bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of distinct baseline tissue biomarkers with response to nivolumab (NIVO) and ipilimumab (IPI) in melanoma: CheckMate 064.
Authors: Rodig Scott , Gusenleitner Daniel , Jackson Donald , Gjini Evisa , Giobbie-Hurder Anita , Jin Chelsea , Chang Han , Lovitch Scott , Horak Christine , Weber Jeffrey S. , Shipp Margaret Ann , Hodi F. Stephen
Published: September 2018

9515

Background: CheckMate 064 (open label, phase 2) randomized advanced melanoma pts to NIVO 3 mg/kg Q2W for 6 doses then IPI 3 mg/kg Q3W for 4 doses (n = 70; cohort A), or the reverse (IPI then NIVO; n = 70; cohort B). More cohort A than cohort B pts had complete or partial response (54% and 31%, respectively). We sought to determine whether common or distinct baseline biomarkers were associated with response for each cohort. Methods: Protein expression of biomarkers identifying a broad array of cell lineages and immunoregulatory factors was determined by IHC and evaluated by 2 pathologists, with concordance. Global transcript expression was determined by RNAseq from frozen tissue. An elastic net predictor was trained on cohort A (α = 0.1, λ = 0.05) using leave-one-out cross-validation. RECIST v1.1 was used to assess tumor response. Results: Patients with tumors showing a pro-inflammatory transcriptional signature at baseline had superior overall response in cohort A, but not cohort B. Consistent with this observation, a parsimonious classifier of 10 immune/IFNγ-related genes predicted BOR (AUC 0.87) and OS (CPH log-likelihood P= 0.0003) for patients in cohort A, but not cohort B. In contrast, low baseline expression of MHC class I protein by malignant cells ( < 50% positive) was associated with disease progression (MHCI < 50% vs ≥50%: 12/13 vs 16/28 progressed) and inferior OS for patients in cohort B (MHCI < 50%: 6.42 mo [2.20, 9.66]; MHCI ≥50%: mOS 18.02 mo [7.98, not reached]: P= 0.0021, log-rank test), but not cohort A. Conclusions: Different pre-treatment biological characteristics of melanoma are associated with clinical response to NIVO followed by a planned switch to IPI (cohort A) and clinical response to IPI followed by NIVO (cohort B). Improved outcome with initial NIVO is strongly associated with a pro-inflammatory signature enriched for IFNγ targets. Inferior outcome with initial IPI is associated with reduction/loss of MHC I antigen presentation machinery. These data imply that NIVO broadly activates innate and adaptive immunity, whereas IPI is reliant upon CD8/MHC class I mediated adaptive immunity to effect clinical response. Clinical trial information: NCT01783938.
Glycemic disorders in melanoma patients treated with anti-PD1.
Authors: Magis Quentin , Gaudy Marqueste Caroline , Monestier Sandrine , Loundou Anderson , Richard Marie-Aleth , Malissen Nausicaa , Beliard Sophie , Grob Jean-Jacques
Published: September 2018

9525

Background: Anti-PD1 are now the backbone of immunotherapy (IT) of metastatic melanoma (MM). Although they are overall well- tolerated, a number of severe immune-related adverse events (IRAE) have been described, among which type 1 diabetes. We observed 3 cases of fulminant diabetes (FD) in our center, and also had the impression that diabetics patients became more difficult to manage when receiving anti-PD1. Methods: Retrospective analysis of blood glucose samples collected before, during and after anti-PD1 treatment (trt ) in all mm patients (pts) receiving anti-PD1 in our department over a 36-month period. Study of FD cases observed. Results: A total of 163 pts were treated with 1920 cures of anti-PD1 including 27 treated within clinical trials. Anti-PD1 was the 1st line of IT in 70% of cases. As a whole, 1470 glycaemia were available. There was no significant difference between the median pre and post-trt glycaemia (5.37 +/-1.6 vs 5.6 +/-1.3 mmol/L (p = 0.033)). In the 28 pts with a type I (n = 0) or II (n = 28) diabetes prior to trt, there was very slight drift toward an increase of glycaemia along with the successive trt infusions (+0.05mmol/L/Cure, p = 0.004 with linear regression tendency test) .Three pts (1.84%) developed a FD revealed by a severe episode of ketosis with acute polyuria polydipsia, hyperglycaemia until 50mmol/L and weight loss. Two additional cases of FD were observed in pts treated within clinical trial comparing anti-PD1 with anti-CTLA4 in adjuvant and metastatic situation (imputability of anti-PD1 likely but uncertain until unblinding). None of these pts had any glucose increase in weeks prior to FD diagnosis. Four out of 5 FD cases had an HLA group at risk for type 1 diabetes development (HLA DRB3/4), a rare group in general population (1%). Conclusions: We could not document any systematic tendency to glycemic disorder in mm pts treated by anti-PD1. In diabetic pts prior to trt, a slight drift toward increase of glycaemia may be explained by other interfering factors (diet, metastatic disease itself, corticosteroids, anxiety etc). FD is not exceptional (2% of patients in our series) and does not seem to be announced by any minor preliminary glycemic disorder. Despite apparently stochastic onset, FD may be associated with HLA DRB3/4 subgroup.
PD-L1 and CD8 expression and association with outcomes in patients (pts) with BRAF V600E/K-mutant metastatic melanoma (MM) who received dabrafenib + trametinib (D+T) in the randomized phase 3 COMBI-v study.
Authors: Schadendorf Dirk , Long Georgina V. , Grob Jean Jacques , Nathan Paul D. , Ribas Antoni , Davies Michael A. , Flaherty Keith T. , Squires Matthew , Jaeger Savina , Powell William , Tan Puay , Robert Caroline
Published: September 2018

