bluuebunny/crossref_metadata_2025 huggingface dataset:
The anti–PD-1 antibody spartalizumab (S) in combination with dabrafenib (D) and trametinib (T) in previously untreated patients (pts) with advanced BRAF V600–mutant melanoma: Updated efficacy and safety from parts 1 and 2 of COMBI-i.
Authors: Long Georgina V. , Lebbe Celeste , Atkinson Victoria , Mandalà Mario , Nathan Paul D. , Arance Fernandez ANA Maria , Richtig Erika , Yamazaki Naoya , Robert Caroline , Schadendorf Dirk , Tawbi Hussein Abdul-Hassan , Ascierto Paolo Antonio , Ribas Antoni , Flaherty Keith , Lee Dung-Yang , Masood Aisha , Gasal Eduard , Dummer Reinhard
Published: May 2019

9531

Background: Checkpoint inhibitors and targeted therapies have improved outcomes in pts with BRAF V600–mutant advanced melanoma; however, many pts progress and new treatment (tx) strategies are needed. BRAF inhibition increases T-cell infiltration, melanoma antigen expression, and PD-1/PD-L1 expression, which may lead to synergistic activity with anti–PD-1 therapy. Methods: COMBI-i is investigating first-line S 400 mg Q4W + D 150 mg BID + T 2 mg QD in pts with unresectable or metastatic BRAF V600–mutant melanoma (NCT02967692). Here we report pooled efficacy and safety data from parts 1 (run-in cohort) and 2 (biomarker cohort). Response was assessed per RECIST v1.1. Results: 36 pts were enrolled (part 1: n = 9; part 2: n = 27); 18 (50%) had stage IV M1c and 15 (42%) had elevated LDH levels. At the data cutoff (median follow-up, 15.2 mo), tx was ongoing in 17 pts (47%). The confirmed objective response rate (ORR) by investigator assessment was 75% (n = 27), with 33% complete responses (CRs; n = 12). Medians for duration of response (DOR; 7/27 pts with events), progression-free survival (PFS; 13/36 pts with events), and overall survival (OS; 7/36 pts with events) were not reached. 12-mo DOR rate was 71.4% (95% CI, 49%-85%). 12-mo PFS and OS rates were 65.3% (95% CI, 47%-79%) and 85.9% (95% CI, 69%-94%), respectively. In pts with high baseline LDH: ORR was 67%, with 3 CRs (20%), median PFS was 10.7 mo (events in 10/15 pts [67%]), and median OS was not reached, with events in 6/15 pts (40%). All pts had ≥ 1 AE; 27 (75%) had grade ≥ 3 AEs. 6 pts (17%) had AEs leading to discontinuation of all 3 study drugs. Any-grade AEs in ≥ 40% of pts included pyrexia, chills, fatigue, cough, and arthralgia. Grade ≥ 3 AEs in > 3 pts were neutropenia, pyrexia, and increased lipase. One pt died of cardiac arrest that was not considered related to study tx. Conclusions: S+D+T showed promising and durable ORR (75%) with CR in 33% of pts. With > 15 mo of follow-up, median PFS was not reached. The safety profile was manageable reflecting individual toxicities of D, T, and S. The global, placebo-controlled, randomized phase 3 (part 3) of COMBI-i is ongoing. Clinical trial information: NCT02967692.
Plasma concentrations of dabrafenib and trametinib (PCD/T) monitoring in advanced BRAFV600mut melanoma patients.
Authors: Funck-Brentano Elisa , Raynal Margot , Alvarez Jean-Claude , Beauchet Alain , Funck-Brentano Christian , Saiag Philippe
Published: May 2019

9541

Background: Dabrafenib (D) and trametinib (T) are highly ative in BRAFV600mut melanoma pts. One previous study suggested high PCD to be associated with adverse effects (AE) but not with tumor response. We investigated the relationship between PCD/T and tumor control or AE. Methods: PCD/T were evaluated with high-performance liquid chromatography/mass spectrometry in D+T-treated metastatic melanoma patients. We analyzed results at steady state (≥2 d for D, 24 d for T after introduction or dose modification) and far from peak concentrations (8 to 14.5 h for D and 20-28 h for T). We collected data of tumor assessments (RECIST 1.1) prospectively stored in our database and AE (CTCAE 4.0) blinded to PCD/T results. Each AE was associated with the closest sample harvested to the beginning of AE, or in the absence of AE with the highest PCD/T level for each patient. Results: We analyzed 75 D and 58 T assays from 36 pts (19M/17F), treated with D+T for metastatic melanoma (Stage IV: N = 35), mostly in first line (69.4%). Initial D dose was 300 mg/d and 2 mg/d for T, reduced in 10 patients (27.7%) for AE: to 30% of D (N = 8) and 25% of T (N = 8). High interindividual variability of PCD (range: 4-945ng/mL, median 70.0) and of PCT (5-25ng/mL, median 8.6) was observed. No differences between mean PCD/T at the time of evaluations showing progressive disease (PD) compared to those without PD pts (146.6±111.6 and 9.3±2.1) and pts with complete (N = 11), partial (N = 1) or stable response (N = 1) (160.6±127.9, P = 0.81 and 10.6ng/mL±2.6, P = 0.29) were observed. No significant relationship was shown between PCD/T and body mass index (r = 0.22 and -0.31), age (p = 0.19 and 0.26), or between PCD/T and D (p = 0.11) or T (p = 0.17) doses, neither between elevated mean PCD/T and any most common AE. Conclusions: This study shows a high interindividual variability but failed to show a relationship between PCD or T and tumor response nor AE. One limit is we did not explore PC of D active metabolites (hydroxy-and desmethylD). It has been shown that there is an auto-induction of D; T inhibits P-gp, a D substrate, suggesting synergistic pharmacological interactions. Thus, D pharmacokinetic seems to be too complex to be easily monitored.
Identification of a gene expression signature predictive of clinical benefit in patients with advanced mucosal melanoma (MCM) treated with immune checkpoint blockade.
Authors: Rapisuwon Suthee , Shoushtari Alexander Noor , Gottesdiener Lee S. , Johnson Douglas Buckner , Wang Daniel Ying , Graham Garrett Thomas , Goerlitz David , Berry Deborah , Atkins Michael B.
Published: May 2019

