Maria , Dalle Stéphane , Schenker Michael , Grob Jean Jacques , Chiarion-Sileni Vanna , Marquez-Rodas Ivan , Butler Marcus , Di Giacomo Anna Maria , Middleton Mark R. , Lutzky Jose , Millward Michael , de Pril Veerle , Lobo Maurice , Weber Jeffrey S. 
Published: May 2019

9584 Background: In both previous 18- and 24-month follow-up reports from CheckMate 238, NIVO demonstrated significantly longer recurrence-free survival (RFS) than ipilimumab (IPI) in patients (pts) with resected stage IIIB/C or stage IV melanoma. Here we provide a more comprehensive analysis of treatment-related adverse events (TRAEs) for NIVO over discrete follow-up intervals and an investigation of the association of these AEs with efficacy (RFS). Methods: Eligible pts were aged ≥15 years and underwent complete resection of stage IIIB/C or IV melanoma. A total of 453 pts were treated with NIVO 3 mg/kg Q2W for up to 1 year. The primary endpoint was RFS. Pts were followed for safety for up to 100 days following their last dose; as of the previous 18-month database lock, all pts had been off study drug for > 100 days. Here safety data were analyzed within discrete time intervals: months 0–3 of treatment (0–3), months 3–12 of treatment (3–12), and from last dose to 100 days after last dose (+100). In addition, the association of TRAEs with RFS was investigated using the 24-month efficacy dataset, accounting for time-delay bias within the first 12 weeks after randomization. Results: The incidence of the first onset of TRAEs reported in ≥5% of pts was highest in the 0–3 time frame; the most common TRAEs with NIVO were fatigue (28% for 0–3 vs 6% for 3–12 vs 2% for +100), pruritus (16% vs 7% vs 1%), and diarrhea (15% vs 7% vs 2%). Most TRAEs with NIVO resolved within 3 months of occurrence, except for endocrine AEs, which could have required hormone supplementation, and skin AEs (median overall resolution time of 48 and 22 weeks, respectively). Similar results were observed in an analysis taking into account repeat occurrences of TRAEs over time. Analyses investigating the association of TRAEs with RFS are ongoing and will be presented. Conclusions: These results in pts with resected stage IIIB/C or IV melanoma are consistent with the established safety profile of NIVO. Based on the time periods analyzed, the majority of TRAEs with adjuvant NIVO occurred early during treatment, and patients had a reduced frequency of TRAEs after the treatment course. The majority of select TRAEs resolved within 3 months. Clinical trial information: NCT02388906.
A sequential dual cohort phase II clinical trial on adjuvant low-dose nivolumab with or without low-dose ipilimumab as adjuvant therapy following the resection of melanoma macrometastases (MM).
Authors: Schwarze Julia Katharina , Vandersleyen Valerie , Awada Gil , Jansen Yanina , Seremet Teofila , Neyns Bart 
Published: May 2019

9585 Background: Optimal dosing and duration of adjuvant treatment with anti-PD-1 checkpoint inhibitors, e.g. nivolumab (NIVO), following complete resection of melanoma (MEL) lymph node metastases has not been established. We investigated a regimen of low-dose NIVO with/without low-dose ipilimumab (IPI) as adjuvant therapy in MEL pts. Methods: After complete resection of MM, pts were treated with IPI 50mg (fixed dose, 1x) plus NIVO 10mg (fixed dose, Q2w x4) (Cohort-A), or NIVO 10mg (Q2w x9, Q8w x4) (Cohort-B). One-year relapse-free survival (RFS) rate served as primary endpoint. Sample size (34 pts) was calculated according to a Fleming one-stage clinical trial design. Recruitment to Cohort-B was closed prematurely following registration of NIVO in the adjuvant setting by EMA. Secondary endpoints were safety, distant metastasis-free survival (DMFS) and overall survival (OS). Quantitative measurement of BRAF/ NRAS mutant circulating tumor DNA (ctDNA), as