bluuebunny/crossref_metadata_2025 huggingface dataset:
Adjuvant bevacizumab as treatment for melanoma patients at high risk of recurrence: Final results for the AVAST-M trial.
Authors: Corrie Philippa , Marshall Andrea , Lorigan Paul , Gore Martin Eric , Tahir Saad , Faust Guy , Kelly Charles G. , Marples Maria , Danson Sarah , Marshall Ernest , Houston Stephen , Board Ruth E. , Waterston Ashita Marie , Nobes Jenny Penelope , Harries Mark , Kumar Satish , Young Gemma , Barker Emily , Dunn Janet , Middleton Mark R.
Published: September 2018

9501

Background: Bevacizumab (Bev) is a recombinant humanised monoclonal antibody to vascular endothelial growth factor (VEGF) shown to improve survival in several advanced solid tumours. As VEGF is a relevant target in melanoma, AVAST-M aimed to evaluate the role of Bev in melanoma patients at high risk of recurrence. Methods: AVAST-M (ISRCTN81261306) is a randomised phase III trial evaluating single agent Bev (7.5mg/kg IV 3 weekly for 1 year) as adjuvant therapy after resection of AJCC stage IIB, IIC and III cutaneous melanoma compared to standard observation (Obs). 1320 patients were needed to detect 8% differences in 5 year overall survival (OS) rate from 40% to 48%; 85% power, 5% alpha level. Primary endpoint was OS; secondary endpoints included disease free interval (DFI), distant-metastasis free interval (DMFI). BRAF and NRASmutation status were obtained in 682 patients in a translational sub-study. Results: From July 2007 to March 2012, 1343 patients were recruited (671 to Bev; 672 to Obs). 56% were male, median age was 56 years (range 18-88 years), 14% were stage IIIA and 59% were stage IIIB/C. With 6 years median follow-up, 505 (38%) patients had died (251 [37%] on Bev; 254 [38%] on Obs); 699 (52%) patients had recurred (335 [50%] on Bev, 369 [55%] on Obs). OS at 5 years was 64% on Bev versus 63% on Obs (Hazard ratio [HR] 0.99; 95% confidence interval [CI] 0.84-1.18, p=0.96). At 5 years, 51% were disease free on Bev versus 45% on Obs (HR 0.85; 95% CI 0.74-0.99, p=0.04) and 59% were distant metastasis free on Bev versus 54% on Obs (HR 0.91; 95% CI 0.77-1.07, p=0.24). A BRAF V600 mutation was found in 44% of tumours assessed; 20% were NRAS mutant. BRAF mutant patients treated with Bev tended to have better DFI (HR=0.79 95% CI 0.58-1.08, p=0.14) and OS (HR=0.79; 95% CI 0.55-1.13, p=0.20); this was not evident for BRAF WT. NRAS mutant patients tended to have worse DFI (HR=1.39; 95% CI 1.03-1.88; p=0.03) and OS (HR=1.18; 95% CI 0.85-1.62, p=0.20) than NRASWT patients. Conclusions: This large, multi-centre trial of melanoma patients at high risk of recurrence has shown that adjuvant Bev improves DFI, but this does not translate into an overall survival benefit. Funding:Cancer Research UK; drug supplied by Roche Products Ltd. Clinical trial information: ISRCTN81261306.
Final results of a phase II multicenter trial of HF10, a replication-competent HSV-1 oncolytic virus, and ipilimumab combination treatment in patients with stage IIIB-IV unresectable or metastatic melanoma.
Authors: Andtbacka Robert Hans Ingemar , Ross Merrick I. , Agarwala Sanjiv S. , Taylor Matthew H. , Vetto John T. , Neves Rogerio Izar , Daud Adil , Khong Hung T. , Ungerleider Richard S. , Tanaka Maki , Grossmann Kenneth F.
Published: September 2018

9510

Background: HF10 is a bioselected replication-competent oncolytic virus derived from HSV-1. Herein, we report the safety and efficacy data of HF10 + ipilimumab (ipi) combination treatment in a Phase II trial in melanoma. Methods: Key entry criteria: age ≥ 18 yrs, ECOG ≤ 2, Stage IIIB, IIIC, or IV unresectable melanoma, ipi naïve (IV administration) and measurable non-visceral lesion(s) suitable for injection. HF10 injected into single or multiple tumors (1 x 107 TCID50/mL/dose, up to 5mL depending on tumor size and number); 4 injections q1wk; then up to 15 injections q3wk. Four ipi IV infusions (3 mg/kg; concurrent with HF10) were administered q3wk. AEs assessed per CTCAE 4.0. Tumor responses were assessed per mWHO and irRC at 12, 18, 24, 36 and 48 wks for patients (pts) continuing on HF10 monotherapy. Primary endpoint was Best Overall Response Rate (BORR) at 24 wks. Dose limiting toxicity (DLT) defined as ≥ G3 non-hematologic/hematologic toxicity, ≥ G2 neurologic toxicity, or allergic event occurring within 1st 3wks of therapy. Results: Of 46 pts enrolled and treated: 59% men, median age 67 yrs (range 28 to 91); disease stage 20% IIIB, 43% IIIC and 37% IV; 57% were treatment naïve and 43% with ≥ 1 prior cancer therapy for unresectable/metastatic melanoma. Most HF10-related AEs were ≤G2, similar to HF10 monotherapy. No DLTs were reported. 37% had ≥G3 AEs, the majority due to ipi. HF10-related ≥G3 AEs (n=3) were embolism, lymphedema, diarrhea, hypoglycemia, and groin pain. Of the 44 efficacy evaluable pts per irRC, BORR at 24 weeks was 41% (16% irCR and 25% irPR); disease stability rate was 68% (16% irCR, 25% irPR and 27% irSD). As of Feb 06, 2017, median PFS was 19 months and median overall survival was 21.8 months. Conclusions: The combination HF10 and ipilimumab treatment demonstrated a favorable benefit/risk profile and encouraging antitumor activity in pts with stage IIIB, IIIC, or IV unresectable or metastatic melanoma. Clinical trial information: NCT02272855.
Overall survival (OS) analysis from an expanded access program (EAP) of nivolumab (NIVO) in combination with ipilimumab (IPI) in patients with advanced melanoma (MEL).
Authors: Hogg David , Chapman Paul B. , Sznol Mario , Lao Christopher D. , Gonzalez Rene , Daniels Gregory A. , Smylie Michael , Kudchadkar Ragini Reiney , Thompson John A. , Sharfman William Howard , Atkins Michael B. , Pavlick Anna C. , Jiang Joel , Avila Alexandre , Demelo Sheena , Hodi F. Stephen
Published: September 2018

