bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of time to switch from ipilimumab to anti-PD1 in anti-PD1 efficacy within the French national cohort, MelBase.
Authors: Allayous Clara , Dalle Stéphane , Leccia Marie Thérèse , Aubin Francois , Mortier Laurent , Beylot-Barry Marie- , Saiag Philippe , Dalac-Rat Sophie , Lacour Jean Philippe , Maubec Eve , Descamps Vincent , Guillot Bernard , Lesimple Thierry , De Quatrebarbes Julie , Arnault Jean-Philippe , Stoebner Pierre-Emmanuel , Porcher Raphael , Ballon Alice , Oriano Bastien , Lebbe Celeste
Published: September 2018

9551

Background: With increasing armamentarium in advanced melanoma management, the impact of various strategies remains to be determined including the importance of time to switch from one treatment to another. We report the impact of time to IPI/APD non-planned switch on APD efficacy in real life patients within MelBase (MB). Methods: MB is a French multicentric biobank dedicated to the prospective follow-up (FU) of unresectable stage III or IV melanoma with 1102 patients included since March 2013. Data were collected (Sept.2016) and analyzed (demography, overall survival (OS), progression-free survival (PFS), response rate, multivariate analysis, safety). Results: 71 patients were treated with IPI/APD sequence. 72% received 4 IPI injections. The median time to switch was 1.7 months (0.36-3). The characteristics at the initiation of APD are: mean age 64 yrs, PS 0-1 80%, elevated LDH 34%, BRAF WT 90%, brain metastasis 25%, ≥ 3 metastatic organ sites (MOS) 49%, median FU 11.9 months, OS 20 months (95%CI:12.6-NR), PFS 3.5 months (95%CI:2.9-6.2). The best overall response was 25%, disease control rate was 54% with a low toxicity profile (17% grade 3/4). In a multivariable analysis, longer time to switch was significantly associated with better OS (adjusted HR 0.38 per 1 more month, 95%CI:0.14-0.93), as well as ECOG 0-1 (aHR 3.11, 95%CI:0.99-9.72) and LDH < ULN (aHR 3.32, 95%CI:1.26-8.75). In addition, the association of time to switch with OS vary significantly according to the number of MOS ( < 3 MOS aHR 0.25, 95%CI:0.10-0.62; ≥3 MOS aHR 0.99 95%CI:0.41-2.39) and AJCC stage (M0/1a/1b aHR 0.06, 95%CI:0.01-0.43 ; M1c aHR 0.77, 95%CI:0.39-1.54). Conclusions: In patients who failed IPI treatment, longer survival after APD was associated to time to switch only in patients with favorable baseline factors. Such results are probably more related to the slow kinetics of the disease than to the delay itself. Our results are different from Blank et al.(ESMO 2016) who tested a planned switch, immediately after 2 IPI perfusions, and showed overall response rate close to IPI+APD association. We are currently conducting a similar study on the reverse sequence (APD/IPI) and the role on IPI efficacy.
The safety and early efficacy of high-dose ipilimumab (IPI) and the combination nivolumab plus ipilimumab (NIVO + IPI) in patients (pts) with uveal melanoma (UM).
Authors: Patel Sapna Pradyuman , Glitza Isabella Claudia , Diab Adi , Amaria Rodabe Navroze , Davies Michael A. , Hwu Patrick , Tawbi Hussein Abdul-Hassan , Hwu Wen-Jen
Published: September 2018

9554

Background: UM metastases occur in 50% of cases and high-risk pts are identified by a gene expression profile. High-dose IPI is approved for adjuvant (adj) treatment (tx) of cutaneous melanoma and NIVO + IPI for metastatic (met) melanoma, yet the safety and efficacy of high-dose IPI or NIVO + IPI has not been established in UM in the adj or met settings. Methods: We performed a phase I/II trial of IPI for the tx of high-risk & met UM (CA184-187). The study consisted of two arms: an adj arm (AA) & met arm (MA) with two dose levels, 3 mg/kg & 10 mg/kg. Dose-finding proceeded on each arm in a 3 + 3 fashion. Pts received IPI once every 3 weeks for four doses followed by maintenance IPI every 12 weeks (for up to one year in AA). The AA treated pts with a Class 2 gene expression profile. This score imparts a 3-year distant metastasis-free survival (DMFS) of 50%. The primary endpoint for the AA was maximum tolerated dose (MTD) and improvement in 3-year DMFS to 70%. The primary endpoint for the MA was MTD & overall survival. The study was later amended to include a cohort of UM pts treated with combination NIVO + IPI in the standard FDA approved schedule. Results: Ten pts were enrolled on AA, 18 on MA, and 20 on NIVO + IPI. Adverse events (AEs) of any Grade (Gr) related to tx occurred in 80% of pts on AA. Gr 3/4 related toxicities observed in more than one pt were: transaminitis (30%) & pruritus (20%). Of these, 10% of the elevated AST and ALT and 10% of the pruritus occurred during the dose-finding portion of the trial at 3 mg/kg. One pt developed biopsy-proven colitis, and one developed diarrhea. Both were treated with high-dose steroids. One pt developed vasculitis manifesting as temporal arteritis with resultant blindness. AEs of any Gr occurred in 44% of pts on MA. Gr 3/4 toxicities observed in more than one pt were: Fatigue (11%) and Hyperbilirubinemia (11%). Only 1 pt (5.6%) developed Gr 3/4 diarrhea, and this was at the 3 mg/kg dose. In the NIVO + IPI cohort, Gr 3 transaminitis & elevated TSH occurred in 10%. Conclusions: High-dose IPI in UM did not demonstrate new or unexpected toxicities. Similarly, the combination of NIVO + IPI was well-tolerated with no new toxicities. Efficacy data will be presented at the meeting. Clinical trial information: NCT01585194.
Multivariate analysis of prognostic factors among 706 mucosal melanoma patients.
Authors: Lian Bin , Cui Chuanliang , Zhou Li , Song Xin , Zhang Xiaoshi , Wu Di , Chi Zhihong , Si Lu , Sheng Xinan , Kong Yan , Tang Bixia , Mao Li Li , Wang Xuan , Li Si Ming , Dai Jie , Yan Xieqiao , Bai Xue , Zheng Nan , Balch Charles M. , Guo Jun
Published: September 2018