9527

Background: The phase 3 COMBI-v study (NCT01597908) showed that D+T significantly improved outcomes vs vemurafenib in pts with BRAFV600E/K–mutant MM. Checkpoint inhibitors also provide clinical benefit in some pts with MM. To date, characterization of markers associated with response to anti–PD-1 therapy has identified positive associations with PD-L1 expression and immune cell infiltration. Here we describe expression of PD-L1 and the T-cell marker CD8 in tumor samples from pts randomized to receive D+T in COMBI-v and associations with clinical outcomes. Methods: Biopsies from 74 of 352 D+T pts (21%) in COMBI-v were assessed for expression of PD-L1 (PD-L1 IHC 22C3 pharmDx assay; Dako) and CD8 (anti-CD8 antibody, clone C8/144B; Dako). PD-L1 positivity was determined as a percentage of stained tumor cells and MEL score (staining on both tumor and mononuclear inflammatory cells; 0 or 1 [negative]: < 1% staining; 2-5 [positive]: ≥ 1% staining; Daud et al. J Clin Oncol. 2016). Results: Of 74 pts analyzed, 54 (73%) had PD-L1–positive tumors, and the largest MEL score subgroup was 2 (45%). A significant association ( P < .0001) was observed between PD-L1 and CD8 expression. Overall response rate, tumor shrinkage, progression-free survival, overall survival (OS), and duration of response with D+T were not associated with PD-L1 (MEL score of ≥ 2) or CD8 positivity. However, a significant association ( P = .04) with improved OS was observed in tumors with high PD-L1 expression (≥ 20% of cells PD-L1 positive), and a trend ( P = .06) was seen in pts with a MEL score of ≥ 3. Among PD-L1–negative pts, improved OS was seen in those with high CD8 positivity ( P = .03), particularly in the stromal compartment. Conclusions: These data, representing PD-L1 and CD8 expression profiles for a BRAF-mutant mm population in the context of outcomes following D+T, showed that clinical benefit was maintained regardless of immune phenotype. The results also suggest that an immune component has an impact on outcomes following targeted therapy. Clinical trial information: NCT01597908.
First-line (1L) avelumab treatment in patients (pts) with metastatic Merkel cell carcinoma (mMCC): Preliminary data from an ongoing study.
Authors: D'Angelo Sandra P. , Russell Jeffrey , Hassel Jessica Cecile , Lebbe Celeste , Chmielowski Bartosz , Rabinowits Guilherme , Terheyden Patrick , Brownell Isaac , Zwiener Isabella , Bajars Marcis , Hennessy Meliessa , Kaufman Howard
Published: September 2018

9530

Background: MCC is a rare, aggressive skin cancer. Avelumab is a fully human anti–PD-L1 antibody. In a phase 2 study in pts with distant mMCC who progressed after prior chemotherapy (JAVELIN Merkel 200; NCT02155647), avelumab showed a manageable safety profile and durable responses, including an objective response rate (ORR) of 31.8%, estimated 6-month durable response rate of 29%, and 6-month overall survival rate of 69%. Here, we report preliminary results from a separate cohort of pts with chemotherapy-naïve mMCC enrolled in the same study. Methods: Eligible pts with mMCC and no prior systemic treatment for metastatic disease received avelumab 10 mg/kg Q2W until confirmed progression, unacceptable toxicity, or withdrawal. Tumors were assessed every 6 weeks (RECIST v1.1). Adverse events (AEs) were assessed by NCI CTCAE v4.0. Results: As of Dec 30, 2016, 29/112 planned pts had been enrolled. Median age was 75.0 years (range 47–87). Median treatment duration was 8.1 weeks (range 2.0–37.9). Of 16 pts with ≥3 months of follow-up, unconfirmed ORR was 68.8% (95% CI 41.3–89.0) with CR in 18.8%; confirmed ORR was 56.3% (95% CI 29.9–80.2; 1 unconfirmed PR with discontinuation). Of 25 pts with ≥6 weeks of follow-up, unconfirmed ORR was 64.0% (95% CI 42.5–82.0). All responses were ongoing at last follow-up, including in 5/5 pts with ≥6 months of follow-up (potential to confirm responses). 20/29 pts (69.0%) had a treatment-related AE (TRAE), including grade 3–4 TRAE in 5 pts (17.2%). TRAEs led to discontinuation in 5 pts (17.2%): 2 pts with infusion-related reaction, and 1 pt each with elevated AST and ALT, cholangitis, and paraneoplastic syndrome. There were no treatment-related deaths. 21/29 pts (72.4%) remain on treatment. Conclusions: In initial results from a cohort of chemotherapy-naïve pts with mMCC, avelumab was associated with early responses and a manageable safety profile, consistent with findings for second-line or later avelumab treatment in a previous cohort. These results suggest that responses mature to become durable and the use of 1L avelumab may increase the probability of response vs later-line treatment. Enrollment and follow-up in this 1L cohort are ongoing. Clinical trial information: NCT02155647.
Micro- and macro-metastatic disease kinetics: Results from the French cohort Melbase.
Authors: Vallet Anais , Dalle Stéphane , Mortier Laurent , Dutriaux Caroline , Leccia Marie Thérèse , Dalac-Rat Sophie , Saiag Philippe , Guillot Bernard , Lacour Jean Philippe , Lesimple Thierry , Arnault Jean-Philippe , Legoupil Delphine , Aubin Francois , De Quatrebarbes Julie , Maubec Eve , Descamps Vincent , Granel Brocard Florence , Stoebner Pierre-Emmanuel , Oriano Bastien , Lebbe Celeste
Published: September 2018