9546

Background: MCM is a rare melanoma subtype (only 1% of melanomas in the US). MCM has a lower tumor mutational burden than cutaneous melanoma (CM). While some patients (pts) with MCM respond to immune checkpoint inhibitor (ICI) therapy, predictive markers of response have not been established. We analyzed a cohort of MCM from pts treated with ICI to identify gene expression signatures associated with tumor response and clinical outcome. Methods: Fifty-eight MCM specimens were collected from 3 institutions. RNA was extracted from FFPE tissue slides and analyzed by NanoString 770 Immune Profiling Panel. Gene expression profiles were linked to anatomical location and disease outcome after ICI therapy: response as defined by RECIST v1.1 and median overall survival (mOS). Results: Fifty-one pts were treated with ICI - anti-CTLA-4 (n = 9), anti-PD1 (n = 38), or both (n = 5) ) and had tumor response evaluation. Three were without response data, 2 were without disease recurrence after surgery, 2 did not receive ICI. Among 51 pts with response data, seven were without long-term follow-up (1CR, 2PR, 3SD). The overall response rate (ORR) was 40.3%, similar to the prior study (Shoushtari et al, Cancer 2016). A signature involving differential expression of 87 immunoregulatory genes correlated with tumor response: ORR: 75% (12/16) signature high vs. 33.3% (7/21) signature low (p = 0.02, high vs. low) vs. 14.3% (2/14) signature average (p < 0.01; high vs. average). mOS for the whole population was 12.4 months. Pts with increased gene signature expression had superior mOS: signature-high: Not reached, signature-low: 8.2 months, (HR: 0.2; 95%CI: 0.07-0.55, p < 0.01). Transcript pathway analysis of the gene signature showed association with chemokine receptors, interleukin-10 signaling, and Treg development. Conclusions: We have identified a gene expression signature that involves chemokine receptors, IL-10 signaling, and Treg development gene sets, that appears to predict for tumor response and mOS in pts with advanced MCM treated with ICI. Further validation of these gene signatures is underway.
Clinical features and response to immune checkpoint inhibitors (ICIs) in pregnancy-associated melanoma (PAM).
Authors: Wang Daniel Ying , Owen Carina N. , Palmieri David James , Cohen Justine Vanessa , Eroglu Zeynep , Long Georgina V. , Sullivan Ryan J. , Balko Justin M. , Carlino Matteo S. , Menzies Alexander M. , Johnson Douglas Buckner
Published: May 2019

9564

Background: Melanoma is one of the most common malignancies diagnosed during pregnancy. Little is known about the clinical outcomes of PAM, in particular, response to ICIs. We performed a retrospective study to assess this issue. Methods: A multicenter retrospective study was performed at 4 large melanoma centers. Patients (pts) with PAM treated with ICIs were identified and examined. Clinical data and molecular data (RNA sequencing, IHC) were explored. PAM was defined as development of advanced melanoma during pregnancy or within 2 years post-partum. Results: 19 pts with PAM were treated with ICIs. Median follow-up was 11.7 months (range 1.4 – 41.9 months). Median age was 29 years (range 16-36). Most pts had a cutaneous primary (N = 17, 89%) including the extremity (N = 8) or trunk (N = 7), and 5% were occult. 11 pts (58%) had a BRAF V600E mutation and 6 (32%) pts received BRAF/MEK targeted therapy. Most pts had prior primary melanoma (N = 12, 63%) and presented with advanced melanoma in the post-partum setting (N = 11, 58%). At advanced presentation, 6 (32%) pts were stage III/M1a and 13 (68%) pts were stage M1b/c/d; 7 (41%) pts had elevated LDH and 13 (68%) had visceral involvement. Among 11 patients treated with combination ipilimumab + anti-PD-1 therapy, 7 (64%) had objective responses (OR) with a 1-year progression free survival (PFS) of 40% and 1-year overall survival (OS) of 100%. By contrast, ICI monotherapy (3 with anti-PD-1/L1 and 4 with ipilimumab) was associated with poorer outcomes (OR in 25% and 33% for ipilimumab and anti-PD-1/L1, respectively). Molecular features (RNA sequencing, immunohistochemistry) will be presented. Conclusions: Patients with PAM represent a unique population and may particularly benefit with combination ICI therapy compared with ICI monotherapy (in a limited sample size). Molecular underpinnings of PAM biology are still being elucidated.
Delta-radiomics for prediction of pseudoprogression in malignant melanoma treated with immune checkpoint inhibition.
Authors: Basler Lucas , Gabrys Hubert , Hogan Sabrina A. , Bogowicz Marta , Vuong Diem , Huellner Martin , Tanadini-Lang Stephanie , Foerster Robert , Dummer Reinhard , Guckenberger Matthias , Levesque Mitchell P.
Published: May 2019