9569

Background: Mucosal melanoma is rare and associated with extremely poor prognosis. Little is known about its outcome and prognostic analysis. In this study, we evaluated prognostic factors among mucosal melanomas. Methods: The survival rates, Relapse Free Survival (RFS), Overall Survival (OS) and prognostic factors were compared for 706 mucosal melanomas at different anatomical sites. Results: Mucosal melanoma from nasal pharyngeal and oral (268 pts), upper and lower gastrointestinal (GI) (221 pts), gynecological and urological (196 pts) had a similar survival with a 1-y survival rate (88%, 83%, 86%), 2-y survival rate (66%, 57%, 61%), 5-y survival rate (27%, 16%, 20%), respectively. Multivariate analysis revealed that Depth of Invasion (p < 0.001), Lymph node metastases (p < 0.001), Distant metastases (p < 0.001) were three independent prognostic factors for OS among 706 pts. Anatomical site (p = 0.031), Depth of Invasion (p < 0.001), Lymph node metastases (p < 0.001) were three independent prognostic factors for RFS among 543 pts. KPS status, Depth of Invasion, Lymph node metastases, Distant metastases were independent factors for OS among nasal pharyngeal and oral pts. Depth of Invasion, Lymph node metastases, CKIT Mutation were independent factors for RFS among nasal pharyngeal and oral pts. Gender, Lymph node metastases, Distant metastases were independent factors for OS among GI pts. Gender, Depth of Invasion, Lymph node metastases were independent factors for RFS among GI pts. Lymph node metastases, Distant metastases were independent factors for OS among Gynecological and Urological pts. Depth of Invasion, Lymph node metastases were independent factors for RFS among Gynecological and Urological pts. Conclusions: This is the first prognostic analysis for mucosal melanoma with the largest sample size for the first time. with few exceptions, It revealed that Depth of Invasion, Lymph node metastases, Distant metastases were independent prognostic factors for OS, Depth of Invasion and Lymph node metastases were independent prognostic factors for RFS. These results should be incorporated into the establishment of stage system and design of future clinical trials involving patients with mucosal melanoma.
Characterizing the tumor microenvironment (TME) in primary melanomas using multiplex immunohistochemistry (mIHC).
Authors: Gartrell Robyn Denise , Marks Douglas Kanter , Hart Thomas , Stack Edward , Lu Yan , Esancy Camden , Gerard Camille , Davari Danielle Rose , Jia Dan Tong , Armenta Paul , White-Stern Ashley , El Asmar Margueritta , Blake Zoe , Fu Yichun , Horst Basil , Saenger Yvonne M. ,   Melanoma Mantra Project
Published: September 2018

9580

Background: Biomarkers are needed in primary melanoma to risk stratify for adjuvant trials. High levels of infiltrating cytotoxic (CD8+) T lymphocytes (CTLs) and low levels of CD68+ macrophages (MΦ) may correlate with prolonged survival but quantification methods are not standardized for clinical practice. HLA-DR is a marker of MΦ activation not expressed by suppressor myeloid cells. A novel pathology technique using mIHC allows for quantitative and spatial analysis of immune cell subsets. Methods: In a pilot set of stage II/III primary melanomas from Columbia University Medical Center (n = 94), clinical follow up is available for 51 cases. 32 had no evidence of recurrence at last follow up (minimum 2 years) while 19 died of melanoma. 5µm slides were stained using Opal multiplexed IHC (mIHC) for DAPI, CD3, CD8, CD68, SOX10, HLA-DR and Ki67. Tumor areas were pre-selected by a dermatopathologist, visualized using Mantra (Perkin Elmer) and analyzed using inForm (Perkin Elmer) and Spotfire (TIBCO). Results: In all patients (n = 94), CTLs are farther from tumor (SOX10+) cells when they are proliferating (Ki67+) (p < 0.0001***), while they are closer to MΦ when they are activated (HLA-DR+) (p = 0.0002***). Next, we evaluated impact on prognosis using disease specific survival (DSS) as an outcome based on median value (n = 51). In this exploratory study no correction for multiple comparisons was made. We find that CTL density correlates with prolonged DSS in tumor (p = 0.0185*) but not in stroma (p = 0.1630 ns). Ratio of density of CD8/CD68+HLA-DR- correlates with DSS in both tumor (p = 0.027*) and stroma (p = 0.017*). Finally, distance from CTLs to HLA-DR- MΦ was significantly greater in non-recurrent melanomas as compared to recurrent ones (p = 0.0167*). Conclusions: HLA-DR expression on MΦ and Ki67 expression on tumor cells correlate with position of CTLs in TME in primary melanoma. CTL density is a favorable prognostic marker while HLA-DR non-expressing MΦ may favor tumor progression. Quantitative mIHC allows for accurate spatial analysis of immune subsets within the TME and the development of novel, more accurate and potentially clinically relevant biomarkers.
Hyperproliferative keratinocytic cutaneous adverse events and inflammatory palmoplantar erythrodysesthesia in melanoma patients treated with encorafenib compared to other BRAF inhibitors.
Authors: Goldinger Simone M. , Graf Natalie P , Galliker Nadja , Conrad Samuel , Dummer Reinhard
Published: September 2018