9522

Background: NIVO (anti-PD-1) and IPI (anti-CTLA-4), alone and in combination, are approved for the treatment of MEL. Phase II and III trials showed improved efficacy for NIVO+IPI versus IPI alone, but with a higher frequency of adverse events (AEs). In the phase II CheckMate 069 trial, the 2-year OS rate was 63.8% for all patients (pts) in the NIVO+IPI group. We report the first OS analysis, as well as updated safety data, from a North American EAP of NIVO+IPI in pts with MEL (CheckMate 218; NCT02186249). Methods: CheckMate 218 included pts with MEL who could have progressed on other therapies, but were anti-CTLA-4 and anti-PD-1 treatment-naive. Pts received NIVO 1 mg/kg + IPI 3 mg/kg Q3W x 4, followed by NIVO 3 mg/kg Q2W until disease progression or a maximum of 48 weeks from the first monotherapy dose. We assessed OS in the US cohort (n = 580) and safety in all pts (n = 732). Pts were followed for a minimum of 1 year in the USA and 6 months in Canada. Results: Of 732 pts, 43% had a BRAFmutation, 84% stage IV MEL, 51% M1c disease, 31% LDH > ULN (9% LDH > 2x ULN), and 13% received ≥1 prior systemic therapy in the metastatic setting. All pts received a median of 3 doses each for NIVO (range: 1–4) and IPI (range: 0–4) in the induction phase; 34% of pts received at least 1 dose of NIVO maintenance. The 1- and 2-year OS rates were 78.6% (95% CI: 74.2–82.4) and 65.3% (95% CI: 56.1–73.0), respectively. AEs of any grade occurred in 717 pts (98%), with grade 3/4 AEs in 470 pts (64%). Immune-modulating medications were used to manage any grade AEs, including grade 1/2 skin and gastrointestinal AEs, in 538 of 717 pts (75%), and to manage grade 3/4 AEs in 279 of 470 pts (59%). The most common treatment-related AEs of any grade were diarrhea (39%), pruritus (26%), and an increase in aspartate aminotransferase level (23%). Treatment-related deaths in 2 pts were reported as drug-induced liver injury and myocardial infarction. Conclusions: In this EAP, which included pts who had received prior systemic therapies for MEL and pts with poor prognostic factors generally not included in clinical trials, NIVO+IPI treatment demonstrated survival outcomes and a safety profile consistent with clinical trial data. Clinical trial information: NCT02186249.
Follow-up of patients with complete remission of locally advanced basal cell carcinoma treated with vismodegib after treatment discontinuation: A retrospective multicentric French study.
Authors: Herms Florian , Haudebourg Luc , Bagot Martine , Dutriaux Caroline , Grob Jean Jacques , Guillot Bernard , Jeudy Geraldine , Lambert Jérôme , Lebbe Celeste , Mateus Christine , Meyer Nicolas , Monestier Sandrine , Mortier Laurent , Poulalhon Nicolas , Prey Sorilla , Robert Caroline , Vabres Pierre , Mouri Mehdi , Basset-Seguin Nicole
Published: September 2018

9535

Background: Vismodegib is a Hedgehog Pathway inhibitor (HPI) indicated for treatment of inoperable locally advanced basal-cell carcinoma (laBCC). Previous studies showed an objective response (OR) rate of 67%, including 34% of complete response (CR). Discontinuation of vismodegib is very frequent, mostly due to intolerable side-effects. Long-term response and predictive factors of relapse after suspension of vismodegib have not yet been evaluated, but should play a crucial role in the management of laBCC patients. Methods: We conducted an observational retrospective study in 9 onco-dermatological French units. Medical charts of laBCC patients treated with vismodegib from March 2012 until June 2016 were reviewed and patients with CR who stopped treatment were selected. Relapse was diagnosed clinically and/or histologically. A survival analysis was conducted, and predictive factors, characterization and management of relapse were studied. Results: 119 laBCC patients achieved CR and stopped treatment. 21 were lost to follow-up and 6 died before relapse. Event-free survival median was 18.4 months (12.1 – 24.1) and cumulative incidence of relapse at 36 months was 59.04% (48.05 - 70.04), implying that more than 40% of patients do not relapse. Multiple BCC and BCC not localized on the head and neck were associated with a higher risk of relapse, independently of the existence of Gorlin syndrome (HR = 3.3 (IC95 = 1.6 - 6.7) and 2.01 (IC95 = 1.05 - 3.87) respectively). Total duration of treatment was not associated with relapse. 50% (n = 27) of patients who relapsed during follow-up were retreated with vismodegib, with an OR of 85.2% (n = 23). 42% (n = 24) were eligible to surgery only and other patients received local treatments. Conclusions: Long term responders after vismodegib treatment discontinuation are frequent independently of the time exposure to the drug before and after CR. Most patients who relapse are still responder to vismodegib rechallenge. Patients with multiple or laBCC not localized on the head and neck are more at risk of relapse after discontinuation. This study emphasizes the interest of treatment of laBCC with HPI.
Association of concomitant use of acid reducing agents in full-dose vemurafenib users with risk of progression in BRAF V600 mutation-positive unresectable or metastatic melanoma patients: A retrospective cohort study.
Authors: Knapen Lotte Marieke , Koornstra Rutger H.T. , Driessen Johanna H.M. , Van Vlijmen Bas , Croes Sander , Schalkwijk Stein J. , Colbers Angela , Gerritsen Winald , Burger David , de Vries Frank , Van Erp Nielka P.
Published: September 2018