well as tumor gene expression profiling were performed. Results: 34 pts (15M/19F, 31 stage III/3 stage IV) and 22 pts (12M/10F, 21 stage III/1 stage IV) were enrolled in Cohort-A/-B, respectively. After a median follow-up of 86w for Cohort-A and 36w for Cohort-B, estimated 12 months (m) RFS-rate was respectively 55% (95% CI, 39–72) and 78% (95% CI, 73-82), 12m OS-rate was 97% (95% CI, 94-100) and 100%, and 12m DMFS-rate was 79% (95% CI, 92-65), no distant metastases occurred in Cohort-B. Median RFS for Cohort-A was 84w (95%, CI 28-139), not-reached in -B. Median DMFS and OS had not been reached at time of analysis in either cohort. All grade treatment-related adverse events were observed in 21 (61%)/17 (77%) with 3 (8%)/1 (4%) grade 3 irAE in Cohort-A/-B, respectively. One patient in Cohort-A had a detectable level of ctDNA at baseline and relapsed 33w after initiating treatment. Tumor profiling is ongoing at time of submission. Conclusions: The investigated adjuvant low-dose regimens have an acceptable safety profile. Survival rates resemble those of standard regimens. These regimens could be economically advantageous alternatives for pts without access to standard regimens. Clinical trial information: NCT02941744.
Neoadjuvant cytoreductive treatment with BRAF/MEK inhibition of prior unresectable regionally advanced melanoma to allow complete surgical resection: REDUCTOR trial.
Authors: Blankenstein Stephanie A. , Rohaan Maartje W. , Klop W. Martin. C. , Van Der Hiel Bernies , Van De Wiel Bart A. , Peeper Daniel S. , Haanen John B. A. G. , Van Akkooi Alexander Christopher Jonathan 
Published: May 2019

9587 Background: The aim of this study is to evaluate the potency of short-term neoadjuvant cytoreductive therapy with dabrafenib and trametinib (BRAF and MEK inhibitor respectively) to allow radical surgical resection in patients with unresectable BRAF-mutated, locally advanced stage III or oligometastatic stage IV melanoma. Methods: A total of 25 patients with BRAF-mutated, unresectable locally advanced stage III or oligometastatic stage IV (≤3 metastases) melanoma will be treated with dabrafenib and trametinib for 8 weeks. Response evaluation by positron emission tomography/computed tomography (PET/CT) will occur at 2 and 8 weeks. If sufficient downsizing occurs, surgical resection will be performed. Biopsies for translational research will be taken at baseline and 2 weeks. The dissection specimen will be stored at 8 weeks. Results: Currently 20 patients have been included. Of these, 2 patients showed PD upon treatment and did not proceed to surgery. In 17/18 (94%) patients resection was possible after neoadjuvant treatment, of which 16 (94%) were R0 resections. Median follow-up time is 28 months with a median recurrence free survival of 9 months in patients undergoing surgery. The 1-year overall survival (OS) was 94% and 2-year OS 82%. Median OS was not reached. Metabolic response rates (RR) on PET/CT at 8 weeks were: 4 (20%) CR, 14 (70%) PR, 0 (0%) SD, 2 (10%) PD. Pathologic RR differed: 7 (35%) CR, 7 (35%) PR, 3 (15%) SD, 0 (0%) PD and in 3 patients (15%) no pathologic response was measured, since no resection was performed. Most patients (85%) experienced any toxicity, of which 50% was grade 1, 20% grade 2 and 3 patients (15%) experienced grade 3 toxicity. The most common reported toxicity was fever. Conclusions: Neoadjuvant dabrafenib and trametinib shows to be a potent cytoreductive treatment, allowing radical resection of metastases in 16/20 (80%) patients with prior unresectable locally advanced melanoma. Patients with no recurrence remained disease-free for a prolonged period of time. If there was recurrent disease, this usually occurred within months after surgery and this may present an opportunity for further tailored adjuvant therapy. Clinical trial information: NTR4654.