9590

Background: BRAF inhibitor (BRAFi) an MEK inhibitor (MEKi) monotherapies have shown to cause more cutaneous adverse events (cuAEs) in monotherapy compared to combination therapy. Encorafenib in combination with binimetinib showed improved PFS in patients with BRAF mutant melanoma (14.9 months). Furthermore, encorafenib showed superiority over vemurafenib. Objective: The aim of this study was to investigate cuAEs of melanoma patients treated with encorafenib and/or binimetinib and compare them to other BRAFi and MEKi induced cuAEs reported in the literature and observed in our control population. Methods: Patients treated with encorafenib, binimetinib, and other BRAFi/MEKi within approved clinical trials at the University Hospital of Zurich were collected and analyzed. Clinical and histological assessments were performed. Results: In 111 patients treated with BRAFi and/or MEKi, 212 related or possibly related cuAEs were identified. The percentage of patients with at least one cuAE is shown in the table below. The most frequent cuAEs observed in patients treated with encorafenib where palmoplantar hyperkeratosis (PPH, 50%), palmoplantar erythrodysesthesia (PPD, 53.8%) and alopecia (42.3%), whereas acanthopapillomas (83%), maculopapular exanthemas (63.3%), PPH and PPD (each 50%) prevailed in patients treated with vemurafenib. The most frequent observed cuAE in patients with dabrafenib/trametinib combination therapy were maculopapular exanthemas (18.2%) and erythema-annulare-like eruptions (18.2%), with encorafenib/binimetinib combination therapy PPH (10.6%) respectivly. Conclusions: Encorafenib showed less hyperproliferative cuAEs as previous BRAFi. However, PPH and PPD seem to occur more often compared to the literature of other BRAFi. Both is supporting the argument that encorafenib is a second generation BRAFi with a longer dissociation time. [Table: see text]
Effect of incorporation of cisplatin to adjuvant chemotherapy for triple-negative breast cancer patients of unknown BRCA mutation status on survival.
Authors: Hung Chia-Yen , Su Ying-Wen , Hsieh Ruey Kuen , Lam Hung-Bun , Chang Yuan-Ching , Yang Po-Sheng
Published: September 2018

e12009

Background: Recently, adding platinum to neoadjuvant chemotherapy (C/T) was associated with improved response rate in early Triple-negative breast cancer (TNBC). Whether incorporation of platinum to adjuvant C/T was associated clinical benefit has not been well investigated. Methods: Patients with resected TNBC who had available staging information and complete treatment at Mackay Memorial Hospital between 2004 and 2010 were enrolled for retrieving cllinical and pathologic information. Patients were monitored until death or Jan 2015. Statistical analysis was performed to determine the association of cancer-related overall survival (OS) and clinicopathological features. For stage I/II patients, 18 out of 115 received cisplatin-containing C/T. The mean OS for stage I/II patients with and without cisplatin-containing C/T was 6.05 years (standard error [SE]: 0.72 ) and 9.55 years (SE: 0.31), respectively ( P=0.07; log-rank test). For stage II/III patients, 20 out of 81 received cisplatin-containing C/T. The mean OS for stage II/III patients with and without cisplatin-containing C/T was 6.51 years (SE: 0.64) and 8.65 years (SE: 0.38), respectively ( P=0.56; log-rank test). In multivariate analysis for stage I-III patients, only age was significantly associated with OS (adjusted hazard ratio [HR]: 1.05; 95% confidence interval [CI]: 1.00-1.10). The adjusted HR for adding cisplatin to adjuvant C/T was 2.17 (95% CI: 0.729-6.44). Conclusions: In this small-numbered retrospective study, adding cisplatin to adjuvant C/T for TNBC with unknown BRCA mutation status did not have OS benefit. [Table: see text]
Correlation between Oncotype DX recurrence score and classical risk factors in early breast cancer.
Authors: Namuche Fernando , Ruiz Mendoza Rossana Esther , Flores Claudio J. , Aguilar Alfredo , Gomez Henry Leonidas
Published: September 2018

e12011

Background: OncotypeDx(ODX) predicts the likelihood of estrogen receptor (ER) positive breast cancer (BC) recurrence and assesses the likely benefit from both hormonal therapy and chemotherapy. Many clinical scores that estimate the risk category of ODX are being tested. Ki67 is frequently incorporated into these assessments, although there is no standard cut-off for its use. Methods: We retrospectively reviewed the electronic medical files of 190 patients with early stage ER+ BC for whom ODX recurrence score (RS) was available from 2014 to 2016. Our objective was to find out the degree to which classical clinicopathological variables -as defined by St. Gallen(SG) 2015- could predict ODX risk category, also to determine an optimal Ki67 cut-off in order to establish an accurate classification. Chi square test was used. Results: Mean age at diagnosis was 59 years (28-89). Mean tumor diameter was 15mm, 84.2% were intermediate grade. Mean expression of ER, PR and Ki67 were 87%, 53% and 22%, respectively. According to ODX 62.1% patients were low risk, 30.5% intermediate risk and 7.4% high risk. An overall concordance of 46.8% (73/190) was found between SG 2015 and the risk category of ODX (75.7% for low, 33.3% for intermediate and 23.9% for high RS). When changing SG Ki67 cutoffs to ≤20% (for low Ki67) and ≥30% (for high Ki67), an overall concordance of 56.3% (107/190) was found (69.6% for low, 47.3% for intermediate and 23.9% for high RS, with p=0.00) (Table 1). Conclusions: In best-case scenario, SG classical clinicopathological variables correctly classified 56.3% of patients of our series. Despite being a specialized center, the utility of classical clinicopathological variables for predicting ODX risk category is limited. [Table: see text]
Biology and prognosis of HER2-negative breast cancer with low-ER and PgR-expressions.
Authors: Nishimura Reiki , Osako Tomofumi , Nishiyama Yasuyuki , Okumura Yasuhiro , Fujisue Mamiko , Toyozumi Yasuo , Arima Nobuyuki
Published: September 2018