9540

Background: Vemurafenib is used for the treatment of adult patients with BRAF V600 mutation-positive unresectable or metastatic melanoma. The approved fixed vemurafenib dose of 960 mg twice daily may result in overexposure. Concomitant use of acid reducing agents (ARAs) may result in underexposure. Both situations are likely to affect treatment outcome. Therefore, the aim of this study was to determine the association between the use of vemurafenib (full-dose versus reduced dose) and/or concomitant ARA use (yes versus no) and the risk of disease progression. Methods: A retrospective cohort study was conducted using data from the electronic health record software of the Radboudumc pharmacy and medical records of the Radboudumc (March 17th 2012 to March 17th 2016). Patients (N = 112) using vemurafenib as first line treatment for melanoma were included. Multivariable cox regression estimated adjusted hazard ratios (HRa) and 95% confidence intervals (CI) of progression in vemurafenib users (full-dose N = 67 versus reduced dose N = 45) and/or concomitant ARA users (N = 38). Adjustments were made for age and sex. Results: The mean follow-up time was 3.5 months and 41 patients (36.6%) developed progression on first line vemurafenib. Co-treatment of ARAs in patients using full-dose vemurafenib was associated with a 4.6-fold increased risk of progression (HRa 4.56; 95% CI 1.51-13.75) as compared to full-dose vemurafenib users not co-treated with ARAs. No increased risk was found for users of vemurafenib in a reduced dose, regardless of concomitant ARA use. Conclusions: Concomitant use of ARAs in full-dose vemurafenib users was associated with an increased risk of progression. Physicians should be cautious to prescribe ARAs to patients tolerating full-dose vemurafenib. The presence of considerable confounding by disease severity, the small number of events and the hypothesis generating character of this study emphasize the need to prospective validate these results.
Outcomes of patients with melanoma who discontinue immunotherapy.
Authors: Rosner Samuel , Bogatch Kita , Postow Michael Andrew
Published: September 2018

9548

Background: The question of when to discontinue (d/c) anti-program death-1 (PD-1) monotherapy (mono) or nivolumab in combination with ipilimumab (combo) immunotherapy (IT) is unknown. Methods: After IRB approval, a single center (Memorial Sloan Kettering Cancer Center), retrospective study was performed of 162 pts with unresectable stage III or IV melanoma treated with either mono (n = 106) or combo (n = 56) IT. Objective response rate (ORR), progression free survival (PFS), and overall survival (OS) were calculated for all pts from the 1stdose of IT. For pts (n = 40; mono and n = 40; combo) who d/c IT due to reasons (Table) other than progression or death, starting from the last date of IT, we then reported PFS, time to treatment failure (TTF) defined as any subsequent surgery/radiation/systemic therapy, and OS. Results: For pts that were alive at time of analysis, the median follow up was 28 mos. For all 162 pts (demographics in Table), ORR was 38.7% (mono) and 60.7% (combo); median PFS and OS were 12 months (mos) and 25 mos for mono; 34 mos and not reached (NR) for combo, respectively. From the last dose of IT, the PFS, TTF, and OS for 40 mono pts and 40 combo pts who d/c IT for reasons other than progression/death are shown in Table. Reasons included CR, toxicity, or other (most commonly protocol completion or prolonged PR). Conclusions: Outcomes in this cohort of pts with long follow-up treated with mono or combo IT are similar to results from other clinical trials. Pts who d/c IT for reasons other than progression/death were a highly selected group. Nonetheless, favorable PFS, TTF, and OS were seen after IT d/c, even in pts who did not obtain a CR. [Table: see text]
A dose escalation phase 1 study of radiotherapy (RT) in combination with anti-cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibody ipilimumab in patients (pts) with metastatic melanoma.
Authors: Boutros Celine , Mateus Christine , Lanoy Emilie , Routier Emilie , Chouaib Salem , Schwob Dominique , Vagner Stephan , Girault Isabelle , Caramella Caroline , Hibat Salima , Tao yun Gan , Cao Kim , Chaput Nathalie , Adam Julien , Soria Jean-Charles , Eggermont Alexander M. , Deutsch Eric , Robert Caroline
Published: September 2018

9549

Background: Preclinical findings have shown a synergy between RT and anti-CTLA-4 monoclonal antibody in several tumor animal models for both local tumor control and distant effects. Preliminary clinical data suggest that it could be due to an abscopal effect of RT. The Mel-Ipi-Rx phase 1 study aimed to determine the maximum tolerated dose (MTD) and safety profile of RT combined with ipilimumab in pts with metastatic melanoma. Methods: A 3+3 dose escalation design was used with 9, 15, 18 and 24 Gy dose of RT (in 3 fractions) at week 4 combined with 10 mg/kg ipilimumab (every 3 weeks for 4 doses). Pts with evidence of clinical benefit at week 12 were eligible for maintenance ipilimumab at 10 mg/kg every 12 weeks starting at week 24 until severe toxicity or disease progression based on immune-related response criteria (irRC). Results: 19 pts with advanced melanoma received ipilimumab between August 2011 and July 2015. Nine pts received the 4 doses of ipilimumab and 2 pts received maintenance ipilimumab (1 and 2 cycles respectively). All pts received the combined RT at week 4 in 3 fractions. All pts presented at least one AE of any grade. The most common AEs were asthenia, diarrhea, desease-related pain and fever. Grade 3 AEs occurred in 8 pts. They included colitis (n = 3), hepatitis (n = 2), anemia (n = 2), asthenia (n = 1), thyroid disorders (n = 1) and nausea/vomiting (n = 1). Nine pts discontinued the study owing to treatment-related adverse events including colitis (n = 6), hepatitis (n = 2) and DRESS (Drug Rash with Eosinophilia and systemic syndrome) (n = 1). DLT occurred in 2/6 pts in the cohort receiving 15 Gy. No drug-related death occurred. According to irRC, 4 partial responses (ORR: 21%) and 4 stable diseases were observed at week 24. The MTD was 9 Gy dose. One pt out of 12 treated in the 9 Gy cohort presented a DLT (grade 3 colitis). The median progression-free survival [95% CI] was 7.2 months [2.4 – 16.8]. The median overall survival [95% CI] was 14.4 months [7.2 – 20.4]. Conclusions: When combined with ipilimumab at 10 mg/kg, in the present design, the MTD of RT was 9 Gy. This combination appears to be associated with antitumor activity. Clinical trial information: 2010-020317-93.
Analysis of mutational burden and adaptive immune response in desmoplastic melanomas treated with PD-1/L1 inhibitors.
Authors: Hu-Lieskovan Siwen , Eroglu Zeynep , Zaretsky Jesse Meir , Kim Dae Won , Algazi Alain Patrick , Johnson Douglas Buckner , Liniker Elizabeth , Kong Ben , Munhoz Rodrigo , Rapisuwon Suthee , Chmielowski Bartosz , Sosman Jeffrey Alan , Scolyer Richard A. , Joseph Richard Wayne , Postow Michael Andrew , Carlino Matteo S. , Hwu Wen-Jen , Long Georgina V. , Ribas Antoni
Published: September 2018