Extra-mammary Paget’s disease (EMPD) of the skin: A comprehensive genomic profiling (CGP) study.
Authors: Tse Julie , Elvin Julia Andrea , Vergilio Jo-Anne , Killian Jonathan Keith , Ngo Nhu , Lin Douglas I. , Ramkissoon Shakti , Severson Eric Allan , Hemmerich Amanda , Pavlick Dean , Ali Siraj Mahamed , Schrock Alexa Betzig , Chung Jon , Reddy Prasanth , McGregor Kimberly , Alexander Brian , Miller Vincent A. , Necchi Andrea , Bratslavsky Gennady , Ross Jeffrey S. 
Published: May 2019

9591 Background: EMPD is an intraepidermal adenocarcinoma which frequently progresses into invasive/metastatic disease. Methods: 29 EMPD underwent hybrid-capture based CGP to evaluate all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and reported as mut/Mb. Microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by IHC (Dako 22C3 antibody). Results: All patients had locally recurrent and/or metastatic disease. The 20 (69%) male and 9 (31%) female patients had a median age of 70 years (range 45 to 101 years). The primary EMPD site, known in 90% of cases and involved the scrotum (6 cases), groin (6 cases), vulva (5 cases), anus (3 cases), perineum (2 cases), abdomen (2 cases), penis (1 case) and buttock (1 case). was used for sequencing in 15 (52%) cases and a metastatic site 14 (48%) cases. The GA/tumor frequency was 5.0. The most frequent currently untargetable GA involved TP53 (48%), CDKN2A (38%), CDKN2B (31%), KMT2C (28%), and MYC (14%). The most frequent potentially targetable GA were identified in ERBB2 (35%), ERBB3 (17%) and PTEN (14%) and rarely in PDGFRA, CDK4/6, NF1/2, and ROS1 (fusion) all at 3%. The ERBB2 GA included short variant (SV) activating mutations (21%), amplifications (10%) and multiple ERBB2 GA in 3%. This finding is in contrast with mammary Paget’s disease which classically features > 90% of cases with ERBB2 amplification. No EMPD cases were either MSI-High or stained positively for PD-L1 expression. The median and mean TMB were 5.2 mut/Mb and 6.3 mut/Mb, respectively; 4 (14%) had TMB ≥ 10 mut/Mb and 1 (3%) had TMB ≥ 20 mut/Mb. Conclusions: EMPD is a rare source of relapsed/metastatic adenocarcinoma which features GA that are distinct from the more common disease originating on the nipple of the breast including a lower ERBB2 GA frequency and lower relative frequency of ERBB2 amplification versus SV mutations. A variety of MTOR pathway, cell cycle and kinase targets are also identified when EMPD undergoes CGP. However, the low TMB and absence of both MSI-High status and PD-L1 expression in EMPD cohort indicates a likely lack of benefit for immunotherapies for patients suffering from this rare form of malignancy.
Resensitization of uveal melanoma (UM) to immune checkpoint inhibition (ICI) by IMCgp100 (IMC).
Authors: Yang Jessica , Orloff Marlana M. , Sacco Joseph J. , Hernandez-Aya Leonel Fernando , Lee Karla , Merrick Sophie , Nathan Paul D. , Pan Samuel , Lutzky Jose , Middleton Mark R. , Nesson Alexandra , Singh-Kandah Shahnaz V. , Hernandez Susana , Sato Takami , Carvajal Richard D. 