9538

Background: In the past decade, the prognosis of advanced melanoma has been greatly improved by new therapeutic agents such as immune and targeted therapies, which are now being evaluated as adjuvant therapies. Although the kinetic of metastatic disease is correlated to patient survival, the unfolding of the dormant disease remains hardly predictable and data from the literature on the topic is controversial (Karakousis, Francken). We hypothesized that the course of the advanced disease could be predicted from time to distant recurrence. Methods: Melbase is a French multicentric cohort dedicated to the prospective follow-up of adults with unresectable stage III or IV melanoma. Date of primary excision, time to recurrence, progression free survival (PFS) and overall survival (OS) of 298 patients treated in first line by immune therapies (IT, n = 148), targeted therapies (TT, n = 68) or within clinical trials (n = 73) were collected on September 5th, 2016. Patients with unknown primary or de novo metastatic melanoma were not included. Time to distant recurrence was analyzed as a continuous variable and as a categorical variable ( < 12 months; 12 to 24 months; ≥ 24 months). Results: Patients’ characteristics at baseline are: mean age 62 years, PS 0-1 84%, elevated LDH 32%, BRAF mutated 39%, brain metastases 18%. Time to recurrence studied as a continuous variable was not correlated to PFS (HR = 0.96; 95%CI: 0.85-1.07) or OS (HR = 0.89; 95%CI: 0.77-1.03). These results remained insignificant after stratification upon treatment or even when time to recurrence was analyzed as a categorized variable. Conclusions: Our data showed no correlation between the time from primary to distant recurrence and PFS or OS in patients treated with TT or IT. Therefore, kinetics of advanced disease cannot be predicted by the history of dormant disease. Dormancy and metastasis proliferation are thus probably driven by different molecular and cellular mechanisms.
Real life outcome of advanced melanoma patients who discontinue pembrolizumab (PEMBRO) in the absence of disease progression.
Authors: Jansen Yanina , Rozeman Elisa A. , Foppen Marnix Geukes , Bastholt Lars , Schmidt Henrik , Van Thienen Johannes V. , Haanen John B. A. G. , Tiainen Leena , Svane Inge Marie , Mäkelä Siru Päivikki , Arance Ana , Hoejberg Lise , Nyakas Marta , Straume Oddbjorn , Blank Christian U. , Neyns Bart
Published: September 2018

9539

Background: PEMBRO improves survival of patients (pts) with advanced melanoma. Optimal duration of treatment in responding pts hasn’t been established. Methods: 12 European hospitals collected data from 509 pts treated with PEMBRO outside an interventional clinical trial. Outcome was evaluated for pts who discontinued PEMBRO in the absence of progressive disease [PD]. Results: After a median follow up of 56 wks [range 1-135], median PFS was 22 wks [95% CI 18-26] and median OS was 70 wks [95% CI 59-81] for the total population. PEMBRO is ongoing in 66 [13%] pts, 344 [68%] pts stopped PEMBRO because of PD, and 99 [19%] pts discontinued PEMBRO without evidence of PD (of which 65 [13%] pts upon pt/MD decision, 26 [5%] pts due to a PEMBRO-related AE of grade < 4 and 8 [2%] pts due to a grade 5 PEMBRO-unrelated AE). Pts discontinuing PEMBRO without PD had a significant [ P <.005] better ECOG PS, less advanced tumor stage, less frequent brain metastases and more often a normal LDH at baseline. There was no significant difference between pts stopping due to AE or upon pt/MD decision. The median time on treatment for the 65 pts who stopped PEMBRO upon pt/MD decision was 55 wks [range 9-112].Their best objective response rate [BORR] was 80% [31 [48%] CR, 21 [32%] PR, 12 [18%]SD, 1[2%]NE]. After a median follow-up of 26 wks [range 1-75] after the last PEMBRO dose, 3 [5%] pts progressed (after 9, 14 and 15 wks). PEMBRO was reintroduced in 1 patient resulting in a CR. The median time on treatment of the 26 pts who stopped PEMBRO due to an AE in the absence of PD was 27 wks [range 1-103]. Their BORR was 77% [9 [35%] CR, 11 [42%] PR, 5 [19%] SD, 1 [4 %] NE]. After a median follow-up of 50 wks [range 12-109] following the last PEMBRO dose, 9 [35 %] pts progressed. Median time to PD was 26 wks [range 7-108]. PD was not correlated with BOR. PEMBRO was reintroduced in 4 pts resulting in 1 CR, 1 PD, 1 SD and 1 NE. Conclusions: In this real life experience, advanced melanoma pts who discontinue PEMBRO treatment upon pt/MD decision, in the absence of PD or AE, were at low risk for short-term recurrence. Pts stopping PEMBRO due to an AE in the absence of PD (having a shorter exposure to PEMBRO and longer FU after discontinuing treatment) seem to have a higher risk for subsequent PD.
A randomized phase II study of ipilimumab at 3 (ipi3) or 10 mg/kg (ipi10) alone or in combination with high dose interferon-alfa (HDI) in advanced melanoma (E3611).
Authors: Tarhini Ahmad A. , Lee Sandra J. , Rao Uma N. M. , Nagarajan Arun , Albertini Mark R. , Mitchell Jerry W , Wong Stuart J. , Taylor Mark A. , Laudi Noel , Truong Phu Van , Conry Robert Martin , Kirkwood John M.
Published: September 2018

9542

Background: Interferon-α (IFN) favors a Th1 shift in immunity. Combining CTLA4 blockade with IFN may downregulate CTLA4 suppressive elements. Prior data from a phase II of tremelimumab and HDI showed promising efficacy supporting the current study. Methods: E3611 had a 2x2 factorial design (A: ipi10 + HDI; B: ipi10; C: ipi3 + HDI; D: ipi3) to evaluate (i) no HDI vs. HDI (across ipi doses) and (ii) ipi3 vs. ipi10 (across HDI status). We hypothesized that median progression free survival (PFS) would improve from 3 to 6 months (mos) with HDI vs. no HDI and with ipi10 vs. ipi3. Based on the log-rank test for 80 patients (pts) these comparisons would have 82% power at 2-sided type I error of 0.10. Results: Median follow up 26.4 mos. PFS and overall survival (OS) (eligible and treated pts; N = 80: 18 III/M1a, 24 M1b, 38 M1c) are shown in Table 1. There were no significant differences in PFS or OS when evaluating HDI vs. no HDI or ipi10 vs. ipi3 (Table 1). Response (RECIST) among response evaluable pts (and 4 pts with early death) (N = 76) is shown in Table 1. Stable disease (SD) in 7 (A), 6 (B), 8 (C) and 6 (D). Adverse events (AEs) were consistent with the toxicity profiles of ipi and HDI and included 3 grade 5 AEs considered at least possibly related: 1 in A (suicide), 1 in B (lung infection and hemorrhage) and 1 in C (adult respiratory distress syndrome). One patient in B died of gastrointestinal bleed and cardiac arrest while on corticosteroids to treat temporal arteritis and vision loss. Conclusions: Within the limitations of the sample size, there were no significant differences in PFS with HDI vs. no HDI or ipi10 vs. ipi3. Response and PFS with ipi10 were superior to historical controls and similar to the combination. Correlative studies are ongoing. Clinical trial information: NCT01708941. [Table: see text]
Impact of gene expression profiles on clinical predictors of survival in patients (pts) with BRAFV600-mutated metastatic melanoma (mM).
Authors: Larkin James M. G. , Lewis Karl D. , Ribas Antoni , Flaherty Keith , Ascierto Paolo Antonio , Dréno Brigitte , Mckenna Edward Francis , Zhu Qian , Mun Yong , Hauschild Axel , McArthur Grant A.
Published: September 2018