e12020

Background: Expression of the estrogen (ER) and progesterone receptor (PgR) is still clinically important in predicting prognosis and determining therapeutic strategies in breast cancer. According to the ASCO and CAP guidelines tumors with ≥1% positively staining cells should be considered ER/PgR positive. The clinical significance of low-ER/PgR-staining (1-9%) tumors were analyzed to investigate the biology and prognosis. Methods: This study examined 3193 consecutive HER2 negative invasive breast cancer cases. Clinicopathological characteristics and prognosis of hormone receptor (HR)-negative (<1%), low-HR-staining (1-9%) tumors and positive (≥ 10%) tumors were compared. The median follow-up period was 75 months. Results: The following is the number of patients in each of the tumor categories: 466 ER cases (14.6%) and 775 PgR cases (24.2%) in the <1% group; 68 ER cases (2.1%) and 218 PgR cases (6.8%) in the 1-9% group; and 2559 ER cases and 2200 PgR cases in the ≥ 10% group. The age groups were; young (≤35 y), premenopausal (36-50 y), postmenopausal (51-65 y) and the elderly (≥66 y). The median ER positive cell rate was significantly lower in the young group. In contrast, the PgR expression was significantly higher in the premenopausal group and significantly lower in the postmenopausal group. Patients in the ≥10% group had significantly smaller tumors, lower Ki-67 values, a lower p53 overexpression and nuclear grade. The elderly group had better disease-free survival (DFS) and the young group had the lowest DFS. In addition, DFS by ER/PgR expression was more favorable in the ≥ 10% group than the other groups. Patients with 1-9% ER had significantly lower DFS than those in the ≥10% elderly group. Patients with 1-9% PgR had significantly lower DFS than those in all the ≥10% groups and significantly lower DFS than those in the <1% premenopausal group. Multivariate analysis for DFS revealed that PgR expression, lymph node metastasis and tumor size were significant prognostic factors. Conclusions: There was a clear difference in the PgR expression rate due to the menopausal status. Moreover, the 1-9% ER and PgR groups had biological features that were similar to ER/PgR-negative tumors.
Effect of obesity on the toxicity profile of patients with breast cancer treated with adjuvant chemotherapy.
Authors: Srinivasalu Vijay Kumar , George Annu Susan , Philip Arun , Kotne Sanketh , Bamroo Sahil , D.K. Vijaykumar , Pillai Ranjini , K Beena , Jose Wesley M , Pavithran Keechilat
Published: September 2018

e12033

Background: There is increasing evidence that obesity is strongly associated with breast cancer (BC) and has a major impact on the patient tolerance, overall survival (OS) and progression free survival (PFS). Chemotherapy dosing as per body surface area (BSA) or the actual body weight is a major dilemma among the oncologists. Moreover, the side effects of chemotherapy in obese patients in an Indian population has not been described previously in literature. We intended to evaluate the major toxicity, OS and PFS in obese BC patients who received adjuvant chemotherapy (ADC) with Adriamycin/cyclophosphamide (AC) and paclitaxel (T). Methods: A retrospective analysis of 331 patients of BC who received 4 cycles of adjuvant AC + T from a single tertiary centre in South India between 2006-2014 were included . All patients were treated as per their BSA which were capped at 2. Body Mass Index (BMI) was divided into normal (18-22.99), Overweight (23-24.99) and Obese ( ≥25 as per Asian guidelines). The toxicity was scored as per NCI-CTCAE criteria. Results: Out of 331 patients, 213 were obese. On comparison of normal and over weight with obese patients, 65 (30.5%) in obese group had significant all grade neuropathy (p = 0.027), 65 (30.5%) had Grade 2 and 3 myelosuppression (p <0.001), 31 (14.5%) had all grade emesis (p = 0.031) and 28 (13.1%) had myalgia (0.001). The 5 year OS and PFS were 93.7% and 82.3% respectively in obese patients, higher than the patients with normal weight with a 5 year OS and PFS of 92.4 % and 76.9% , but was not statistically significant. Conclusions: Higher rates of severe toxicities were seen in obese BC patients who received ADC as per their BSA. The 5 year OS and PFS was better in obese BC patients, but was not statistically significant. [Table: see text]
Clinical outcomes in very early breast cancer (≤ 1cm): A national population based analysis.
Authors: Muzaffar Mahvish , Naqash Abdul Rafeh , Vohra Nasreen A. , Liles Darla K. , Wong Jan H.
Published: September 2018