9558

Background: Desmoplastic melanoma (DM) is a rare subtype of melanoma characterized by a dense fibrous stroma, resistance to chemotherapy and no actionable driver mutation for targeted therapy. We investigated the efficacy of PD-1/L1 inhibitors and correlation with genetic landscape and tumor immune microenvironment in DM. Methods: Retrospective analysis of 1054 pts with melanoma treated with anti-PD-1/L1, resulting in 57 pts with unresectable or metastatic DM. Available baseline biopsies were analysed by digital quantitative immunohistochemistry (IHC) for CD8 and PD-L1 and by whole exome sequencing (WES), compared to available tissue from non-DM pts treated with anti-PD1/L1 at UCLA. Results: At a median follow up of 20 mo, 40 pts (70%, 95% CI 57-82) had an objective response by RECIST 1.1 criteria, including 18 (45%) CRs with no relapse observed to date. Responses were similar in DM subsets (23 pure, 29 mixed and 5 indeterminate). Kaplan-Meier estimated 1-year and 2-year overall survival were 85% (95% CI 78-98) and 74% (95% CI 64-89). WES revealed a median of 1282 (interquartile range 517-1692) non-synonymous somatic mutations per tumor in DM tumors (n = 17), significantly higher (p = 0.02) than the median of 462 (interquartile range 230-1150) in non-DM (n = 23). Mutations in NF-1 were the most common (13/17) followed by loss-of-function TP53 and ARID2, and > 82% of single nucleotide mutations were UV damage signatures. IHC analysis from 19 DM and 13 non-DM revealed a strikingly higher percentage of PD-L1 positive cells in the tumor parenchyma in DM (p = 0.04), highly associated with CD8 density and PD-L1 expression in the tumor invasive margins, indicating an active adaptive immune response. No genetic mechanisms known to cause constitutive PD-L1 expression were detected in these samples. Conclusions: Patients with advanced DM derive significant clinical benefit from PD-1/L1 inhibitors, likely related to the high mutational burden and a highly active adaptive immune response as the main mechanism of immune escape prior to therapy. Our results challenge the general conception that dense fibrous stroma around the malignant cells interferes with immune cell infiltration and efficacy of immunotherapy.
Mutation burden as a potential prognostic marker of melanoma progression and survival.
Authors: Simpson Danny , Ferguson Robert , Martinez Carlos N. , Kazlow Esther , Moran Una , Heguy Adriana , Hanniford Douglas , Hernando Eva , Osman Iman , Kirchhoff Tomas
Published: September 2018

9567

Background: Recently, tumor mutation burden (TMB) has been shown to increase the presentation of neoantigens that stimulate immune tumor recognition, resulting in improved immunotherapy (IT) outcomes in melanoma and other cancers. As melanoma is highly immunogenic, here we tested whether TMB associates with immune recognition during tumor progression, hence impacting melanoma overall survival (OS), independently of IT treatment. Methods: We have generated somatic mutation data from 314 IT-naive metastatic melanomas from The Cancer Genome Atlas (TCGA). In the TCGA cohort, TMB has been calculated for 210 genes (200GS) previously established from TMB studies of anti-CTLA4 and anti-PD1/PD-L1 IT. For validation, we have sequenced exonic regions of 20 genes (20GS) with the highest TMB among 200GS in 89 IT-naive metastatic melanomas ascertained at New York University Langone Medical Center. The TMB was defined using total number of somatic, non-synonymous mutations in either 200GS (TCGA discovery) or 20GS (validation), respectively. For discovery and validation cohorts, OS from primary diagnosis of samples with high TMB was compared against low TMB, using thresholds established in previous studies. Results: We found that total TMB predicts better OS (p = 0.03, HR = 2.64) in TCGA melanomas. Restricting the analysis only to the established 200GS, this association became more significant in all patients (p = 0.01, HR = 2.67) as well as in patients without IT (p = 0.01, HR = 2.67). In the validation stage of 89 melanomas without prior IT treatment, a high TMB in a subset of 20GS accurately determined favorable OS (p = 0.02, HR = 2.69) and confirmed TCGA observations from the 200GS. Conclusions: Here we show, for the first time, that in addition to IT, high TMB predicts more favorable OS in patients that never received IT, potentially serving as a novel marker of prognosis of melanoma and likely other immunogenic tumors at early stages. In addition, our study suggests that TMB test can be robust when applied to only a small subset of genes that trigger significantly higher immunogenicity. This may also eventually assist with accurate sub-selection of early stage patients likely to respond to IT regimens.
Investigation of the immune infiltrate of melanoma metastases under immune checkpoint inhibition.
Authors: Hassel Jessica Cecile , Flossdorf Michael , Hänzelmann Sonja , Winkler Julia , Roth Jasmin , Lauenstein Claudia , Appel Lena , Streit Enrico , Halama Niels , Faryna Marta , Enk Alexander , Offringa Rienk , Sahin Ugur , Poschke Isabel
Published: September 2018