9556

Background: Treatment of BRAFV600-mutated mm with V and C+V has clinical benefit. Prior analyses established PFS/OS prognostic models in pts with mm based on clinical variables. This exploratory analysis evaluated the impact of immune and cell cycle gene signatures (GS) from baseline mm (Wongchenko et al, Pigment Cell Melanoma Res2015;28:822) on survival outcomes and associated prognostic models. Methods: Data from all eligible pts with GS data in the BRIM-2, -3, -7, and coBRIM studies were pooled for analysis. The independent effect of GS on PFS/OS outcomes was tested by multivariate Cox proportional hazards models. Recursive partitioning (RP) for censored response variables in a conditional inference framework was performed in the pooled dataset to model relationships between prespecified covariates, GS, and PFS/OS. Prognostic subgroups identified by the model for all pooled pts were applied to pooled treatment cohorts (dacarbazine [D], V, and C+V). Results: GS data were available for 608 pts across pooled studies. Immune GS was associated with improved survival vs cell cycle for PFS (HR = 0.75, 95% CI 0.62–0.89, P= 0.0015) and OS (HR = 0.74, 95% CI 0.61–0.90, P= 0.0024) in multivariate models. HR point estimates were consistent across treatment cohorts. PFS RP models identified baseline LDH, tumor size, and GS as prognostic factors, giving 4 groups with distinct outcomes. GS was not identified as a prognostic factor in OS RP models. C+V improved PFS/OS outcomes vs V across prognostic subgroups. Immune GS was significantly (one-sided Cochran-Armitage trend test) more prevalent in the favorable prognostic groups previously defined for PFS and OS for the V ( P< 0.0001 for both) and C+V cohorts ( P= 0.0240 and P= 0.0269, respectively), but not the D cohort. Conclusions: PFS/OS was significantly improved for pts with immune GS. RP modeling confirmed the importance of GS as an independent prognostic factor for PFS but not OS. The preferential association of immune GS with favorable prognostic subgroups in the C+V and V but not D cohorts and known effects of MAPK signaling on immune response merit further exploration in prospective studies.
Predictive biomarkers of ipilimumab toxicity in metastatic melanoma.
Authors: Gowen Michael , Tchack Jeremy , Zhou Hua , Giles Keith Michael , Paschke Scott , Moran Una , Fenyo David , Tsirigos Aristotelis , Pacold Michael , Pavlick Anna C. , Krogsgaard Michelle , Osman Iman
Published: September 2018

9559

Background: There are no predictive biomarkers of ipilimumab (IPI) toxicity. Of metastatic melanoma (MM) patients (pts) receiving IPI (3mg/kg), 35% require systemic therapies to treat immune-related adverse events (irAEs) and 20% must terminate treatment (Horvat et al., JCO 2015). Here we tested the hypothesis that a pre-existing autoantibody (autoAb) profile is predictive of IPI irAEs. Methods: We measured autoAb levels in pre- and post-treatment sera from mm pts who received IPI (3mg/kg) monotherapy on a proteome microarray containing ~20,000 unique full-length human proteins (HuProt array, CDI Laboratories). Clinical data were prospectively collected with protocol-driven follow-up. IrAEs were categorized by CTCAE guidelines as none (grade 0), mild (grade 1-2), or severe (grade 3-4). AutoAb levels were standardized using median quantile normalization and considered positive hits if > 2-SD above the peak array signal and differed by ≥2 fold with p < 0.05 between toxicity groups (Non-parametric Analysis/Wilcox test). Results: Seventy-eight sera from 37 mm pts were analyzed. Antibodies against CTLA-4 were significantly elevated post IPI treatment (p < 0.0001), validating the assay. The pre-treatment levels of 190 IgG autoAbs were significantly different in pts who experienced irAEs (n = 28) compared to those with no irAEs (n = 9). Comparison of severe irAE (n = 9) and no irAE (n = 9) groups revealed 129 IgG autoAbs that significantly differed in pre-treatment sera. Localization and pathway analysis (UniProt, KEGG, Reactome) showed 81/190 (43%) of the autoAbs targeted nuclear and mitochondrial antigens and were enriched in metabolic pathways (p = 0.015). AutoAbs associated with irAEs did not correlate with treatment response. Conclusions: AutoAbs to antigens enriched in metabolic pathways prior to treatment may predict IPI-induced toxicity in MM. The subcellular localization of targeted antigens could explain the autoimmune toxicities associated with IPI. Studies in larger cohorts and in pts receiving other checkpoint inhibitors and/or combination therapies are essential to determine the validity of the data. If validated, our results would support the discovery of the first toxicity predictor in cancer immunotherapy.
Circulating tumor DNA as a predictor for response to treatment in BRAF V600E mutant malignant melanoma.
Authors: Braune Jan , von Bubnoff Dagmar , Follo Marie , Graf Erika , Philipp Ulrike , Glaser Laura , Pfeifer Dietmar , Hahn Felix , Duyster Justus , Meiss Frank , Von Bubnoff Nikolas
Published: September 2018