e12034

Background: The utilization of screening mammogram has resulted in increased diagnosis of very small breast cancers including T1a (≤5 mm), T1b ( > 0.5 but ≤1 cm). These small tumors have excellent prognosis with cancer-specific survival rates as high as 90% to 95%.This study evaluates outcomes in very early breast cancer in a national database. Methods: Patients with stage I breast cancer, tumor ≤ 1cm (T1aN0, T1bN0) diagnosed between 2006 and 2011 were selected from the SEER database. We excluded patients with missing biomarker information. Treatment outcome and prognostic factors for disease-specific survival (DSS) and overall survival (OS) were evaluated. Results: We identified 70,543 cases and included 54,796 patients with stageT1aN0M0 and T1bN0M0 in the final analysis.The mean age was 62.09 yrs(CI 95% 62.2-61.99),84% are white,7% black and 7% Other.89% were ER positive,11% ER negative and 3% had Her 2 positive tumors.71% of patients had T1b. ≤ 1cm breast cancer cases increased from 15% in 2006 to 18% in 2011.The 5-year disease specific survival (DSS) and overall survival (OS) for patients with stage T1aN0T1b N0 was 98.7% and 93.7%, respectively. Estrogen receptor(ER) positive tumors were associated with improved 5-yr DSS 99% vs 96% in ER negative (p < 0.0001) and OS in ER positive 94% vs 92%( p < 0.0001).Among white patients 5-yr DSS was 98.8% and OS was 93.7% while 5yr-DSS was 94%,OS 91.5% among black vs 5-yr DSS 99% and OS 96.3% in others( Asian or Pacific Islanders,AI), (p < 0.0001).Tumor subtype was not associated with significant difference in outcome but T1a tumor was associated with OS 94.5% vs 93.4% with T1b tumors(p < 0.0001) On cox model analysis factors which correlated with prolonged DSS and OS are race (p < 0.0001),older age (p < 0.0001), ER positivity (p < 0.0001) and tumor less than 5mm (p = 0.0006). Conclusions: Very early breast cancer is associated with excellent outcome but has some heterogeneity. Nonwhite/Non Black race was associated with better survival compared to white and black patients.ER positive tumors, older age were also associated with better outcome. This data while reassuring also brings into question of overtreatment of this disease subset.
Association of fatigue and insomnia with inflammatory cytokine and hematopoetic stem cell levels in breast cancer patients undergoing adjuvant radiation therapy.
Authors: Liu Fei-Fei , Shi Willa Wei , McCusker M , Li Madeline , Su Jie , Williams Justin , Spence Tara , Xu Wei , Han Kathy Chai-Zung , Bratman Scott Victor , Yip Kenneth
Published: September 2018

e12048

Background: Fatigue and insomnia are frequent conditions experienced by breast cancer patients during adjuvant radiation therapy (RT). Our group reported that fatigue correlates with reduced CD34+ circulating hematopoetic stem cell (HSC) levels. Our current study examined the role of inflammatory cytokines in mediating fatigue and insomnia following adjuvant RT. Methods: Phlebotomies were conducted on 148 breast cancer patients undergoing adjuvant RT at five time points: prior to RT (D1), after two (D2) and five (D5) days of treatment, during the final week of RT (Df), and one month post-RT completion (M1). CD34+, CD45+, circulating blood cell (CBC), and 17 inflammatory cytokine levels were assessed. Patients also completed questionnaires at each time point, including the multidimensional fatigue inventory (MIF-21), insomnia severity index (ISI), and hospital anxiety and depression scale (HADS). Results: CD34+, CD45+ and CBC levels decreased during treatment with adjuvant RT, with the lowest levels observed at Df (p<0.001). General fatigue significantly worsened throughout treatment from D1 to Df, returning to baseline at M1, (p<0.001; adjusted for insomnia, depression and anxiety). General fatigue worsened as CD34+ counts, hemoglobin and CBCs increased (p<0.001). Insomnia increased with reduced CD34+, CD45+ and CBCs (p<0.05). TGF-β1, MCP-1, MMP-2, IL-1ra and IFN-α2a cytokine expression varied throughout RT (p<0.01), most significantly at Df. Elevated MCP-1, TNF-RII and TNF-a levels correlated with worsening general fatigue, increased insomnia, and reduced activity and motivation (p<0.001). MMP-2 increased as IL-1ra, CD34+, CD45+ and CBC counts decreased (p<0.001). Further, the 52 patients who received prior adjuvant chemotherapy had elevated levels of fatigue, insomnia and anxiety, which correlated with high HSCs levels. Conclusions: Our findings demonstrate that fatigue and insomnia are associated with reduced HSCs and increased MCP-1, TNF-RII and TNF-a pro-inflammatory cytokines. This examination of the effect of RT on fatigue and insomnia is one of the most comprehensive longitudinal clinical evaluations of its kind.
Impact of Oncotype-DX testing on choice of chemotherapy.
Authors: Yip Walter , Dobosz Krzysztof , Illmann Caroline , Willemsma Kaylie , Simmons Christine E.
Published: September 2018

e12049

Background: The Oncotype DX test has been shown to change treatment plans in ~30% of cases, but it is unclear if it changes the type of chemotherapy offered. We sought to determine if the availability of Oncotype DX testing in BC resulted in a change in the type of chemotherapy regimens used on early stage breast cancer pts. Methods: This was a cohort study in which pts treated in the 2 years prior to the availability of Oncotype Dx testing were compared to pts treated in the 2 years after it became available in BC. Charts were audited and divided into pre- and post- availability of Oncotype DX testing. The groups were compared for differences in length of chemotherapy (12 vs > 12 weeks), type of agents used (anthracycline vs non-anthracycline) and myelosuppressive potential of regimen chosen. Results: A total of 831 pts fulfilled enrollment criteria; 360 were seen in the pre Oncotype era and 471 were seen in the post Oncotype era. A total of 250 (30.1%) pts were treated with chemotherapy in both cohorts with a median age of 59 for both groups (range of 29-80 and 24-80 respectively, p = NS). There was a decrease of 11.5% in pts receiving chemotherapy from 36.6% to 25.1% (p = 0.0003). Of the pts who received chemotherapy, there was a shift away from regimens containing anthracycline (49.2% vs 32.2%, p = 0.0070) and a shift towards more myelosuppressive chemotherapy regimens (p = 0.0344). There was a significant difference in the duration of chemotherapy regimens chosen with post Oncotype era pts receiving short course chemotherapy 69.5% of the time, compared to only 56.8% in the pre Oncotype era (p = 0.0491). Conclusions: The availability of Oncotype DX testing has resulted in a shift towards use of shorter, more myelosuppressive, non-anthracycline containing chemotherapy protocols. Since being publicly available, fewer pts are receiving chemotherapy but our data suggests a 10% change in treatment plan compared to the 30% change seen in other literature. Further study is warranted to ensure long term outcomes are not negatively impacted by the move towards shorter chemotherapy regimens.
The effect of aromatase inhibitors use on endothelial function among postmenopausal women with breast cancer.
Authors: Maor Ronny , Maor Elad , Wanous Amanda , Pruthi Sandhya , Lerman Amir , Sandhu Nicole
Published: September 2018