9575

Background: Distinguishing progressive disease (PD) from pseudoprogression (PP) in patients treated with immune-checkpoint inhibition (ICI) is challenging and usually requires confirmation follow-up imaging or invasive diagnostic techniques. This project aimed to identify predictive radiomic signatures for PP from CT imaging. Methods: The response to ICI of 105 metastatic melanoma patients with 645 metastases was retrospectively correlated with radiomic signatures (172 total features). All metastatic lesions were delineated at 3 time points: prior to ICI (t0), at 3 (t1) and 6 months (t2). Response was defined individually for each metastasis using RECIST 1.1, comparing baseline t0 to t2. Three prediction models for PP were built: CT radiomics at t0 and t1, as well as the relative difference between both t0 and t1 (delta-radiomics). Results: Median follow-up was 18 months and 2-year OS and PFS were 72% and 25%, respectively. Median OS: not reached, median PFS: 6 months. Response per lesion at t1: 13% complete remission (CR), 19% partial remission (PR), 52% stable disease (SD) and 16% PD. At t2: 16% CR, 31% PR, 38% SD and 15% PD. 106 progressive lesions were identified at t1, of which, 26 changed to SD, 1 to CR and 3 to PR at t2, resulting in 30 PPs (4.7%). Metastasis location significantly influenced response rates but was not associated with PP (p = 0.4). Lung metastases had significantly higher response rates than soft tissue (p < 0.001), liver (p < 0.001) and bone metastases (p = 0.008). Univariate analysis followed by removal of correlated features revealed no significant radiomic features associated with PP at t0. One independent feature was identified at t1 (AUC 0.74), while delta-radiomics was the best performing approach, identifying four independent features (AUC 0.72 to 0.81). A final multivariate delta radiomics logistic regression model was generated and internally validated, achieving an AUC of 0.81 (± 0.11, 10-fold cross-validation). Conclusions: Metastasis location significantly influenced response rates and CT-based delta-radiomics is a promising biomarker for early differentiation between pseudoprogression and true progression in metastatic melanoma patients treated with ICI.
Comprehensive genomic profiling reveals distinct patterns of driver mutations and chromosomal alterations in acral and mucosal melanomas.
Authors: Zou Zhengyun , Ou Qiuxiang , Ren Yu , Lv Qing , Qin Lanqun , Zhao Lianjun , Su Shu , Wu Xue , Bao Hua , Wang Ao , Zhu Dongqin , Wang Xiaonan , Shao Yang , Liu Baorui
Published: May 2019

9576

Background: The incidence of melanoma subtypes differs significantly among ethnicities. Ultraviolet (UV) radiation-driven melanomas are common in Caucasians, while non-cutaneous melanomas including acral and mucosal melanomas are more frequent in Asians. It will be of great interest and clinical relevance to decipher the molecular pathogenesis of different melanoma subtypes. Methods: We retrospectively studied a cohort of 89 Chinese melanoma patients who underwent surgical resection of their primary tumors followed by chemotherapy. Genomic profiling of primary melanomas was performed using next generation sequencing by targeting 422 cancer-relevant genes. The Kaplan-Meier method and logrank test were used for survival analysis, and a cox model was used for multivariate survival analysis. Results: Acral melanomas (54/89, 60%) were the most common subtype of this cohort, while cutaneous and mucosal subtypes accounted for 25% and 15%, respectively. Mutation profiling revealed that BRAF was most frequently mutated in cutaneous melanomas, but aberrant BRAF, RAS, KIT, and NF1 were almost evenly represented in acral and mucosal melanomas; of note, mucosal melanomas had a propensity for concurrent driver mutations. Chromosomal alterations were detected across all subtypes, and chr7p amplification significantly correlated with poor prognosis while independently of melanoma subtypes. Furthermore, acral and mucosal melanomas demonstrated higher rates of focal copy number variations (CNVs) than cutaneous melanomas. The amplification of CDK4/CCND1 and NOTCH2 was observed predominantly in acral melanomas , and RAD51 loss was significantly enriched in mucosal melanomas correlating with poor survival. In addition, the tumor mutation burden (TMB) was significantly lower in acral or mucosal melanomas than in cutaneous melanomas. Conclusions: Our findings revealed distinct patterns of driver mutations and chromosomal alterations in acral and mucosal melanomas in contrast to cutaneous melanoma, and highlighted the association of chromosome 7p amplification and RAD51 deletion with unfavourable survival in melanoma patients treated with standard chemotherapy.
The solved and unresolved issues of melanoma staging: A comparison of American Joint Committee on Cancer (AJCC) 7th versus 8th edition.
Authors: Bajaj Shirin , Collado Anthony , Moran Una , Donnelly Douglas MacArthur , Johannet Paul , Shapiro Richard L. , Berman Russell S. , Weber Jeffrey S. , Zhong Judy , Osman Iman
Published: May 2019

9578

Background: The recently revised (AJCC) Staging Manual, 8th edition, introduced changes including removal of mitotic index and addition of the IIID substage. There is active debate on the utility of this revision, especially, without the inclusion of a novel prognostic biomarker, during an era of major therapeutic shifts and amidst accrual of adjuvant clinical trials for high-risk resected primary melanoma. We examined whether re-staging primary melanoma patients using the new AJCC 8 system yielded improved prognostication as compared to AJCC 7. Methods: We compared the impact of changes in staging criteria in stage I-III melanoma patients who were prospectively enrolled in a NYU clinicopathological database between January 2010 and December 2016 with active protocol-driven follow up (FU). We assessed primary tumor category (T) and nodal status (N) according to both AJCC 7 and 8. Progression free survival (PFS) and overall survival (OS) curves were generated for both editions and then stratified by substage. We analyzed discordance using Cox Regression Models. Results: 1,379 patients (56% male, mean thickness 1.6, median FU 34.8 months) were included in the analyses. All but one patient remained in the same ‘major’ stage using AJCC 7 and 8 (stage I- 998; II- 224, 225; III- 157, 156) whereas 44% of stage III substage classifications were discordant comparing AJCC 7 to 8. Despite removing mitoses as a criterion for Stage I, there was no significant change between editions in PFS/OS when evaluating major and substages of stage I. Stage IIC patients had worse PFS/OS than stage IIIA patients in AJCC 8 (PFS p = 0.04, OS p = 0.02). AJCC 8, which implemented four rather than three substages, had improved PFS prognostication (c-index = 0.59 vs 0.66, p = 0.05 for AJCC 7 vs 8). Conclusions: Our results reinforce the added value of AJCC 8 compared to 7, as removing an operator dependent variable is more practical for stage I, and increased influence of thickness/ulceration and the addition of a new substage is more prognostically informative for stage III. Nevertheless, the poor prognosis of stage IIC patients, despite nodal negative disease, continues to be an unaddressed gap within our current staging framework.
Predictors of adjuvant chemotherapy for breast cancer patients with an intermediate Oncotype-DX score: A SEER-based population study.
Authors: Goranta Sowmya , Haykal Tarek , Bala Areeg , Al-Dulaimi Ragheed , Bachuwa Ghassan , Pandit Trailokya Nath , Danish Rizwan
Published: May 2019