9570

Background: Tumor infiltrating lymphocytes (TIL) play a crucial role in the therapeutic impact of immune checkpoint blockers. Methods: We investigated metastases from 56 melanoma patients before and during treatment with immune checkpoint blockers (i) immunohistochemically, (ii) with TCR repertoire profiling and (iii) analysis of the transcriptome. The patients were treated with ipilimumab (n = 25) or pembrolizumab (n = 23) or ipilimumab/nivolumab (n = 7); half of them had a disease control, the other half progressed as best response to treatment. Results: In contrast to previous reports immunohistochemical analysis of the immune infiltrate revealed no significant difference in the number of CD8+ TILs in pretreatment samples of responders and non-responders. Instead, the number of CD4 + TILs including regulatory T cells (Treg) and the number of PD-1 + cells was higher in responders especially when receiving pembrolizumab. Samples taken at least 6 weeks after start of the immune checkpoint blocker showed a significant higher number of immune cells in responders through all T cell subsets (CD3,4,8,FoxP3, PD-1), B cells (CD20) as well as macrophages (CD68, CD163). TCR repertoire profiling by deep TCR sequencing demonstrated that responders develop a more diverse repertoire under treatment (p = 0.05). Pretreatment samples as well as the size of the top 10 TCR clones posttreatment did not differ significantly in responders and non-responders. By RNA sequencing no differential expression profiles between responders and non-responders was found pretreatment. Posttreatment samples expressed different genes compared to pretreatment samples in responders including MHC molecules, CDK2/4, Myc, TNF family members and different apoptosis-inducing genes. There was no differential gene expression in non-responders pre- and posttreatment. Conclusions: Pretreatment metastases from responders and non-responders do not differ much. With treatment responding patients have significant higher numbers of immune cells including T- and B- cells as well as macrophages and develop a more diverse TCR repertoire. RNA sequencing revealed a differential expression pre- versus posttreatment only in responding patients.
Molecular and immune predictors of response and toxicity to combined CTLA-4 and PD-1 blockade in metastatic melanoma (MM) patients (pts).
Authors: Chen Wei-Shen , Andrews Miles Cameron , Spencer Christine , Tawbi Hussein Abdul-Hassan , Lazar Alexander , Tetzlaff Michael T. , Patel Sapna Pradyuman , Hwu Patrick , Hwu Wen-Jen , Diab Adi , Glitza Isabella Claudia , Amaria Rodabe Navroze , Burton Elizabeth M. , Woodman Scott Eric , Davies Michael A. , Gershenwald Jeffrey E. , Sharma Padmanee , Allison James Patrick , Futreal Andrew , Wargo Jennifer Ann
Published: September 2018

9579

Background: Combined treatment with ipilimumab and nivolumab (Ipi/Nivo) achieves clinical responses in > 50% of mm pts. However, responses are not universal and toxicity may be limiting, thus biomarkers of response and toxicity are needed to optimize and personalize this therapy. Methods: Tumor biopsies were collected before (n = 29) and on treatment (n = 7) from mm pts (n = 40) treated with Ipi/Nivo. Whole exome sequencing (WES), gene expression profiling, TCR sequencing, and immunohistochemistry (IHC) were performed to define molecular and immune features of the tumors. Radiographic responses in patients were assessed via RECIST 1.1criteria, and patients were classified as responders (R) deriving clinical benefit (with SD, PR, CR) and non-responders (NR) not deriving clinical benefit (PD). Toxicity was also scored, with patients dichotomized into low toxicity ( < grade 2) versus high toxicity ( > grade 3) re: immune-related (IR) toxicities. Results: In this cohort, the response rate was 80%, with 53% of patients experiencing > grade 3 toxicity. There was no significant difference in baseline mutational load in responders (R) vs non-responders (NR) to Ipi/Nivo, but NR had a higher burden of copy number alterations (CNA; p = 0.013), with frequent alterations detected in PTEN, JAK2, and B2M. There were no significant differences in baseline CD8+ T cell density, expression of immune-related genes, or T cell clonality for R vs NR pts. Ipi/Nivo treatment increased intratumoral T cell clonality, but this did not correlate with response. A more diverse peripheral T cell repertoire at baseline was detected in pts who developed IR toxicity (p < 0.05). Conclusions: This data suggests that responses to Ipi/Nivo in mm may occur in the absence of high mutational load or brisk immune infiltrate at baseline. Putative mechanisms of resistance to Ipi/Nivo include high burden of CNA and alterations in PTEN, JAK2, and B2M. Together these studies identify candidate biomarkers of resistance and toxicity for Ipi/Nivo, though they need to be tested in larger cohorts and across cancer types.
Patient/oncologist decisions about adjuvant chemotherapy in ER+ve, HER2-ve early breast cancer following endopredict testing.
Authors: Bloomfield David J , Arbon Amy , Cox Jane , Hack Berkin , Hall Julia , Harper-Wynne Catherine , Hinde Sebastian , Jenkins Val , Mackay James , Matthews Lucy A , May Shirley F , Moss Adrian , Patel Gargi Surendra , Simcock Richard , Thanopoulou Eirini , Westwell Sarah , Wlaszly Dominika , Fallowfield Lesley
Published: September 2018