9564

Background: Available biomarkers LDH and S100B possess limited sensitivity and specificity to predict outcome in melanoma. In this pilot study we evaluated the use of circulating tumor (ct)DNA harboring BRAF and NRAS mutations as a predictive biomarker for treatment response and progression-free survival (PFS) in patients with locally advanced or metastatic melanoma. Methods: We analyzed 89 retrospective plasma samples from 32 unselected pts, and 158 samples from 12 pts included in a prospective trial (DRKS00009507). We included stage III disease with planned resection or stage IV disease before initiation or change of medical treatment. Blood samples were taken at baseline at d +8, d +28, and thereafter at 3 months intervals for up to two years. We developed a hydrolysis probe based, Locked Nucleic Acid assay to detect BRAF V600E and wild type ctDNA by droplet digital PCR. Results were correlated with LDH, S100B and PFS. Results: Sensitivity of BRAF V600E specific assay was 0.01% with a limit of Blank of 0.28 copies/well. Of 31 stage IV pts with retrospective samples, 23 were positive for BRAF V600E ctDNA at least once (74%). Positive pts had a mean of 9 (range: 1-17) and 483 (range: 0.1-16,388) BRAF V600E copies/mL for stage III and stage IV respectively. The presence of ctDNA at baseline predicted poor PFS (hazard ratio [HR] 1.487, 95% CI 0.34-6.45). A negative slope in BRAF V600E ctDNA was a favorable prognostic factor for PFS (hazard ratio [HR] 0.230, 95% CI 0.04-1.20) with a median PFS of 3.42 vs. 2.56 months (Range 1.87-8.9 vs. 0.89-5.02). Residual ctDNA at the first time point after initiation or change of treatment was related to a shorter PFS (hazard ratio [HR] 2.02, 95% CI 0.39-10.53). Based on 144 measurement pairs, BRAF ctDNA strongly correlated with S100 (r = 0.73) and LDH (r = 0.52). Conclusions: Residual ctDNA early after change or institution of treatment predicted tumor progression at first clinical response assessment. A positive to negative conversion or a decrease indicated a more favorable course. These data support the use of ctDNA as an early predictive marker for treatment response. We will examine whether two or more detected mutations indicate clonal heterogeneity and confer adverse prognosis. Clinical trial information: DRKS00009507.
Correlation between baseline parameters and overall survival in patients with advanced melanoma treated with ipilimumab.
Authors: Geukes Foppen Marnix Heimen , Jordanova Ekatarina S. , Van Thienen Johannes V. , Punt Simone , Van De Wiel Bart , Haanen John B. A. G. , Blank Christian U.
Published: September 2018

9572

Background: Checkpoint inhibitors (IT) have revolutionized treatment options for patients (pts) with advanced melanoma. Recently, we proposed a framework of 7 parameters (PM) describing requirements for a sufficient anti-tumor immune response (the “cancer immunogram”). In a first analysis we tested pts from our ipi cohort for outcome. Using this framework pts benefitting the most from treatment with ipi might be selected upfront, and in the future also from other checkpoint inhibitors. Methods: Using Kaplan-Meier- and Cox-regression-analysis correlations between 6 of these PM at baseline and overall survival (OS) were investigated in a single center cohort of pts treated with 3 mg/kg ipi for metastatic melanoma. Results of the 7thPM are currently being finalized. Results: PM assessed were: LDH (≤ULN vs > ULN), erythrocyte sedimentation rate (ESR,≤ULN vs > ULN), absolute lymphocyte count (ALC, < 1000/mm3 vs ≥1000/mm3) and IHC on tumor material for CD8+ T-cell infiltration ( < median vs ≥median), PD-L1 expression ( < 1% vs ≥1% positive cells) and MHC-class I expression (loss vs weak/positive). We analyzed 179 pts treated with ipi between 2010 and 2013. Median age was 55 years (19–88) and 61% of pts were male. Minimum follow-up of pts alive was 42 months(mo). Data were available as follows:177 cases LDH, 159 ALC/ESR, 118 PD-L1, 99 CD8 and 68 MHC-class I. Median OS was 7.1 mo. In univariable analysis LDH (HR 2.5, 95%CI 1.8-3.5), ALC (HR 1.6, 95%CI 1.1-2.4), ESR (HR 2.4, 95%CI 1.5-3.8) and CD8 (HR 1.8 95%CI 1.2-2.8) were significant for OS ( p< 0.01). Pts with all 4 favorable PM had a median OS of 25.1mo(95%NR), pts with 3 PM 15.8 mo(95%CI 7.0-24.7), 2 PM 8.1 mo(95%CI 1.0-15.3), 1 PM 4.8 mo(95%CI 3.3-6.3) and no favorable PM 1.7 mo(95%CI 0–4.9). In multivariable analysis LDH(HR 2.4,95%CI 1.5-4.0) and CD8(HR 1.7,95%CI 1.1-2.8) were the only independent PM. Pts with a normal LDH and high CD8 had a median OS of 15.8 mo(95%CI 9.5-22.2) vs 3.8 mo(95%CI 1.8-5.7) for pts that did not ( p< 0.01). Conclusions: In conclusion, low values of baseline LDH and high values of CD8 are the strongest PM associated with a favorable outcome in pts with advanced melanoma, treated with ipi. The other PM added low effect on the pts outcome upon ipi.
Interim analysis of survival outcomes in a prospective cohort evaluating a prognostic 31-gene expression profile (GEP) test for melanoma.
Authors: Hsueh Eddy C. , DeBloom James R. , Lee Jonathan H. , Sussman Jeffrey J. , Slingluff Craig L. , McMasters Kelly
Published: September 2018