e12014

Background: Oncotype-DX Assay is a 21-gene based recurrence score (RS) that helps stratify breast cancer patients based on their risk of recurrence. It is often used to help identify patients that may benefit from adjuvant chemotherapy (AC). Prior to the TAILORx Trial results, there were no guidelines for AC in patients with an intermediate score (18-30). Management of these patients was often at the clinical judgement of the provider. We sought to determine predictors of AC among these patients, and measure treatment effect on survival. Methods: We queried the Surveillance, Epidemiology, and End-Results database for breast cancer patients newly diagnosed between 2010-2015. We included patients with T1-T3, hormone receptor positive, HER2-negative, and lymph node-negative breast cancer with an intermediate RS. Male patients, those younger than 40 years, tumors 5 mm or less, and incomplete records were excluded. Univariate and multivariate analysis was performed to derive independent predictors of AC. Cox Proportional-Hazards Model was done to examine the effect of AC on survival. Results: We included 14,710 patients of whom 4,508 (30.6%) received AC. Patients that received AC were younger (55.4 years [8.8] vs 60.0 [9.7], p < 0.001), grade III or higher (29.8% vs 16.4%, p < 0.001), and had a higher RS (23.9 [3.6] vs 21.5 [3.1], p < 0.001). Higher T stage was associated with a higher rate of patients receiving AC (p < 0.001). Marital status was also associated with AC; a higher proportion of patients who received AC were married (67.9% vs 64.4%, p < 0.001). There was no significant association between race/ethnicity or insurance type with AC. Multivariate analysis showed that RS (OR: 1.24 [1.23-1.26], p < 0.001), T stage (OR: 1.67 [1.21-2.30], p < 0.001), and a grade III tumor (OR: 1.85 [1.64-2.09], p < 0.001) were the strongest predictors of AC. The age decile 80-89 years (OR: 0.05 [0.02-0.10], p < 0.001) was the most negative predictor of AC. AC did not have an effect on 5 year overall survival (97.6% vs 96.0%, p = 0.28). Conclusions: Between 2010-2015, our study shows 30.6% of breast cancers patients with an intermediate Oncotype-DX score were given AC. The decision to treat was largely based on tumor size, grade and age. AC had no effect on overall survival.
Plinabulin (Plin) combined with half-dose pegfilgrastim (Peg) compared with full-dose peg alone for chemotherapy- induced-neutropenia (CIN): Neutrophil, bone pain, and immunosuppressive effects.
Authors: Blayney Douglas W. , Ogenstad Stephan , Shi Yuankai , Zhang Qingyuan , Feng Jifeng , Sun Tao , Du Lihua , Huang Lan , Mohanlal Ramon
Published: May 2019

e12017

Background: Peg is used for CIN prevention. Plin, a novel, non-G-CSF agent is in Phase (Ph) 3 trials for CIN prevention and as an anticancer (NSCLC) agent. In contrast to Peg, Plin does not cause bone pain and maintains absolute neutrophil counts (ANC) within the normal range. Furthermore, Peg, but not Plin, increases Neutrophil-to-Lymphocyte Ratio (NLR) and Lymphocyte-to-Monocyte Ratio (LMR) to immune suppressive values; i.e. NLR>5 and LMR<3.2 (Blayney, ASCO 2018, ESMO 2018, ASCO-SITC 2018). We tested the effects on CIN, bone pain and immune-suppressive profile (i.e. NLR> 5 and LMR<3.2), comparing Plin+half Peg dose to full dose Peg alone (the current CIN standard of care). Methods: Early stage Breast Cancer patients (pts) received high febrile neutropenia (FN) risk TAC (docetaxel, doxorubicin, cyclophosphamide) and either full dose Peg 6 mg (Peg6; n=22) or Peg 3 mg (half dose) + Plin 20 mg/m2 (Peg3/Plin; n = 21) in a Ph 2 trial (NCT03294577). Peg was given ~24 hrs after TAC, and Plin ~30 min after TAC. Blood was drawn for ANC, NLR, MLR daily on Day (D) 0 to D15 in cycle 1. Validated bone pain assessments were done at predose D1, 2,3,4,6,7 and 8 in cycle 1. NLR and LMR were calculated from D6 on (ANC effects with Peg or Plin occur after D6). Results: Grade 4 and Grade 3/4 Neutropenia occurred in 59.1% and 81.2% of pts in the Peg6 arm vs 52.4% and 57.1% in the Peg3/Plin arm. Peg3/Plin was well-tolerated and non-inferior to Peg6 for duration of severe neutropenia (P<0.05). FN occurred in 1 pt each in Peg6 and Peg3/Plin. Bone pain with Peg3/Plin was less vs Peg6: frequency of pts with at least 1,3 or 5 days of bone pain was 90.9%, 36.7% and 18.2 % with Peg6, whereas 33.3%, 14.3% and 4.76% with Peg3/Plin (p<0.0001 for at least 1 day). Frequency of NLR≥5 and LMR≤3.2 was higher with Peg6 vs Peg3/Plin (p<0.045 to P<0.0004 between D8 to D15). Clinical trial information: NCT03294577. Conclusions: Half dose Peg combined with Plin is equally effective against CIN as full dose Peg, but with much less bone pain and immune-suppressive potential.[Table: see text]
Intraoperative radiotherapy in early-stage breast cancer: Multidiciplinary management and analysis of outcome.
Authors: Kim Elizabeth Min Hui , AL-Halabi Hani , Shakibnia Lily , Cavanaugh Sean
Published: May 2019