e12002

Background: Endopredict is a multigene test including tumor size and nodal status; it predicts low or high risk of distant recurrence in patients (pts) with ER+ve, HER2–ve breast cancer treated with adjuvant endocrine therapy alone. We compared adj chemotherapy decisions pre and post Endopredict test results, pts’ anxiety, decisional conflict and oncologists’ (oncs) confidence about decisions made. Methods: 14 oncs in 8 UK hospitals saw 149 pts judged by clinical teams to have equivocal indications for chemotherapy. Pts and oncs discussed provisional treatment decisions based on conventional prognostic factors. Initial decisions were reconsidered when Endopredict results were available. Pre and post-test pts completed Spielberger’s State/Trait Anxiety inventory (STAI) and a decision conflict scale (DCS). Oncs answered questionnaires probing:- basic demographic,/clinical details, agreement with, and confidence about treatment decisions (endocrine (E) therapy +/- chemotherapy(C)) Results: 66.7% pts with an initial E alone decision and a high risk result upgraded to E+C. 9.4% pts with initial E+C decisions and high risk results down-graded to E. None of 46 pts initially favouring E alone who were low risk changed decisions. 82.8% who initially wanted E+C and had low risk scores downgraded to E alone. Endopredict results increased oncs’ confidence (8% ‘strongly agreed’ pre-test, 50% post-test). Oncs neither agreeing nor disagreeing with decisions fell (24% to 5%). Anxiety was stable in pts with unchanged decisions. Pts whose therapy was downgraded had significantly lower anxiety scores (p<0.01); those whose treatment was upgraded had increased scores (p<0.001). Likewise overall uncertainty on DCS fell post-test (p<0.023) Conclusions: Endopredict results increased oncs’ and pts’ decision-making confidence, improved matching of risk with therapy decisions and thus a potential for improved outcomes. Clinical trial information: ISRCTN69220108. [Table: see text]
Proliferation-based prediction for overall survival in locally advanced HER2(+) breast cancer.
Authors: Pedregal Manuel , Rojo Federico , Carames Sanchez Cristina , Lobo Francisco , Izarzugaza Yann , Cristobal Ion , Zazo Sandra , Moreno Irene , Zenzola Victor , Correa Andrea , Martinez Imanol , Hernández Roberto , Garcia-Foncillas Jesus
Published: September 2018

e12007

Background: Breast cancer prognosis is influenced by several factors including Ki67 expression which may have a predictive role in luminal breast cancer patients. The aim of this study was to assess the value of Ki67 in breast cancers with positive hormonal receptors and HER2 overexpressed and to evaluate its impact on survival. Methods: Seventy eight consecutive patients diagnosed with locally advanced HER2 positive breast cancer who were treated with adjuvant therapy based on HER2 treatment were selected for this study (2004-2014). The adjuvant chemotherapy schemes were 44% TCH, 16% FEC, 11% AC/T and 29% other therapies. The median of followup was 68 months. Tumor proliferation was assessed immunohistochemically by Ki67 expression and calculated as percentage of stained tumor cells from this cohort previous to adjuvant chemotherapy administration and the results obtained were correlated with disease status and outcome. Results: High proliferation defined as a percentage > 15 of tumor cells was observed in 69% of the breast cancer patients cases. High proliferation significantly predicted longer overall survival (OS) (Log rank 0,012). At 10 years of follow-up, 93% of the patients with KI67 high expression were alive versus 43% of patients without overexpression. Multivariate analysis confirmed the clinical significance of Ki67 predicting OS for luminal HER2 breast cancer patients (p 0,04 y HR 9,6). Conclusions: High proliferation identifies a setting of luminal-B HER2+ subtype breast cancer patients with a significantly longer overall survival.
Longterm blood cell counts after intraoperative radiotherapy with or without whole breast radiotherapy in breast cancer patients.
Authors: Sperk Elena , Wersal Cornelia , Weiss Christel , Keller Anke , Kipke Anette , Tuschy Benjamin , Suetterlin Marc , Wenz Frederik K.
Published: September 2018

e12014

Background: After radiotherapy changes in blood cell counts (BCC) can be seen. Leukocytopenia may have a negative impact on the immune system, outcome and quality of life of breast cancer survivors. No reports on changes of the three blood cell lines (leukocytes=WBC, erythrocytes=RBC, thrombocytes=PLT) after IORT w/o whole breast radiotherapy (WBRT) in breast cancer patients have been reported. Methods: 256 patients had IORT during breast conserving surgery. In 198 patients WBRT (46-50Gy/2Gy) + IORT (20Gy) and in 58 patients IORT as accelerated partial breast irradiation=APBI (20Gy) was given. Preoperative BCC were used as baseline. In 214 patients BCC were available after 1-90 days, in 139 during the 1st year, in 86 in the 2nd, in 66 in the 3rd, in 51 in the 4th and in 34 in the 5th year of follow-up. Dunnett-tests were used to calculate adjusted p-values (p<0.05=significant). Results: After IORT/WBRT a decrease of WBC was seen during the 1st year. Afterwards no changes were seen. After IORT APBI no changes were seen during 5 years follow-up. RBC was decreased at all time points after IORT/WBRT, and through the 1st year after IORT APBI. PLT decreased during the 1st year and stayed low during 5 years after IORT/WBRT. No changes in PLT were seen after IORT APBI. Hemoglobin (HGB) decreased after 3 months, during the 1st and 5th year after IORT/WBRT. After IORT APBI, HGB decreased only during the 1st year and stayed stable during follow-up. Conclusions: Decreases of all blood cell lines were seen at least transiently after IORT/WBRT. PLT and RBC stayed decreased. After IORT APBI, HGB and RBC decreased only during the 1st year and WBC and PLT remained stable during the whole follow-up. [Table: see text]
Breast cancer in "young" women: Age cutoff and clinicopathologic features.
Authors: Nie Gang , Wang Haibo , Song Yuhua , Mao Yan , Cao Weihong , Hu Haiyan
Published: September 2018