9573

Background: DecisionDx-Melanoma has been validated as an accurate prognosticator of cutaneous melanoma (CM) metastasis risk. The GEP test classifies CM pts as Class 1 (low risk) or Class 2 (high risk). Interim survival analysis from two clinical registry studies (NCT02355574/NCT02355587) designed to prospectively evaluate outcomes in pts for whom the GEP test was performed is described. Methods: Eleven US dermatologic and surgical centers participated in the IRB-approved protocols. Physicians enrolled CM pts who were ≥16 years old and had successful GEP test results. Endpoints of recurrence-free (RFS), distant metastasis-free (DMFS) and melanoma-specific survival (MSS) were assessed using Kaplan-Meier and Cox regression analysis. As an interim analysis at year 3 of an expected 5-year study, the critical alpha level (p-value) was 0.01. Results: At the time of data extraction, 322 pts were accrued and completed at least one follow-up visit. Median age was 58 years (range 18-87), median Breslow thickness (BT) was 1.2mm, 55% were male, 20% (58/296) were ulcerated, and 15% (36/237 biopsied) had a positive sentinel lymph node (SLN). Median follow-up time was 1.5 years for pts without a recurrence. Of 25 recurrent cases, 80% (20/25) were Class 2 and 40% (10/25) were SLN-positive. Two percent of Class 1 pts had a recurrence compared to 6% (12/201 biopsied) of SLN-negative pts. Of the SLN-negative pts who recurred, 75% (9/12) were called Class 2. Combined GEP and SLN risk prediction identified 88% (21/24) of recurrences. Kaplan-Meier event rates for each class are shown in the table. In Cox multivariate analysis, BT and GEP Class 2 were significant predictors of recurrence (p<0.01 for each). Conclusions: Results of this analysis show that the GEP test provides prognostic information that complements conventional staging and significantly enhances identification of high risk CM pts, consistent with reported validation studies.The results support use of the test for guiding surveillance decisions and enrollment of CM pts in clinical trials. Clinical trial information: NCT02355574, NCT02355587. [Table: see text]
Primary melanoma histologic subtype (HS) impacts melanoma specific survival (MSS) and response to systemic therapy.
Authors: Lattanzi Michael , Lee Yesung , Robinson Eric Michael , Weiss Sarah A. , Moran Una , Simpson Danny , Shapiro Richard L. , Berman Russell S. , Pavlick Anna C. , Wilson Melissa , Kirchhoff Tomas , Zhong Judy , Osman Iman
Published: September 2018

9577

Background: Unlike other solid tumors, the impact of primary HS on melanoma survival and response to systemic therapy is not well studied. Nodular melanoma (NM) has a worse prognosis than superficial spreading melanoma (SSM), which is usually attributed to thicker primary tumors. Herein, we examine the hypothesis that HS might have an impact on MSS independent of thickness and that NM and SSM exhibit different mutational landscapes that associate with response to checkpoint inhibitor immunotherapy (IT) and BRAF targeted therapy (TT) in the metastatic setting. Methods: Primary NM and SSM patients prospectively enrolled at NYU (2002 - 2016) were compared to the most recent SEER cohort (1973 - 2012) and analyzed with respect to MSS. Next-Generation Sequencing (NGS) was performed on a subset of matched tumor-germline pairs, allowing a comparison of the mutational landscape between NM and SSM. In the metastatic setting, survival analyses were used to compare outcomes and responses to treatment across HS. Results: The NYU cohort of 1,621 patients with either NM (n = 510) or SSM (n = 1,111) was representative of the analogous SEER cohort (21,339 NM, 97,169 SSM), with NM presenting as thicker, more ulcerated, and later stage (all p < 0.001). Among the NYU cohort, NM was found to have lower rates of TIL (p = 0.047), higher mitotic index (p < 0.001), and higher rates of NRAS mutation (p < 0.001). In multivariate Cox models, NM was a significant predictor of worse MSS, independent of thickness and stage (p = 0.01). NM had a significantly lower mutational burden across the exome (p < 0.001). Some of the most under-mutated genes noted in NM were NOTCH4, BCL2L12 and RPS6KA6 (all p < 0.01). Among patients treated with TT (n = 56), NM remained a significant predictor of worse MSS (p = 0.004). However, there was no difference in response to IT. Conclusions: NM and SSM show divergent mutational patterns which may contribute to their different clinical behaviors and responses to BRAF targeted therapy. More studies are needed to better understand the key molecular and cellular processes driving such differences. Integration of HS data into prospective clinical trial reporting is needed to better assess its impact on response to treatment.
Explanation model using pathological data for treatment outcome of patients with early-stage breast cancer with hormonal receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative.
Authors: Prasongsook Naiyarat
Published: September 2018

e12006

Background: The decision to initiate adjuvant chemotherapy for early-stage breast cancer patients with HR+ and HER2- is still unclear. Although the 21-gene Recurrence Score (RS) assay is a validated testing and becomes an emerging decision-making tool; it is still controversial guidance on adding adjuvant chemotherapy for patients with intermediate RS. This study aimed to develop the explanation model by using pathological information for prediction of the best outcome from adjuvant systemic treatment in these patients.Methods: Early-stage breast cancer patients with HR+, and HER2- who underwent complete resection registered within electronic medical record from 2003 to 2013 were included. Patient’s characteristics and pathological information were collected and analyzed. Univariate and multivariate analysis were conducted by using stepwise logistic regression. The explanation model was explored by using association between multivariate models and overall survival (OS).Results: 236 patients who underwent complete surgery treatment were included. 121 patients (51%) were treated with sequential adjuvant treatment, and 115 patients (48%) with anti-hormonal therapy alone. Clinicopathological parameters between two groups were demonstrated in Table1. Tumor size (≥2 – 5 cm), Estrogen receptor-negative/ Progesterone receptor-positive (ER-/PgR+), and Ki-67 expression were statistically significant multivariate independent prognostic factors for OS. When we adjusted for tumor size, HR status, and Ki-67 expression, the explanation model predicted 10-year OS was 99.2% for patients with sequential adjuvant treatment, whereas 89.5% for patients with adjuvant anti-hormonal alone (difference: 9.7%); p-value = 0.01.Conclusions: We found substantial discordance in 10-year OS benefit between early-breast cancer patients with HR+, HER2- with sequential adjuvant therapy and adjuvant hormonal therapy alone. Adjuvant chemotherapy should be considered in early-breast cancer patients with 2-3 cm in tumor size, ER-/PgR+, and Ki 67 expression.
A clinicopathological prediction model for recurrence in patients with early-stage hormone-receptor-positive, HER2-negative breast cancer at King Chulalongkorn Memorial Hospital.
Authors: Uttamapinan Suleepon , Iampenkhae Kroongpong , Rattananupong Thanapoom , Poovorawan Nattaya , Sriuranpong Virote , Parinyanitikul Napa
Published: September 2018