e12036

Background: The TARGIT-A trial investigated the efficacy of using single-dose targeted intraoperative radiotherapy (IORT) in place of whole-breast external beam radiotherapy (EBRT) for treating breast cancer. IORT is an effective alternative to EBRT for adjuvant treatment of select patients with estimated conversion rate of 15%, who required additional EBRT following complete pathologic staging. An institutional study was performed to evaluate the rate of patients who received IORT but still required EBRT, in-breast-tumor recurrence rate (IBTR) and overall survival (OS). Methods: Institutional retrospective review of patients treated with IORT was performed, including age at the time of IORT, histology, AJCC stage, margin, and clinical features as outlined in ASTRO and ABS guideline. Conversion rate, IBTR and OS was calculated. Reason for conversion to EBRT assessed. Results: From 1/1/2016 to 1/1/2019, 35 patients underwent IORT concurrent with lumpectomy and sentinel node biopsy within the ASTRO and ABS guideline. Patients median age 60 (51-79 yo) and all had ER+, clinical T(0.5 -2.5cm)N0 with intraoperative sentinel node frozen section evaluation. Zeiss IORT consisted 50 KV x-rays with spherical applicators, and a dose of 20Gy was prescribed at the surface of the applicator. 14.2% (5/35) were recommended EBRT. Conversion was due to microscopic disease found on final surgical pathology (3 node positive and 2 positive surgical margin). 4 patients successfully completed EBRT and 1 patient declined EBRT. 100% underwent adjuvant endocrine treatment. IBTR was 0% and OS was 100% with a median follow-up of 18.6 months (range of 2 – 35 months). Conclusions: Pathologic false negative rate contributed to EBRT conversion rate but remained below 15% TARGIT-A threshold. IORT concurrent with lumpectomy within a risk adapted approach is a good option for eligible patients using evidence-based guideline and multidisciplinary team model. Continued cohort assessment for IBTR, OS and toxicity outcome will be prospectively assessed.
Oncotype DX DCIS use and clinical utility: A SEER population-based study.
Authors: Yuan Yao , Van Dyke Alison Len , Kurian Allison W. , Negoita Serban , Petkov Valentina I.
Published: May 2019

e12046

Background: OncotypeDX DCIS is a 12-gene assay designed to predict the 10-year risk of local recurrence and to guide treatment decisions, specifically the benefit of radiation therapy in breast ductal carcinoma in situ (DCIS). The test became available in December 2011 and is not currently recommended by guidelines. The Surveillance, Epidemiology and End Results (SEER) program captures cancer data at the population-level and has been conducting annual linkages with Genomic Health Clinical Laboratory, the only lab performing the test, to identify patients receiving the test. Methods: SEER cases diagnosed with in situ breast cancer (DCIS or papillary in situ) between 2011-2015 were included in the analysis. SEER data on patient demographics, tumor characteristics, and treatments were combined with linkage variables for OncotypeDX DCIS tests reported by Genomic Health. Logistic regression was used to identify which patient related factors were associated with having received the test and to evaluate the relationship between test generated risk categories and treatments. Results: Of the 68,826 in situ breast cancer cases, 2,155 were linked to DCIS test data. Test utilization increased from < 1% to 5.3% for patients diagnosed in 2011 vs. 2015. Patients were less likely to receive the test if they had larger and higher-grade tumors, were divorced, had Medicaid insurance, and were in the lowest socioeconomic status tertile. The majority of patients (68%) were at low risk, 17% intermediate, and 15% in the high risk group. Patients at intermediate or high risk were more likely to receive radiation (OR = 2.4, 95% CI: 1.8-3.2 and OR = 3, 95% CI: 2.3,4.1, respectively) than the low risk group. High risk patients were more likely than low risk patients to receive chemotherapy (OR = 4.3, 95% CI: 1.2, 14.4) and to undergo mastectomy than lumpectomy (OR = 1.47, 95% CI: 1.12-1.93). Conclusions: Clinical adoption of the OncotypeDX DCIS test has been slow. The association between multiple demographic factors and receiving the test indicated disparities in the US population. Clinical factors also influenced whether patients received the test. OncotypeDX DCIS results appeared to guide clinical decisions.
Bisphosphonate use in geriatric breast cancer patients on aromatase inhibitors in a rural population.
Authors: Johnson Alexander , Agbisit Christian , Robinson Kathy , Delfino Kristin , Desai Meghna R.
Published: May 2019