e12019

Background: Age of patients play a key role in outcome of breast cancer, and therefore influences choice of treatment. In most studies, "young" is defined as being below 40 or 35 years. However, there are conflicts concerning definition of younger and older patients. In this study, we aim to establish a more appropriate age cut-off between “younger” and “older” breast cancer patients. Methods: A total of 5984 female breast cancer patients recruited in the Breast Cancer Registry of the Affiliated Hospital of Qingdao University during 2008 to 2014 were enrolled. Patients were divided into 11 groups by every 5 years’ age difference. The clinical characteristics and overall survival (OS) were compared among these age groups. Results: Among the five groups under age 45 (n = 1771, 30.0%), larger proportion of patients underwent breast conservation surgery in the “30-34” group (p = .027), and more patients were found with family history in the “25-29” group than in other groups (p = .029). No significant difference was found in OS (p = .059), clinicopathological stage, lymph node status, ER/PR status, HER2 status, or Ki-67 status among those five groups. For patients above 45 (n = 4813, 70.0%), differences were found in OS (p = .001) and significant differences with clinicopathological features (lymph node status, ER/PR status, HER2 status and Ki-67 status) were shown between younger and the older age groups (p = .001) among the six groups, except for family history (p = .066). Conclusions: Clinicopathological characteristics and survival status are similar among breast cancer patients under 45 years and vitiate among older patients. Age 45 is an appropriate cut-off for clinical grouping of breast cancer patients by age .
The underlying mechanism contributing to P-gp over-expression and drug resistance in the MCF-7 breast cancer cells induced by adriamycin.
Authors: Wang Guangji , Aa Jiye , Ge Chun
Published: September 2018

e12028

Background: Continuous exposure of breast cancer cells to adriamycin (ADR) induces the over-expression of P-glycoprotein (P-gp) and multiple drug resistance. However, the biochemical process and underlying mechanisms are not clear. Our previous study revealed that ADR increased reactive oxygen species (ROS) generation and reduced glutathione (GSH) biosynthesis, while N-acetylcysteine, the ROS scavenger, reversed the over-expressed P-gp induced by ADR. Methods: Based on MCF-7 breast cancer cells and the adriamycin-resistant MCF-7 subline (MCF-7R), we investigated the P-gp expression on mRNA, protein and function level by qPCR, western blotting, flow cytometry and laser scanning confocal and so on, under SLC7A11 down-regulation/over-expression, cystine depletion/supplement, increased ROS generation and combined factors. Results: The present study showed that ADR inhibited cystine influx (source material of GSH) and SLC7A11 transporter (in charge of cystine uptake) in MCF-7 cells. For the first time, we showed that a down-regulation/silence of SLC7A11, or cystine deprivation, or an enhanced exposure of ROS agents directly and significantly increased P-gp expression; yet, a combination of either an inhibited/silenced SLC7A11 or cystine deprivation and an increased ROS dramatically promoted the P-gp expression in MCF-7 cells. On the contrary, an over-expression of SLC7A11, or sufficiently supplementary cystine, or scavenger of ROS significantly depressed P-gp expression and activity. Moreover, the down-regulation of SLC7A11 and cystine deprivation induced an elevation of ROS and P-gp that could be reversed by N-acetylcysteine. It was suggested that ROS and SLC7A11/cystine were the two relevant factors responsible for the upregulated expression and function of P-gp. Conclusions: This study provided the direct evidences suggesting that ROS triggered over-expression of P-gp and demonstrated that the combination of either an inhibition of SLC7A11 or cystine influx and elevated ROS was the underlying mechanism contributing to P-gp over-expression induced by ADR. It was indicated that the SLC7A11 might be a potential target modulating ADR resistance.
Analysis of factors related to adjuvant chemotherapy decision in early breast cancer patients with intermediate recurrence score.
Authors: Qu Feilin , Wu Jiayi , Chen Xiaosong , Huang Ou , He Jianrong , Zhu Li , Chen Weiguo , Li Yafen , Shen Kunwei
Published: September 2018

e12032

Background: The 21-gene Recurrence Score (RS) assay has been routinely used to guide systemic chemotherapy in patients (pts) with estrogen receptor positive, node-negative early breast cancer (EBC). However, there has been less clarity in recommendation of adjuvant chemotherapy (ACT) in pts with intermediate RS (IRS). According to the definitions of IRS in retrospective NSABP B14, B20 trials and prospective validation of TAILORx trial, we adopted the broaden cut-offs of 11-30 in our study. We sought to analyze the factors related to ACT decision in this subset of pts. Additionally, the role of Adjuvant!Online (AOL) was evaluated in ACT decision. Methods: A cohort of 564 pts with RS of 11-30 was retrospectively analyzed from January 2014 to October 2016 in Ruijin Hospital Shanghai Jiaotong University School of Medicine. The Oncotype DX RS, a RT-PCR 21-gene assay, was performed on RNA extracted from formalin-fixed paraffin-embedded tissue. The AOL was used to determine pts’ clinical risk. Predictive factors of chemotherapy usage in different clinical risk catogories were also assessed. Results: 267 (47.3%) pts received chemotherapy. Age, tumor grade, pathologic type, pT, pN, molecular subtype and RS were significantly correlated with ACT decision ( p <0.05). These factors were all independent predictors of ACT usage ( p<0.05) in mutivariable model. AOL was successfully measured in 504 (89.4%) pts, of whom 279 (49.5%) were at low clinical risk and 225 (39.9%) had high clinical risk. The distribution of RS correlated significantly with AOL clinical risk catogories. The predictive factors of ACT administration in high and low clinical risk subgroups were highly consistent with the overall population, except pT in high clinical risk pts. Discordances between clinical risk and ACT decision were found in 158 pts (28.0%), probably due to different age, molecular subtype and RS. Conclusions: Age, tumor grade, pathologic type, pT, pN, molecular subtype and RS were independent predictors of ACT administration in EBC pts with IRS. AOL should not be used alone to aid chemotherapy decision in this subset of pts.
Clinical implications of genomic-directed therapies by comprehensive genomic profiling in breast cancer patients at a large academic cancer center.
Authors: Parrondo Ricardo Daniel , Mariotti Veronica , Gonzalez Velez Miguel , Leslie Lori Ann
Published: September 2018