e12015

Background: Genetic recurrent score has been increasingly applied in combination with clinicopathology for predicting recurrence and guiding the potential role of adjuvant chemotherapy in patients with early breast cancer. However, lack of accessibility limits its use for clinical practice especially in developing countries. Our study aims to formulate model for predicting risk of recurrence in patients with hormone-receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative early breast cancer. Methods: Five hundred and twenty nine HR-positive, HER2-negative early breast cancer patients who were diagnosed during 2005 to 2015 in King Chulalongkorn Memorial Hospital were retrospectively reviewed. All potentially clinicopathologic prognostic factors for recurrence were analyzed using multivariable logistic regression. Results: Ninety eight HR-positive, HER2-negative early breast cancers developed distant recurrences after a median follow-up of 65.7 months (IQR, 41.2 - 92.3). There was no difference among recurrent and non-recurrent groups in term of age and menopausal status. However, greater number of patients in non-recurrent group had earlier stage (stage I or II). Most of patients in both groups received hormonal therapy, while more patients in the recurrent group received adjuvant (82.7% vs. 70.8%; P = 0.017) and neoadjuvant chemotherapy (35.1% vs. 11.2 %; P < 0.001). From multiple logistic regression using clinical and pathologic variables, lymphovascular invasion (LVI), percentage of Ki-67, and tumor size were independent predictors of recurrence (OR 3.04; P < 0.001, OR 1.02; P = 0.001, and OR 1.18; P= 0.05, respectively). The prediction model for 10-year recurrent risk appears as “log (odd) = - 3.535 + 0.020 (percentage of Ki-67) + 0.165 (Tumor size in cm) + 1.111 (LVI)”. Probability of recurrence is defined as odd / (1+odd). This model yields a C statistic above 0.7 on validation in independent population. Conclusions: A new clinicopathologic prediction model provides comprehensive recurrent risk estimation for Thai patients with HR-positive, HER2-negative early breast cancer.
A comparative analysis of clinicopathological characteristics and disease-free survival (DFS) outcomes in breast cancer patients: Mammograpghy vs symptomatic diagnosis.
Authors: Karaca Mustafa
Published: September 2018

e12018

Background: Our goal was to compare clinicopathological characteristics and DFS time among breast cancer patients diagnosed with mammography or symptoms. Methods: This was retrospective analysis of 828 patient files. Diagnosis was done with mammography or symptom,considering the followings:age,menopause,hormone and HER2 receptor,grade,histologic subtype,lymphovascular(LVI) and perineuronal invasion(PNI),adjuvant chemotheraphy,adjuvant herceptin,adjuvant hormone and adjuvant radiotheraphy use.Recurrence dates,locations and last appointment dates were noted. Results: Breast cancer was detected by mammography in 324 patients vs by sysmptom in 504.The difference in most cases between these two methods were significant,and respectively:positive ALND 30% vs 53.7% p=0.0001,LVI 13.7% vs 31.6% p=0.0001,PNI 7.2% vs 18.1% p=0.0001,adjuvant chemo 67% vs 85% p=0.0001,adjuvant hormone use 87.3% vs 82% p=0.001.However, recurrence rates did not differ sigificantly among two groups 12% vs 12.6% p=0.4.The median follow-up and DFS time was 48 and 37 months,respectively.Prognostic parameters were also analyzed.Pathologic staging p=0.002,PNI p=0.027,LVI p=0.0001,hormone receptor status p=0.0001,triple negativity p=0.016,luminal A group p=0.048 were found statistically significant on DFS.Diagnosis with mammography was found to have no statistically significant effect on DFS. Conclusions: Although patients diagnosed with mammography had better prognostic parameters,recurrence rates were similar with symptomatic patients at the time of diagnosis.At survival analysis,recurrence rates were calculated to be similar to those of symptomatic patients’ group.
Relationships of cyclin E with clinical outcome and biomarkers in older women with early operable primary breast cancer.
Authors: Syed Binafsha Manzoor , Green Andrew R. , Morgan Dal , Ellis Ian O. , Hunt Kelly , Keyomarsi Khandan , Cheung Kwok-Leung
Published: September 2018

e12031

Background: Cyclin E is one of the factors responsible for transition from G1 to S phase of cell division. Cytoplasmic cyclin E has recently been shown to be associated with the greatest risk of breast cancer recurrence (Hunt KK et al. Clin Cancer Res. 2016 Nov 23). This study aimed to analyse intracellular relationships of cyclin E with clinical outcomes and with other biomarkers in a specific patient population. Methods: Over 37 years (1973-2010), 1,758 older (≥70 years) women with early operable (<5cm) primary breast cancer were managed in a dedicated clinic in Nottingham. Of these 813 patients underwent primary surgery and 575 had good quality tumour samples available for tissue microarray construction and immunohistochemical studies of biomarkers. Cytoplasmic expression of cyclin E with or without nuclear expression was considered positive. Results: Cytoplasmic cyclin E expression was associated with poor clinical outcomes on multivariate analysis (see table below). Cytoplasmic cyclin E expression was significantly associated with negative ER(<0.001), PR(p=0.008), CK19(p=0.009) and positive expression of Ki67(p=0.04), p53(p=0.02), CK5(p=0.001), CK17(p=0.04), LKB1(p=0.04), HER3(p=0.03) and HER4(p=0.04). No correlation was found with HER2, BRCA2, CK5/6, CK18, EGFR, CD44, MDM2, MDM4, E-Cadherin and MUC1. Conclusions: Cytoplasmic cyclin E is associated with poor clinical outcome and biomarkers of poor prognostic significance in older population with breast cancer. Cyclin E may serve as a potential therapeutic target in future. [Table: see text]
Trastuzumab-related cardiotoxicity in patients with non-limiting cardiac comorbidity.
Authors: Martinello Rossella , Becco Paolo , Vici Patrizia , Airoldi Mario , Del Mastro Lucia , Garrone Ornella , Barone Carla , Pizzuti Laura , D'Alonzo Alessia , Bellini Elisa , Milani Andrea , Bonzano Alessandro , Montemurro Filippo
Published: September 2018