e12048

Background: Aromatase inhibitors (AIs) are commonly used in treatment of ER & PR + breast cancer in postmenopausal women. It is well known that AIs can lead to bone loss. Bisphosphonates have been used to counteract bone loss due to AI use. The objective of this study was to evaluate the use of bisphosphonates in elderly females above 65 years, with ER + breast cancer on AIs, in a rural setting, and to examine the effects of oral vs. IV bisphosphonates on overall survival (OS) in geriatric patients. We also examined the effects of alcohol use on bone health in this population. Methods: An institutional database of 269 patients with histologically confirmed invasive or in-situ breast cancer with age 65 or older at the time of diagnosis was reviewed in an IRB approved fashion. 176 patients were ER+ and had DEXA diagnosed osteoporosis or osteopenia.They were treated with anastrozole n = 88 (50)% or letrozole n = 88 (50%). Type of bisphosphonate treatments used ,impact of alcohol consumption & data on OS were collected from the database. Results: 176 patients (65.4%) were ER+ and had DEXA diagnosed osteoporosis or osteopenia. Alendronate was used in 15 patients (8.5%), ibandronate was used in 3 patients (1.7%), risedronate was used in 1 patient (0.6%), and zoledronate was used in 44 patients (25%). IV bisphosphonates were used in 44 patients (69.8%) and oral were used in 19 patients (30.2%). Majority of patietns were on calcium + D supplementation.10% of non-alcohol users had osteopenia/osteoporosis compared to 15% of former alcohol users and 29% of current alcohol users. LogRank testing found no significant difference between survival based on bisphosphonate use . Similar statistical analysis found no significant difference between survival based between IV and oral bisphosphonates. Conclusions: Our study showed that geriatric patients with ER + breast cancer on AI therapy were adequately managed for osteopenia and osteoporosis with the use of bisphosphonates (oral and IV) in a rural setting. There was no significant effect on overall survival (OS) , with use of bisphosphonates during AI therapy. No significant difference in OS was identified for patients taking IV vs. oral bisphosphonates,but this was attributed to very small number of patients that experienced death as an event in this population. Bisphosphonates were also well tolerated, with only 1 patient noting ONJ and one patient with renal toxicity. Current and former alcohol use was found to be correlated with increased rates of osteopenia/osteoporosis in this population.
Effectiveness of scalp cooling in reducing chemotherapy-induced alopecia: A single center prospective study in Lebanon.
Authors: Haidar Nour , Nasr Lewis , Nasr Fadi
Published: May 2019

e12075

Background: Hair loss (alopecia) is recognized as one of the most common and distressing side effects of chemotherapy. The scalp cooler first used in 1970s against the Chemotherapy CIA (chemotherapy induced alopecia). This study aimed at assessing the effectiveness of scalp cooling (PAXMAN Cooler ORBIS II SCALP COOLER) in reducing chemotherapy-induced alopecia. Methods: This prospective study was conducted at the Mount-Lebanon Hospital in the one day chemotherapy between 01 January 2017 and 31 December 2018. 109 women diagnosed with breast cancer with stage I or II undergoing neoadjuvant, and adjuvant chemotherapy were enrolled. Patients with scalp cooling 54.1% (n=59), control 45.9 % (n=50). Scalp cooling done by using the scalp cooling device. The primary end point was to assess the hair loss using the dean’s scale after multiple cycles of chemotherapy. The clinical assessment and alopecia evaluation were done after each chemotherapy cycle. The secondary endpoint was the side effect of the scalp cooler such as headache. Results: The Mean age was 55.73 ± 11.9 years. 82.56 %received Anthracycline-based chemotherapy regimen with Docetaxel, and 14.69 % Anthracycline-based chemotherapy regimen with Paclitaxel and 2.75 % took only anthracycline with cyclophosphamide. The effectiveness of hair preservation was successfully reported as 62.7% grade 0, 22.01 % grade 1 and 15.29% grade 2. There were highly significant differences between patients underwent scalp cooling and patients without scalp cooling with different regimens of chemotherapy (P value <0.0001). The major side effect, the headache where was reported in 25.7% from the total (P value <0.0001). Conclusions: Hair preservation in stage I , II breast cancer undergoing multiple regimens of chemotherapy was significantly more effective in the scalp cooling group.
Neoadjuvant chemotherapy with docetaxel, carboplatin and biosimilar trastuzumab in Her2-positive early breast cancer.
Authors: Oukkal Mohammed , Challal Souad , Abed Benmelha Nawel , Benachenhou Nabil , Boubnider Mohcen Wahib , Kouchkar Amal , Terki Nadia , Benkhedda Ghania , Brahimi Ghania , Belkaid Roza , Bouzid Kamel
Published: May 2019

e12080

Background: Evaluation of the histological response after neoadjuvant chemotherapy with Docetaxel-carboplatin and bio similar Trastuzumab (CANMAB 150mg) in Her2 positive breast cancer. The primary end point was pathologic complete response (pCR) rate, determined from surgical specimens. Methods: Between March 2017 and June 2018, we treated 39 patients with Her2-positive breast cancer satge II (61,5%), III (38,5%), with a neoadjuvant schedule of docetaxel (75 mg/m2), carboplatin (AUC 6) and biosimilar trastuzumab (CANMAB 150mg: 8 mg/kg loading dose then 6 mg/kg) every 3 weeks. Patients were diagnosed at a mean age of 48 years; 52,28% had hormone receptor-positive tumors and 87,17% of patients were node positive. All pts received 6 cycles of chemotherapy followed by surgery and one year of biosimilar trastuzumab. Results: We report the preliminary results of a prospective study on the use of the biosimilar trastuzumab combined with preoperative chemotherapy in Her2 positive breast cancer. Thirty nine patients (100%) completed six cycles of therapy. Surgery was breast conservative in 6 (15,38%) of 39 patients. Fifteen of the Thirty one patients (48%) achieved a pCR, Twelve of the twenty six node-positive patients (46,15%) experienced nodal conversion. There was a significantly lower response in HR-positive patients compared to HR-negative ones (26,7 vs 73,33%). No case of congestive heart failure was observed. Conclusions: The use of biosimilar trastuzumab with docetaxel and carboplatin achieved promising efficacy, with a good pCR rate (48%) in stage II or III Her2-positive breast cancer.
Significance of systemic and local immune responses to the pathological therapeutic effect of neoadjuvant chemotherapy in breast cancer.
Authors: Kim Ryungsa , Kawai Ami , Wakisaka Megumi , Funaoka Yuri , Sawada Sayaka , Shimoyama Mika , Yasuda Naomi , Hidaka Masayuki , Morita Yukitaka , Ohtani Shoichiro , Arihiro Koji
Published: May 2019