Published: May 2019

9592 Background: ICI responses in UM are rare (~5% with anti-CTLA4/PD1 monotherapy; 10-12% with combination ICI). IMC is a bispecific agent composed of a high affinity T cell receptor targeting the gp100 melanoma antigen fused to an anti-CD3 scFv that increases intratumoral CD8+ T cell infiltration and PD1/PDL1 expression, and may enhance response to post-IMCgp100 ICI. Methods: We previously reported on 19 UM pts treated in the phase I dose escalation cohort of IMC (IMCgp100-102). We performed a retrospective analysis of clinical features and response to pre- and post-IMC ICI for the 12 pts in this cohort as well as 17 other pts (n = 29) treated with post-IMC ICI at 7 centers from 8/2016 to 1/2019. 21/29 pts (including 10/12 pts from IMCgp100-102) are evaluable for response and/or survival and are included in the analysis. Results: Baseline characteristics (n = 21): median age 56 (range 45-69); 57% female; median number of prior therapies 2 (range 1-4). Pre- and post-IMC ICI included: IPI+NIVO (3 pre; 8 post), anti-PD1 monotherapy (7 pre; 8 post), and anti-CTLA4 monotherapy (4 pre; 5 post). 20 pts were evaluable for post-IMC ICI response (1 died before restaging): 3/20 (15%) had partial responses (53-78% regression); 5/20 (25%) had stable disease (SD) > 16 weeks; 1/20 had SD of unknown duration. Median PFS and OS from the initiation of post-IMC ICI were 4.9 (95% CI 2.7-10.7) and 10.1 (95% CI 5.7-NR) months, respectively. 13 pts received pre-IMC ICI, all with eventual disease progression. 3 pts had treatment duration or SD lasting > 6 months. Of these 3 pts, 2 had clinical benefit (defined as objective response or SD > 16 weeks) with post-IMC ICI. There was no clear association between rates of Gr ≥ 2 irAE with pre- or post-IMC ICI and response. For the 10 evaluable pts treated on IMCgp100-102, no marked difference in prior response to IMC (3 SD among 5 ICI responders vs 2 SD among 4 ICI non-responders) or mean tumor shrinkage with IMC (-14.0% vs -18.0%) was observed, but rates of Gr ≥ 2 fever, rash, and/or hypotension with IMC were higher among ICI responders (80% vs 50%). Conclusions: Survival outcomes with post-IMC ICI compare favorably to historical figures in pretreated UM pts. IMC may re-sensitize pts who had prior clinical benefit with ICI to subsequent ICI.
Validation of a panel of risk factors for predicting breast cancer reappearance.
Authors: Corso Giovanni , Veronesi Paolo , Maisonneuve Patrick , Goldhirsch Aron , Sacchini Virgilio , Caldarella Pietro , De Scalzi Alessandra Margherita , Galimberti Viviana 
Published: May 2019

e12004 Background: The aim of this clinical study was to assess a panel of risk factors for ipsilateral breast tumor recurrence (IBTR) and de novo contralateral breast cancer (BC) after primary BC treatment. Methods: Retrospectively, 15,168 consecutive patients with primary monolateral BC were enrolled in this monocentric study (1994-2006). Clinicopathological features, follow-up and survival at 15 years were considered for statistical analysis. Results: Significant increased risk for IBTR were verified with younger age ( < 50 years) [HR = 1.31 (1.15-1.49), p < 0.0001], lobular subtype [HR 1.40 (1.15-1.70), p = 0.0007)], pT3 [HR 1.90 (1.42-2.54), p < 0.0001] or pT4 [HR 2.70 (1.47-4.97), p = 0.001], metastatic axillary lymph nodes [HR 1.50 (1.29-1.73), p < 0.0001], peritumoral vascular invasion (PVI) [HR = 1.27 (1.10-1.46), p = 0.001], luminal B [HR 1.57 (1.33-1.87), p < 0.0001], HER2-positivity [HR 1.85 (1.32-2.59), p = 0.0004] and triple-negative subtype [HR 1.76 (1.28-2.43), p = 0.0005]. Older age ( > 70 years) [HR 1.50 (1.05-2.15), p = 0.03] and positive family history [HR 1.86 (1.48-2.34), p < 0.0001] were risk factors for