e12064

Background: Data on long-term cardiovascular effects and safety of aromatase inhibitors (AI) are limited and conflicting. The purpose of the current study was to evaluate the effect of AI on vascular injury as assessed by peripheral endothelial function among women with breast cancer. Methods: This is an observational, prospective study of 96 postmenopausal women with breast cancer at initiation of treatment, with or without AI. All participants underwent baseline and 6-12 months follow up non-invasive peripheral endothelial function measurement. Reactive hyperemia index (RHI) was measured using the EndoPAT test. The primary endpoint was endothelial function deterioration of at least 20% between baseline and follow-up. Results: Mean age of the study population was 66±7 years. There was no statistical difference in demographic data between the groups. Compared with the control group, more women in the treatment group demonstrated worsening of RHI (53% vs. 42%, p = 0.207) between baseline and 6-12 month follow up measurement. There was no statistical difference between the groups at baseline. When RHI deterioration was evaluated as a dichotomous variable, with a 20% cutoff, women in the AI group demonstrated higher rates of RHI deterioration (28% vs. 8%, p=0.020). The risk of AIs for endothelial dysfunction was correlated with burden of cardiovascular (CV) risk, such that in women with >3 CV risk factors, AIs were associated with increased risk of RHI deterioration (42% vs. 10%, p=0.016), whereas in women with <2 CV risk factors, rates of RHI deterioration were similar in AI and control groups (20% vs. 7%, p = 0.232). Conclusions: This study suggests that AI therapy may be associated with vascular injury as detected by deterioration in endothelial function. The effect is more pronounced among women with higher baseline CV risk factor burden. The results of this study have potentially important implications for patients with breast cancer being treated with AI and for women at increased lifetime risk of breast cancer who may use AI for breast cancer risk reduction. Clinical trial information: NCT00719966.
Detecting bone loss in early breast cancer survivors: The Arm-DXA method.
Authors: Al-Farhat Yousuf , Peter Auth
Published: September 2018

e12066

Background: Breast cancer survivors who are on adjunct therapy with Aromatase Inhibitors (AIs) or premature menopause due to chemotherapy are known to have an increased risk of osteoporosis and bone fracture. Being at high risk for osteoporosis, these patients should be screened using with dual energy X-ray absorptiometry (DXA) to measure bone mineral density (BMD) according to national guidelines. This study screened the population of patients with early Breast cancer utilizing the Arm-DXA as a user friendly and efficient method. Methods: All Breast cancer patients at the Tolna County Cancer Center, Szekszárd who are diagnosis of early invasive breast cancer were scanned using Arm-DXA during their regular visit to the center. Cancer patients under hormone therapy were scanned annually. Patients who have metastatic disease or known to have osteoporosis were excluded from the study. A total of 431 patients were subject of an arm-DEXA scan for BMD during the period February 2015 to September 2016. Results: Out of the 431 patients, normal T score >-1,5 detected in 223 patients (51,7%), clinically significant osteopenia (CSO) T score -1,5- -2,5 detected in 129 patients (29,9%), and osteoporosis T score < -2,5 detected in 79 patients (18,3%). For the 224 Patients who were under hormone therapy or/and chemotherapy about 29,9% (n: 67) had a CSO, and 20,5% (n:46) had osteoporosis. Conclusions: This study highlights the fact that osteoporosis is under-detected in early breast cancer survivors who are on or after hormone and chemotherapy. About 48% of early breast cancer survivors found to have osteoporosis or clinically significant osteopenia in our study. Our BMD test results shows that half the 224 patients who were under hormone therapy need to take treatment (zoledronic -acid or denosumab ) to prevent bone fracture.
How well is interdependent care managed across specialties in breast cancer? Metrics and pre-implementation data from the 4R in Oncology Project.
Authors: Weldon Christine B. , Trosman Julia Rachel , Perez Claudia B. , Kulkarni Swati , Khan Seema Ahsan , Hansen Nora , Nelson Valerie , Stein Jennifer , Simon Melissa A. , Strauss Jonathan Blake , Benson Al Bowen , Espino Sasa M. , Bunce Mikele , Pan Wayne , Friedewald Sarah M. , Gradishar William John
Published: September 2018

e12067

Background: The “NCI ASCO Teams” Project emphasized management of interdependent cancer care across specialties as crucial to teamwork, yet a considerable challenge (Taplin JOP 2015). Interdependent care requires well-managed timing and sequencing of events across specialties. We developed the 4R model (Right Information / Care / Patient / Time) to manage interdependent care and facilitate teamwork (Trosman JOP 2016). 4R is being implemented at 3 centers: academic, community and safety net. Pre-implementation, we identified guideline recommended interdependent care whose timing / sequencing is challenging, developed relevant adherence metrics and gathered current state data. Methods: Interviews with 42 clinicians across breast cancer (BC) specialties at the 3 sites, using theme analysis to identify challenging interdependent care. Guidelines and literature were used to define adherence metrics. Clinical data were reviewed for 216 Stage I-III patients at 3 sites to measure adherence. Results: We identified 7 BC interdependent care events for which timing / sequencing is a challenge - Table. Adherence ranged from 0% to 100%, and was < 50% for 5 of the 7 care events. Preoperative BRCA 1/2 results and neoadjuvant consult showed highest adherence, yet were most frequently noted as a challenge: interviewees reported substantial ad-hoc efforts applied to managing timeliness of these events. Conclusions: Identified challenges and adherence gaps support the need for the 4R implementation for systematic, consistent and timely delivery of interdependent care. Established metrics will allow pre / post 4R implementation comparison and may inform broader adoption of the 4R model. [Table: see text]
Dual-imaging assessment of ultrasonography and mammography in nipple discharge patients: A cohort study.
Authors: Li Bo , Yang Yihe
Published: September 2018