e12084

Background: Activation of the immune response including T lymphocytes, natural killer (NK) cells, and tumor microenvironment factors (TMEFs) is important in inducing a therapeutic response after neoadjuvant chemotherapy (NAC) in breast cancer. We examined the significance of systemic and local immune responses to the pathological therapeutic effect of NAC in breast cancer. Methods: From 2012 to 2018, 38 patients with stage II–III breast cancer received NAC with anthracyclines and taxanes followed by surgery. Therapeutic effects were evaluated according to the histopathology criteria for the assessment of therapeutic effects in breast cancer indicated by the Japanese Breast Cancer Society. Peripheral NK (pNK) cell activity was measured by chromium release assay. Levels of TMEFs were assessed by next-generation sequencing for CD4, CD8, NK, FOXP3, CTLA-4, PD-1, PD-L1, IL-2, IL-6, IL-12, IFN-γ, IL-10, TGF-β, and VEGF in FFPE sections collected from preoperative VAB samples and surgical specimens. Results: The stages, tumor subtypes, and therapeutic outcomes were as follows: II (N = 21), III (N = 17); luminal (N = 22), HER-2 positive (N = 12), TN (N = 4); G1a (N = 8), G1b (N = 13), G2a (N = 7), G2b (N = 4), G3 (i.e. complete) (N = 6). A G2 or better therapeutic effect were significantly associated with high post-NAC levels of NK, and potentially associated with higher CD4, CD8, and lower CTLA-4 after NAC. Multivariate logistic regression analysis showed that a G2 or better therapeutic effect was significantly associated with higher NK after NAC (OR = 1.07; 95% CI, 1.00–1.14; P = .0255). Disappearance of axillary lymph node metastasis was significantly associated with increased NK and pNK cell activity, as well as decreased VEGF level, and potentially associated with lower CTLA-4 after NAC. Conclusions: Increased NK cells after NAC are critical in producing a better therapeutic effect in collaboration with increased CD4 and CD8, and decreased CTLA-4 and VEGF. Systemic activation of pNK cells may improve the elimination of metastatic tumor cells in axillary lymph nodes by coordinating with release of immunosuppression derived from VEGF and activation of immune cells in the tumor microenvironment in breast cancer patients after NAC. An immune checkpoint inhibitor targeting CTLA-4 may improve NAC efficacy for breast cancer.
Impact of serum vitamin D on the response and the prognosis in breast cancer patients treated with neoadjuvant chemotherapy.
Authors: Tokunaga Eriko , Masuda Takanobu , Ijichi Hideki , Koga Chinami , Tajiri Wakako , Tanaka Junko , Nakamura Yoshiaki , Taguchi Kenichi , Okamoto Masahiro
Published: May 2019

e12088

Background: Neoadjuvant chemotherapy (NAC) is one of the standard therapeutic strategies for operable early breast cancer (BC). A relationship between chemotherapy response and the prognosis has been suggested, especially in HER2+ or triple negative breast cancer (TNBC). Recently, the impact of vitamin D (VD) on pathological complete response (pCR) after NAC has been reported, however, there are no data regarding the relationship between VD level and the efficacy of NAC in Japanese BC patients. Methods: This study included 236 patients with BC at clinical stage I-III, who were treated with anthracycline and taxane-based NAC. HER2-directed therapies were used for HER2+ tumors. Serum 25, hydroxyl VD levels were evaluated using by ELISAusing blood samples obtained before NAC. VD deficiency was defined as <20 ng/ml. Results: Pathological complete response (pCR) was obtained in 52 patients (22.0%). The pCR rate was significantly higher in the patients with HER2+ or TNBC compared with hormone receptor (HR)+/HER2-tumors (p<0.0001). Median VD level was 10.7 ng/ml, and only 7 patients (3.0%) had a VD level ≥20 ng/ml. These results show that most Japanese women are deficient for VD. VD levels increase with age, and the VD levels are significantly higher in postmenopausal patients than in the premenopausal patients (p=0.0029). Patients were dichotomized into VD-low and -high groups at the median value (10.7 ng/ml). Serum VD was not associated with pCR in the all cohort, however, pCR rate was higher in VD-high group in premenopausal patients, especially in the patients withHER2+ or TNBC (p=0.0328). High VD was significantly associated with better prognosis in terms of relapse-free survival (p=0.0327) and distant metastasis-free survival (p=0.0051). This association was observed both in pre- and post-menopausal patients, especially in the patients with HER2+ or TNBC. Conclusions: High VD levels were associated with high pCR rate in premenopausal patients with HER2+ or TNBC. High VD levels were also associated with better prognosis operable BC patients treated with NAC, although VD levels of most Japanese BC patients were lower than the cut-off value.
Serial circulating tumor DNA analysis indicating the efficacy and prognosis of neoadjuvant chemotherapy for locally advanced breast cancer.
Authors: Zhou Yidong , Xu Yaping , Gong Yuhua , Zhou Jiaolin , Lu Yaping , Wang Changjun , Yao Ru , Peng Li , Guan Yan-Fang , Wang Jiayin , Xia Xuefeng , Yang Ling , Yi Xin , Sun Qiang
Published: May 2019