contralateral BC. Significant protective factors for IBTR were mucinous subtype [HR 0.45 (0.27-0.77), p = 0.003], total mastectomy [HR = 0.37 (0.30-0.46), p < 0.0001], hormonotherapy [HR 0.56 (0.45-0.69), p < 0.0001], chemotherapy [HR 0.77 (0.66-0.90), p = 0.001] and external radiotherapy [HR 0.39 (0.31-0.50), p < 0.0001]. Hormonotherapy was also confirmed as a protective factor for contralateral second BC [HR 0.51 (0.38-0.69), p < 0.0001]. Cumulative incidence for IBTR at 5, 10, and 15 years was higher than for than for contralateral BC. Conversely, overall survival for IBTR was lower than for contralateral BC. Conclusions: We classified factors influencing IBTR and contralateral BC into high- and low-risk groups. The high-risk group for IBTR included: age < 50 years, positive axillary nodes, PVI positivity, luminal B, HER2-positive, lobular and triple-negative subtypes. The low-risk group included: adjuvant treatments (hormone-chemotherapy, external radiotherapy) and mucinous histotype. We hypothesize that in the low-risk group, adjuvant treatments exert a strong impact in the prevention of IBTR risk (HER2-positive and triple negative BC should be considered also for neo-adjuvant therapies); this was not confirmed in the high-risk group, in which a more aggressive surgery is still theoretically justified. The proposed panel represents the basis for a nomogram to predict BC reappearance.
Decisions on adjuvant chemotherapy for patients with breast cancer based on clinical and evolving Oncotype DX criteria.
Authors: Zekri Jamal , Al-Foheidi Meteb Owaish , Alata Maaz Kamal , Rasmy Ayman Ahamd , Rasool Haleem J. , Abdelrahman Hossam A. , Hussain Adnan , Sorour Yasser , Mashhour Miral 
Published: May 2019

e12009 Background: Oncotype-DX assay recurrence score (ODX-RS) cut-off values have recently changed in response to the results of the TAILOR-X trial. We aim to explore decisions for ACT based on physicians’ clinical assessment and on evolving ODX-RS. Methods: Patients who underwent ODX testing after curative surgical resection of estrogen receptor positive (ER+), Her2 non-over-expressed (Her2-) and lymph node negative (LN-) BC were included. Patients with micro-metastases to LNs were excluded. Data was collected retrospectively from the electronic records. Management of these patients was guided by the results of the old ODX-RS-1 (<18, 18-30 & ≥31) risk grouping. For the purpose of this study, treatment decisions were also assumed according to TAILOR-X results (ODX-RS-2). Decisions of 3 medical oncologists on ACT were solicited by blinding them to the RS values to investigate inter-physicians discrepancy and concordance with ODXA RS-1&2. Results: Sixty six consecutive patients fulfilled the inclusion criteria. Median age was 50.5 (range: 21-73) years. There was one male patient and 37 out of 65 females (56.9%) were pre-menopausal. Median tumor size was 21.5 (range: 10-55) mm and the grade were I, II and III in 6 (9.1%), 46 (69.7%) and 41 (21.2%) patients respectively. The 3 oncologists’ had discrepancies about ACT recommendations in 29 (44%) patients. Based on majority opinion (≥2 oncologists), ACT would have been recommended to 22/41 (53.7%) and 24/46 (52.2%) patients with low risk tumors according to ODXA RS-1 and ODXA RS-2 respectively. Similar number of patients (n=12) would have received ACT regardless of ODXA RS cut-off value (table). Conclusions: Decisions on ACT for patients with ER+/Her2-/LN- early BC should be guided by ODX-RS to prevent overtreatment and discrepancies in management. Broadly, ODXA RS-1 and ODXA RS-2 seem to guide ACT decisions in similar proportions of patients. Nevertheless minor differences exist and need to be studied in larger cohorts. [Table: see text]