e12079

Background: Nipple discharge (ND) is a common complaint of women. There is no consensus on clinical approach in these patients. We investigated the diagnostic ability of combination of ultrasound (US) and mammogram (MG) in Chinese ND patients without palpable mass. Methods: 827 patients with ND as only chief complaint presented in the First Hospital of China Medical University (Shenyang, China) between 2008 and 2015 were included. Palpable mass, physiological NP and/or elevated PRL were excluded. All patients underwent dual-imaging examinations of US and MG. Indication of surgical excision included 1) BI-RADS categories 4b, 4c, 5 in either US or MG, and/or 2) US suspected papilloma. Patients met surgical indications served as study arm (N = 742). Patients did not meet surgical indications but underwent surgery served as control arm (N = 85). Reason of surgery in the control group were patients’ choices and surgeons’ clinical judgment. Histological diagnosis provided by surgery were analyzed. In our institution, breast cancer, papilloma, and/or papilloma with atypical dysplasia were regarded as histological indication of surgery. Chi-square tests were applied. Results: Histology revealed 88 (11.9%) breast cancer in the study arm and 0 breast cancer in the control arm ( p= 0.0008); 167 (22.5%) papilloma with atypical dysplasia in the study arm and 12 (13.6%) papilloma with atypical dysplasia in the control arm ( p= 0.08); 335 (45.1%) papilloma without atypical dysplasia in the study arm and 27 (30.7%) papilloma without atypical dysplasia in the control arm ( p= 0.02). A total of 590 (79.5%) in the study arm and 39 (44.3%) in the control arm met histological indication of surgical intervention ( p< 0.00001). Conclusions: This dual-imaging assessment of US and MG is sensitive in detecting breast cancer in ND without palpable mass patients. It showed diagnostic ability in detecting papilloma with/without atypical dysplasia, but needs further improvement.
Diagnostic accuracy of core needle biopsy by image guidance and vacuum assistance.
Authors: Dabbous Firas M , Friedewald Sarah M. , O'Meara Ellen , Weaver Donald L. , Wernli Karen , Ray Kimberly , Rauscher Garth H
Published: September 2018

e12081

Background: Half of the women in the US undergoing annual screening mammography over 10 years require at least one additional imaging study. Of these women, 7%-17% undergo biopsies, the majority of which (77%) are benign. We sought to estimate the accuracy of core needle biopsy (CNB) by method of imaging guidance and use of vacuum assistance (VA). Methods: Data were pooled from four registries participating in the Breast Cancer Surveillance Consortium (bcsc-research.org) including facilities that perform both VA and non-VA CNB. Each registry collects data on screening mammography and breast pathology reports linked to their state cancer registries or regional Surveillance, Epidemiology and End Results registry. Sensitivity was defined as the proportion of positive biopsies among all cancers diagnosed within 12 months of biopsy. PPV3 was defined as the percentage of all biopsies performed that were positive for cancer. We estimated the adjusted average population risks/rates by modality using marginal standardization with logistic regression in STATA.Results: : Among the 37,270 CNBs, breast malignancy was found in 9,241 women (28.6%), of which 2,276 (25%) were ductal carcinoma in-situ. Sensitivity was 90.5% (95% CI 82.6-98.4) for non-VA Stereotactic (n = 415), 95.4% (95% CI 94.7-96.1) for VA Stereotactic (n = 18,733), 96.1% (95% CI 95.4-96.7) for non-VA ultrasound (n = 14,803), 95.1% (95% CI 93.7-96.5) for VA Ultrasound (n = 3,271) and 82.3% (95% CI 59.9-104.6) for non-VA MRI (n = 48). PPV3 was 12.2% (95% CI 9.0, 15.3), 17.7% (95% CI 17.2, 18.3), 28.6% (95% CI 27.8-29.4), 32.1% (95% CI 30.4-33.8) and 16.9% (95% CI 5.3, 28.5), respectively. For stereotactic biopsies, VA was associated with improved PPV3 (p = 0.01) without any change in sensitivity compared to non-VA Stereotactic biopsies.Conclusions: Our multicenter data confirm that VA-stereotactic CNB and ultrasound CNB with or without VA have high sensitivity and thus represent effective alternatives to open surgical biopsy.
Comparison of terminal duct lobular units in the nipple areolar complex by tumor subtypes-the implication for nipple sparing mastectomy.
Authors: Schnarr Kenna , Fan Fang , Amin Amanda Leigh , Balanoff Christa , Mammen Joshua , Wagner Jamie Lynn
Published: September 2018