e12089

Background: The efficacy evaluation of neoadjuvant chemotherapy (NCT) for locally advanced breast cancer (LABC) is still a questionable issue. The clinical imaging is always discrepant from pathological assessment postoperatively, and conventional tumor markers, such as CEA and CA15-3, did not show significantly correlation with the response to NCT in breast cancer patients. Analysis of circulating tumor DNA (ctDNA) from blood may provide a promising alternative. Methods: Collectively, 63 tissue and 204 blood samples from 32 patients with LABC were collected. There were four sampling nodes for blood collection: at baseline, during chemotherapy, after chemotherapy and after operation. Hybrid capture-based genomic profiling with a 1021-gene panel was carried out for both tissue and blood samples. Results: Totally, 151 somatic mutations were detected in tissue samples from 32 patients. TP53 (n = 14, 43.75%) and PIK3CA (n = 13, 40.63%) were the most recurrent mutant genes. Among 11 patients with HER2 overexpression, 10 (90.91%) carried ERBB2 amplification. All of 21 patients with normal HER2 present diploid ERBB2. The overall concordance between HER2 overexpression and ERBB2 amplification was 96.88%. At least one tissue mutation could be detected in blood collected at baseline for 21 patients, during chemotherapy for three patients, after chemotherapy for nine patients, and after operation for four patients. There was no tissue mutation in blood collected during and after chemotherapy for four patients reached pathologic complete response (pCR). The median of pathological tumor decrease in situ was 54.63% (17.07% to 98.04%) for patients with tissue mutations in blood collected either during or after chemotherapy, and 86.53% (7.69% to 98.04%) for patients without tissue mutation in both blood samples. Furthermore, the median number of pathologically involved lymph nodes was 3.5 (0 to 16) and 1 (0 to 9) for two patients cohort, respectively. All of four patients with tissue mutations in postoperative blood experienced distant metastasis during follow-up, while only 7.14% (2/28) of those without tissue mutation relapsed. The median DFS was 9.8 and 22.7 months, respectively (HR 26.14, 95% CI 1.161 to 588.5, p < 0.0001). Conclusions: Sequential genomic profiling of blood ctDNA can be used to evaluate the therapeutic efficacy of NCT, as well as the postoperative survival. This study highlights the feasibility of integrating ctDNA profiling into the clinical management for LABC undergoing NCT. Clinical trial information: NCT02797652.
Investigating the utility of breast cancer (BC) molecular signatures and immune signature profiling (ISP) as predictors of pathological complete response (pCR) to neoadjuvant chemotherapy + trastuzumab (NAC+T) in HER2+ BC.
Authors: Stemmer Salomon M. , Shvartser Yulia , Shemesh Itay Israel , Peretz Idit , Yerushalmi Rinat , Hendler Daniel , Haviv Izhak , Brauer Heather Ann , Castro Michael
Published: May 2019

e12109

Background: Trastuzumab targets HER2 directly as well as contributes to activation of the immune system against the tumor. We investigated the utility of BC molecular signatures and ISP as predictors of pCR to NAC+T in HER2+ BC pts. Methods: The analysis included 73 consecutive HER2+ BC pts with pathological samples at diagnosis, who received NAC+T. RNA was extracted from 73/22 biopsy/surgical specimens (FFPE). RNA was analyzed using NanoString PanCancer Immunoncology 360 (IO360) panel with PAM50 spike-in. Raw gene counts were log2-transformed and normalized (using housekeeping genes). The analysis assessed 47 gene signatures including immune related and PAM50 signatures. Signatures were computed after removing samples with low expression of the housekeeping genes and normalization. Signature scores range from ~0 to 10 and have an average value of 5 in tumor samples from The Cancer Genome Atlas. Results: Overall, 46% of the pts achieved pCR; of 13 pts who were IHC 2+ and FISH positive, one achieved pCR. Significant associations were found between response to NAC+T (pCR, no response) and molecular signatures/ISP from the initial biopsy (Table). For pts who did not experience pCR and who underwent surgery, paired sample analysis was performed assessing molecular signatures/ISP in the initial biopsy sample vs the surgical sample. This analysis demonstrated a significant increase post-treatment (compared to the initial biopsy sample) in Risk of Recurrence (ROR) score (p=.036), interferon (IFN) downstream signature (p=.038), and antigen‐processing machinery (APM) loss (p=.002). Conclusions: Combining molecular BC signatures and ISP on biopsy samples may have a predictive value in HER2+BC pts for whom NAC+T is considered. Luminal A pts and IHC 2+ (FISH positive) are unlikely to achieve pCR with NAC+T. [Table: see text]
Long-term toxicity profile of trastuzumab emtansine (T-DM1): A multicenter real-life study.
Authors: Buono Giuseppe , Fabi Alessandra , Del Mastro Lucia , Cannita Katia , La Verde Nicla Maria , Ardito Raffaele , Riccardi Ferdinando , Montemurro Filippo , Cazzaniga Marina Elena , Garrone Ornella , Zambelli Alberto , Conte Benedetta , Caputo Roberta , Cianniello Daniela , Bonotto Marta , Bartoletti Michele , Parola Sara , De Placido Sabino , Di Maio Massimo , Arpino Grazia
Published: May 2019

e12507

Background: T-DM1 is widely used in HER2 positive metastatic breast cancer (MBC) patients (pts), often for many cycles until progression. However, little is known about its long term toxicity. The aim of this study was to evaluate the safety profile of T-DM1 when delivered for ≥12 cycles. Methods: HER2 positive MBC pts who had received ≥12 cycles of T-DM1 across 18 Italian cancer centers were enrolled from January 2017 to September 2018. The 12 cycles cut-off was chosen based on the EMILIA trial median PFS (9.6 months), to identify a patient population treated with T-DM1 for longer time. Tumor and clinical characteristics were collected. Standard haematological tests, blood chemistries and side effects (nausea, vomiting, diarrhea, stomatitis, asthenia) were recorded cycle by cycle, according CTCAE criteria version 4. Haematological and laboratory toxicities were available for 86 patients, while other toxicities for all 115 patients. Results: Overall, 115 pts were enrolled. Median age was 54.5 (range 29.6–81.9); median time from diagnosis of metastatic disease to first T-DM1 cycle was 32.5 months. T-DM1 was administered as 2nd line and 3rd line of treatment in 45.2% and 27.8% of pts, respectively. Median number of cycles was 18 (range 12-59). Complete response, partial response and stable disease rates were 11.4%, 43% and 45.6%, respectively. Treatment related side effects are shown in table 1. Interestingly, no increased liver toxicity was observed in pts with liver metastases. Analysis of mean CTCAE grade by cycle showed that no relevant incremental toxicity was observed during long term T-DM1 therapy. Conclusions: T-DM1 is safe and well tolerated in these long responding pts. We found no relevant cumulative toxicity. Patients should be treated with T-DM1 as long as their tumor responds, as no safety issues are related to its long term use. [Table: see text]