e12037

Background: Increased use of comprehensive genomic profiling (CGP) has recently led to improved genomic characterization of tumors, increased access to individualized therapies and increased availability of clinical trials in breast cancer patients. The aim of this study was to evaluate the clinical impact of genomic profiling in breast cancer patients with the use of a CGP assay at a large cancer center. Methods: We retrospectively analyzed 101 consecutive breast cancer patients who received CGP at the John Theurer Cancer Center between 12/2011 and 08/2016. Genomic alterations (GAs) were identified using the FoundationOne assay (Foundation Medicine, Cambridge, MA). GAs, number of available genomic-directed therapies and number of available clinical trials were reviewed. The CGP interrogated up to 315 genes and introns of 28 genes. Results: Median age at diagnosis was 58 years (range: 35-83 years). With a median follow-up of 189 months (range 1-189), median survival was 163 months (range 142-184). A total of 560 GAs were found in our population, with a median of 5.0 GAs/sample (range 0-16), a median of 2.0 therapies/patient (range 0-11), and a median of 11.0 clinical trials/patient (range 0-36). The most frequent GAs found were TP53 (47.5%, n = 48), PIK3CA (34.7%, n = 35), MYC (22.8%, n = 23), CCND1 (19.8%, n = 20), FGF3 (16.8%, n = 17), FGF4 (15.8%, n = 16), and ZNF703 (14.9%, n = 15). A significant positive correlation was found between number of GAs and the number of available targeted therapies and clinical trials (r = 0.5 and r = 0.7, p = 0.00, respectively). Increasing age is a predictor of having a PIK3CA mutation (OR = 1.05; CI:1.01-1.09, p = 0.00) while decreasing age is a predictor of having a MYC mutation by logistic regression (OR = 0.95; CI:0.91-0.95, p = 0.03). Conclusions: The systematic use of CGP led to the identification of a high number of GAs, which correlated with a median of 2.0 individualized therapies and a median of 11.0 clinical trials available for breast cancer patients. The clinical impact of genomic-directed individualized therapies needs to be further investigated in prospective, randomized studies.
First prospective multicenter Italian study on the impact of the 21-Gene Recurrence Score (RS) in adjuvant clinical decisions for ER+/HER2- early breast cancer (BC) patients.
Authors: Dieci Maria Vittoria , Guarneri Valentina , Giarratano Tommaso , Mion Marta , Tortora Giampaolo , Morandi Paolo , Gori Stefania , Merlini Laura , Oliani Cristina , Pasini Felice , Bonciarelli Giorgio , Griguolo Gaia , Orvieto Enrico , Del Bianco Paola , De Salvo Gian Luca , Conte Pier Franco
Published: September 2018

e12038

Background: The Breast-DX Italy prospective study evaluated the impact of the 21-gene RS on adjuvant treatment decisions for early BC patients. Methods: The study was conducted in 9 centers of the Veneto Region (2 hub and 7 spoke). All consecutive patients with ER+/HER2-, T1 to T3, N0 to N1 early BC who met protocol-defined clinicopathological criteria for “intermediate risk” were included. Pre-RS and post-RS physicians’ treatment recommendations and treatment actually received were collected. Results: From November 2014 to August 2016, n=124 N0 and n=126 N1 patients were enrolled (65% at hub and 35% at spoke centers). The majority had PgR+ (86%), G2 (71%) and pT1c (63%) BC. Median age was 55 yrs, median Ki67 was 20% (range 2-70%). The distribution of RS was: <18 (61%), 18-30 (32%) and >30 (7%). Main factors associated with higher RS were G3 and higher ki67. The addition of chemotherapy (CT) to hormonal therapy (HT) was initially recommended for 48% of the patients (38% of N0 and 57% of N1 patients; 54% and 37% of patients enrolled at hub and spoke centers, respectively). The post-RS recommendation changed from the pre-RS recommendation for 40 patients, mostly from CT+HT to HT (n=30; n=25 with low and n=5 with intermediate RS). Change was more frequent for N1 patients (Table). Of the 72 N1 patients initially recommended to CT+HT, 28% had a post-RS indication to HT alone. The crude number of patients with pre-RS recommendation to CT significantly exceeded the number of patients who finally received it (absolute difference =31; p<0.001). The majority of CT treatments were spared at hub vs spoke centers (n=24 and n=7, respectively). Conclusions: Pre-RS indication to HT alone was frequent, in particular for N0 patients and at spoke centers. The use of the 21-gene RS further contributed in sparing CT administration, more so for N1 patients and at hub centers. The impact of the RS when used at discretion of the clinicians is currently under investigation in the prospective ROXANE study. [Table: see text]
Relationship of pathological features and a 21 gene expression assay in young women with early breast cancer.
Authors: Mutonga Martin Boniface Gitobu , Speedy Sedona , Uthe Regina , Kindy Kelly , Brownlee Aisha , Jain Sarika , Gradishar William John , Flaum Lisa E. , Santa-Maria Cesar Augusto
Published: September 2018

e12050

Background: There is emerging evidence that a 21 gene expression assay recurrence score (RS) is prognostic independent of age. In practice, pathological markers may influence decision to recommend adjuvant chemotherapy. Methods: The primary objective of this study is to investigate the relationship between the RS and pathological markers between younger (29-49) and older (50-79) women with early stage ER+ breast cancer. Pathological markers investigated included the progesterone receptor (PR), grade, Ki-67, and P53. Patients who underwent 21 gene assay testing between 2002 through 2012 were sequantially identified. Data was extracted via the institutional tumor registry or chart reviewing. For each pathological feature, mean RS was compared between younger and older patients by t-tests. Trends in chemotherapy recommendation were assessed between younger and older patients within each RS risk category (≤10, 11-25, ≥26). Results: Between 2002 and 2012, 344 eligible patients were identified. 133 were ≤49 years of age, and 211 ≥50. There was no difference in distribution of RS across age (R2=3x10-4). Between younger and older patients, there was no difference in mean RS for any pathological marker (table 1). Within each age group, mean RS was always higher in tumors that were PR negative, grade 2/3, Ki67 >10%, and P53 ≥10% (p<0.05, respectively). In patients with a RS ≤10, 0% were recommended adjuvant chemotherapy irrespective of age. In patients with a RS 11-25, 39% of younger and 40% of older women were recommended chemotherapy. In patients with a RS ≥26, 100% of younger and 98% of older women were recommended chemotherapy. Conclusions: The relationships between pathological features and RS are consistent across age, supporting observations that the RS can predict benefit irrespective of age. See table. [Table: see text]