e12082

Background: Nipple-sparing mastectomy (NSM) has gained popularity for surgical treatment of breast cancer. Terminal duct lobular units (TDLU) have been shown to be present in 25% of nipple areolar complex (NAC). Pathologic tumor subtype influence on presence of TDLU in the NAC has not been assessed. In addition, criteria for technically performing the dissection below the NAC have not been established. We sought to evaluate TDLU characteristics by tumor subtype and determine NSM dissection criteria below the NAC. Methods: A retrospective review was performed of 120 total and skin sparing mastectomies, 30 of each breast cancer subtype, from 1/2013 to 1/2015. The NAC of each mastectomy was assessed for number of TDLU and distance from TDLU to the skin. Results: Thirty of the 120 mastectomies (25%) had TDLU present below the NAC. Of the 30 with TDLU, there was no statistically significant difference in number of TDLU present based on tumor grade (gd) (gd 1 vs 2, p = .67; gd 1 vs 3, p = .24). Compared to luminal A, luminal B showed statistical significance (p < .05) for number of TDLU at the NAC whereas Her 2 and triple negative breast cancer (TNBC) were not statistically significant (p = .09 and .10). In mastectomies with TDLU present, gd 2 (p < .05) and gd 3 (p = .05) had a closer skin distance than gd 1. When compared by tumor subtype, there was no difference in TDLU to skin distance (table). Conclusions: NSM has been adopted as a safe oncologic approach to breast cancer treatment. Although presence of TDLU in luminal B subtype was statistically significant, this may not be clinically significant, as there were only 2 of 30 cases with TDLU. Our study indicates that a careful dissection at the level of the dermis below the NAC is necessary, as 25% of women will have TDLU present. This will provide an appropriate oncologic outcome similar to total and skin sparing mastectomy. Tumor subtype does not appear to be exclusion criteria for NSM. However, more aggressive dissection may be necessary to clear all TDLU from below the NAC in higher gd cancers. [Table: see text]
Homogeneity of variance of measures associated with objective assessment of esthetic outcome after treatment with radiation therapy in early breast cancer.
Authors: Williams Norman R.
Published: September 2018

e12085

Background: Breast cancer is an increasingly treatable disease which means that many women will live a long time with the esthetic consequences of their treatment. The majority of women with early breast cancer are given whole breast external beam radiation therapy (EBRT) after lumpectomy (breast conservation). It has been demonstrated, using an objective assessment of esthetic outcome in patients from a randomized trial that “redness”, a surrogate for radiation induced erythema grade I or II, is significantly greater after one year in patients receiving EBRT compared with those receiving intraoperative radiation therapy (IORT). However, it has been observed that not all women given EBRT have detectable erythema, which implies that there is a greater variability in this group. In order to test this hypothesis a test of unequal group variances was performed. Methods: 991 frontal digital photographs were analyzed from women participating in the TARGIT A Trial (NCT00983684) at four sites (Lublin, Mannheim, Copenhagen and Perth). Photographs taken at baseline (before surgery), 1 and 2 years (after surgery and EBRT or IORT) were objectively assessed, blinded to treatment received, by BCCT.core software which produces overall Harris scores, and scores for various measures of symmetry, color and scar. The scores for color were analyzed in SAS v9.4 using PROC GLM. Results: cEMDL, a color score associated with "lightness", showed significant heterogeneity of variance (using Levene's and Welch's Tests, p < 0.0001) in the women treated with EBRT, but not in those treated with IORT (p = 0.4). However, cX2b (associated with "redness") showed significant heterogeneity of variance in both the EBRT and IORT treated groups (p < 0.0001), although the point estimates moved in different directions. Conclusions: This study demonstrates that there are complex changes in skin color following radiation therapy to the breast, and assumptions regarding homogeneity of variance should be checked if required by the statistical analysis.
Does tumor size in T1-T2 early breast cancer (EBC) still have a prognostic role?
Authors: Kasangian Anaid Anna , Moretti Anna , Biagioli Elena , Bernardin Elena , Cordovana Andrea , Gherardi Giorgio , Farina Gabriella , Bramati Annalisa , Piva Sheila , Dazzani Maria Chiara , Paterno Emanuela , La Verde Nicla Maria
Published: September 2018

e12087

Background: Theprognosis of EBC patients (pts) depends on pts characteristics and tumor biological/ histopathological features. The correlation between tumor size, expressed as the largest diameter in TNM staging, and overall survival (OS) and disease free survival (DFS) is well recognized. According to TNM, tumors classified as T2, could have different volumes (V); e.g. a tumor of 2,1 cm has a V of 4500 mm3, while a tumor of 4,9 cm has a V of 60000 mm3. Despite belonging to the same class, the two different V may have a different prognosis. The aim of the study is to establish if the role of tumor size has been surpassed by other factors. Methods: The purpose is to evaluate the correlation between V and DFS/OS, in a T1-T2 population, who underwent breast surgery and sentinel lymph node biopsy, in our institution from 01.01.2005 to 30.09.2013. V was evaluated with the measurement of three half-diameters of the tumor (a, b and c), and calculated with this formula: 4/3 * π * a * b * c. Results: 341 pts with T1-T2 EBC who underwent surgery were included. 86,5% were treated with conservative surgery. 85,1% had a luminal subtype, 9,1% triple negative (TN) and 7,4% Her2 positive (+). Median V was 942 mm3 (range 0,52-31651,2). 44 pts (12,9%) relapsed and 23 pts died. With a median follow-up of 6,5 years, the univariate analysis for DFS showed a correlation between age (p 0,016), tumor size (p 0,032), V (p 0,078), histological grading (p 0,001), molecular subtype (p < 0,001). The multivariate analysis confirmed the statistically significant correlation only for molecular subtype (p 0,005), showing a worse prognosis for TN and Her2+ subtypes. Regarding OS, a statistically significant correlation was shown by the univariate analysis both for histological grading (p 0,018) and molecular subtype (p 0,001). The multivariate analysis confirmed that TN and Her2+ subtypes negatively influence OS (p 0,005). Conclusions: In our study neither V nor tumor diameter seem to correlate with DFS and OS in T1-T2 tumors; the only parameter that strongly influences DFS and OS, is molecular subtype, confirming the worse prognosis of TN and Her2+ versus luminal tumors. These findings encourage clinics to choose adjuvant treatment not based on dimensional criteria but on biological features.