e12043

Background: Significant and symptomatic cardiac comorbidity (CC) is a contraindication to adjuvant trastuzumab (T) in breast cancer patients (pts). However, some pts with asymptomatic, non-limiting CC and normal baseline left ventricular ejection fraction (LVEF) receive T in the clinical practice. We sought to describe the tolerability of T in these pts. Methods: Retrospective analysis of pts with baseline asymptomatic non-limiting CC receiving adjuvant T with chemotherapy (CT) at 6 Institutions between Jul 2006 and Jan 2016. Results: Thirty-seven patients HER2-positive, operable BC at high risk of relapse BC were studied. Median age was 64y (range 36-82, 80% post-menopausal), median baseline LVEF was 61% (range 50-85%) and median BMI 26 (18-42, obesity 22%). Thirteen patients (35%) received T with adjuvant anthracycline and taxane-based, 19 (51%) taxane-based and 3 (8%) other adjuvant CT regimens (13 pts sequential, 22 pts concomitant with CT) and 2 (5%) with endocrine therapy. Prior non-limiting CC was ischemic heart disease (35%), valvular disease (30%), atrial fibrillation (19%), conduction disorders (13%), aortic aneurism (3%), and other (19%). Nine (29%) pts experienced TRC: congestive heart failure (1 pt, 3%), LVEF reduction (6 pts, 16%) and rhythm disturbances (1 pt, 3%). TRC occurred in pts with ongoing multiple cardiovascular risk factors (i.e. obesity and hypertension). Seven pts discontinued T because of TRC (19%), 5 permanently (14%) and 2 temporarily (5%). These latter pts, were able to resume and complete T after TRC resolution. At the end of adjuvant treatment, all pts showed LVEF within normal limits, except one of those who experienced a TRC (last FU value 46 %). Conclusions: This is the first analysis of TRC in pts receiving adjuvant T in the presence prior non-limiting CC. Despite the small size, our analysis shows that T is feasible in these pts and most of the TRC events were reversible at T withdrawal. Caution is needed in pts with significant ongoing cardiovascular risk factors, but when adjuvant T is deemed beneficial on breast cancer outcomes, non-limiting CC should not preclude treatment.
Adherence and persistence to adjuvant hormonal therapy in early stage breast cancer patients: A population-based retrospective cohort study in Israel.
Authors: Sella Tal , Chodick Gabriel
Published: September 2018

e12051

Background: Adjuvant hormonal therapy has been consistently proven to improve multiple outcomes in early breast cancer. Nonetheless, data on rates of adherence and persistence with therapy outside West Europe and North America are scarce. We assessed the adherence and persistence with adjuvant hormonal in a retrospective population based cohort of breast cancer survivors in Maccabi Health Services (MHS), Israel. Methods: We identified women who were diagnosed with breast cancer and initiated adjuvant hormonal therapy between January 2000 and November 2008. Subjects were followed retrospectively from first dispensed tamoxifen or aromatase inhibitor (AI) and up to the earliest of the following events: disease recurrence (indicated by surgery, radiotherapy, chemotherapy or other related therapies), leaving MHS, death, or completion of 5 years of treatment. Discontinuation of therapy was defined as a 180-day or longer treatment gap. Adherence with therapy was assessed using proportion of days covered (PDC) during follow-up period. Survival analysis was used to determine the effect of adherence on all-cause mortality. Results: A total of 4178 women with breast cancer were followed for a median 7.8 years. Over 90% of patients received tamoxifen as the initial hormonal agent. Mean PDC was 84% with lower rates associated with younger age, smoking status, comorbidities and year of diagnosis. Residential area did not affect adherence. Differences were not found. Discontinuation of therapy occurred in 23% of study patients. Among persistent patients, 70% were optimally adherent with therapy (PDC>=80%). Association between adherence with therapy and survival is investigated. Conclusions: Adherence to adjuvant hormonal therapy among Israeli breast cancer patients with national health insurance is high in comparison to international reports. Nevertheless, suboptimal adherence was identified among younger (<45y) patients. Because of the efficacy of hormonal therapy in preventing recurrence and death in women with early-stage breast cancer, interventions are necessary to identify and prevent suboptimal adherence among high risk subgroups.
Outcomes related to delayed initiation of anti-HER 2 therapy in pregnant HER2 positive breast cancer patients.
Authors: Oke Oluchi , Warneke Carla L. , Chavez-Mac Gregor Mariana , Milbourne Andrea , Litton Jennifer Keating
Published: September 2018

e12059

Background: Overexpression of HER2 is associated with aggressive breast cancers. In non-pregnant HER2+ breast cancer patients, anti-HER2 therapy is usually initiated after surgery or in the neoadjuvant setting. However, for pregnant HER2+ breast cancer patients, anti-HER2 therapy must be delayed until after delivery due to fetal toxicity. We describe here the outcomes of pregnant patients with HER2+ breast cancer at a single center. Methods: Twenty-three pregnant HER2+ breast cancer patients were treated between November 1989 to October 2016. Median age at diagnosis was 31.8. (Table 1) We report Kaplan-Meier estimates of OS from diagnosis and PFS from surgery. The effect of time from diagnosis to anti-HER2 therapy (TTH) on OS and PFS from HER2 therapy initiation was assessed using Cox proportional hazards regression models. Results: Seventeen patients received anti-HER2 therapy after delivery, 6 did not – 4 were treated prior to the use of HER2 therapies, and 2 were lost to follow-up. Median TTH was 181 days. All but 3 patients started HER2 treatment within 2 months of delivery. Twenty-one received anthracycline-based chemotherapy during pregnancy. Three patients have died, with all 3 receiving HER2 therapy, but one only at relapse due to diagnosis before routine trastuzumab use. Median follow-up was 3.4 years (range 0.2-16.2 years), and 5-year OS was 80% (95%CI 41-95%). Five patients progressed. Median PFS was 3.1 years (range 0.3-14.2 years), and 5-year PFS was 75% (95%CI 46-90%). Delay of initiation of HER-2 therapy did not appear to be associated with OS or PFS from date of HER-2 therapy initiation (both n = 17, HR 1.01, 95%CI 0.97-1.06, P= 0.52). Conclusions: In this small case series, we did not detect adverse outcomes associated with delaying initiation of anti-HER2 therapy in pregnant patients with HER2+ breast cancer. Larger series are needed to further evaluate this concern. [Table: see text]